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Our mission is to find cures for human diseases., harvard stem cell institute (hsci) scientists are working together across harvard schools, centers, and teaching hospitals, harnessing the power of stem cells to change medicine for the better..

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HSCI bridges the gaps in traditional research funding to encourage bold thinking and launch scientific careers.

Through our disease programs , we channel world-class resources, both intellectual and technological, toward some of the most prevalent, devastating diseases for which stem cell research holds promise.

In addition, our seed grants and junior faculty programs provide funding for innovative, early-stage projects in stem cell research. This allows up-and-coming scientists to pursue "high risk/high reward" avenues of research that might be difficult to fund from other sources.

Melanocyte stem cells affected by overstimulation of the parasympathetic nerve

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Quote that reads "We think the drug screening approach is the fastest way of getting something into patients. Can we identify a drug that makes the human a bit more like a fish and activates the right cells to have more regenerative-like healing"?

How a small fish could lead to better strategies to repair tendon tears

Hsci principal faculty jenna galloway, phd, is working to better understand the healing process after tendon tears with the hope of identifying new therapies that could help..

Man in front of a laboratory setting

Jason Buenrostro lands MacArthur 'Genius Grant '

Buenrostro has been named a 2023 macarthur fellow for developing powerful new technologies that provide detailed views — right down to the single cell — of which genes get turned on and off in various contexts., 2024 call for applications: barry family hsci innovation award for early investigators, hsci community events, hsci faculty.

HSCI principal faculty members

HSCI has been breaking down barriers to collaboration in stem cell science since 2004. We provide fertile ground for more than 350 research faculty and their labs, across the university’s schools, centers, teaching hospitals, and partner companies, to share knowledge and pursue bold new ideas.

With Harvard as a wellspring of discovery and a strong network that embraces new ways of working, we are better equipped than ever to change human health in ways that will benefit all of society.

Executive Committee

Principal faculty, affiliate faculty, from lab to clinic, company startups.

A key part of our mission is to move research out of the lab and into the clinic. Since our founding, we have been forging a clear path to translating discoveries into products that benefit patients. Now, we have the flexibility to organize people across institutions and sectors to tackle specific biological problems so we can make a lasting difference in people's lives.

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Clinical Trials

Stem cell therapy.

Displaying 75 studies

The purpose of this study is to assess the effectiveness and safety of Cx601, adult allogeneic expanded adipose-derived stem cells (eASC), for the treatment of complex perianal fistula(s) in patients with Crohn's disease over a period of 24 weeks and a follow-up period up to 52 weeks.

The purpose of this study is to evaluate the safety of using unlicensed cord blood units from the National Cord Blood Program in unrelated  patients needing stem cell transplants, by carefully documenting all infusion-related problems.

The purpose of this study is to collect human menstrual blood at the time of gynecology visits in order to conduct future studies on the isolation and characterization of human menstrual blood and endometrial stem cells to better individualize treatment for abnormal uterine bleeding (AUB) and study the therapeutic properties of human menstrual-derived Mesenchymal Stem Cells (MSCs).

The purpose of this study is to collect fat and blood vessel wall tissue for processing into adult stem cells and then test those cells for specific biological markings.

The purpose of this study is to assess optimal dosing frequency, effectiveness and safety of adipose-derived autologous mesenchymal stem cells delivered into the spinal fluid of patients with multipe system atrophy (MSA).

Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurological condition characterized by autonomic failure, parkinsonism, and/or ataxia. There is no available treatment to slow or halt disease progression. 

The purpose of this study is to explore patients’ perceptions using educational interventions to debunk or prebunk misinformation of advertisements about unproven stem cell interventions (SCIs). 

The purpose of this study is to assess the safety and tolerability of intravenously delivered mesenchymal steml cells (MSC) in one of two fixed dosing regimens at two time points in patients with chronic kidney disease.

The purpose of this study to test the feasibility and safety for autologous (from your own body) skin cells that are manufactured into stem cells of cardiac lineage to be delivered into the heart muscle to determine if those stem cells will strengthen the heart muscle and can be used as an additional treatment for the management of  congenital heart disease. 

The purpose of this study is to assess the effectiveness and safety of Cx601, adult allogeneic expanded adipose-derived stem cells (eASC), for the treatment of complex perianal fistula(s) in patients with Crohn's disease over a period of 24 weeks and a follow-up period up to 52 weeks.

The purpose of this study is to evaluate the long-term safety of a single dose of darvadstrocel in participants with Crohn's disease (CD) and complex perianal fistula by evaluation of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs).

The aim of this study is to measure the differences in quality of life and mood of hematopoietic stem cell transplant (HCT) patients and their caregivers staying at a hospital hospitality house (HHH), such as the Gift of Life Transplant House, the Help in Healing Home, and the Gabriel House of Care versus staying at a hotel/rental apartment or house. The goal is to investigate if staying in a HHH, with its different environment and support systems and programs, has a positive impact on the quality of life (QOL) and mood of patients undergoing a HCT and their caregivers.

The purpose of this study is to assess the safety and feasibility of mesenchymal stem cells therapy in patients with advanced chronic obstructive pulmonary disease.

The purpose of this study is to evaluate the pharmacokinetics (PK), safety and tolerability of pegcetacoplan in patients with TA-TMA.

The purpose of this study is to produce, using current Good Manufacturing Practices (cGMPs), a bank of 50 primary fibroblast cell lines from skin biopsies obtained by consenting donors who meet 21 CFR 1271 donor eligibility criteria, and to use fibroblasts in the cell bank generated in aim 1 to produce new induced pluripotent stem cell lines using Good Manufacturing Practices (cGMPs). These iPSC lines will then be screened to identify those with optimal characteristics for treatment purposes, as well as for the potential generation of transplantable tissues and therapeutics for chronic disease.

The purpose of this study is to determine the safety and feasibility of allogeneic, culture-expanded BM-MSCs in subjects with painful facet joint arthropathy.

The purpose of this study is to determine determine the safety of intraspinal delivery of mesenchymal stem cells (MSCs) to the cerebral spinal fluid of patients with Amyotrophic Lateral Sclerosis (ALS) using a dose-escalation study.

This study aims to evaluate the safety of local delivery of AMSCs for recurrent GBM by noting the incidence of adverse events, as well as radiological and clinical progression.

To assess the preliminary efficacy of local delivery of AMSCs for recurrent GBM by comparing the clinical, survival, progression, and radiographic outcomes from patients enrolled in our study to historical controls from our institution.

The purpose of this trial is to compare the treatment strategy of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1 to 1 (1:1) ratio. All participants will be followed for 72 months after randomization (Day 0, Visit 0).

The purpose of this study is to evaluate the effectiveness of ibrutinib in reducing the incidence of NIH moderate/severe chronic GVHD.

To determine the safety and toxicity of intra-arterial infused autologous adipose derived mesenchymal stromal (stem) cells in patients with vascular occlusive disease of the kidney.

The objective of this study is to evaluate the safety and feasibility of autologous mononuclear cells (MNC) collected from bone marrow (BM) delivered into the myocardium of the right ventricle of subjects with Ebstein anomaly undergoing surgical Ebstein repair. Additionally, the potential cardiovascular benefits will also be evaluated. This add-on procedure is anticipated to pose little risk to the subject and has the potential to foster a new strategy that leverages the regenerative capacity of individuals with congenital heart disease during the surgically mandated Ebstein repair.

To assess the safety and feasibility of mesenchymal stem cells therapy in patients with transplant related bronchiolitis obliteran syndrome (BOS).

This phase I/II trial studies the side effects and best dose of oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) infected mesenchymal stem cells and to see how well it works in treating patients with recurrent ovarian cancer. Mesenchymal stem cells may be able to carry tumor-killing substances directly to ovarian cancer cells.

The purpose of this study is to assess the safety and tolerability of intra-arterially delivered mesenchymal stem/stromal cells (MSC) to a single kidney in one of two fixed doses at two time points in patients with progressive diabetic kidney disease. 

Diabetic kidney disease, also known as diabetic nephropathy, is the most common cause of chronic kidney disease and end-stage kidney failure requiring dialysis or kidney transplantation.  Regenerative, cell-based therapy applying MSCs holds promise to delay the progression of kidney disease in individuals with diabetes mellitus.  Our clinical trial will use MSCs processed from each study participant to test the ...

The purpose of the present study is to investigate the safety and efficacy of a single intrathecal injection of autologous, culture expanded AD-MSCs specifically in subjects with severe traumatic SCI when compared to patients undergoing physical therapy.

The overall goal of this study is to determine the safety and feasibility of infusing adipose-derived mesenchymal stem cells directly into the artery of renal allografts with biopsy-proven rejection in order to reduce inflammation detected in the graft.   We contend that future studies will show that administering immunomodulatory cells directly into the allograft will be more effective and safer than the current approaches of delivering massive doses of systemic immunosuppression.

Study participation involves receiving mesenchymal stem cells (MSC), created from the adipose tissue (body fat) of a donor, and infused into the main artery of a transplanted ...

The purpose of this study is to assess the safety of autologous mesenchymal stromal (stem) cell transfer using a biomatrix (the Gore Fistula Plug) to treat perianal fistula.

The purpose of this study is to collect, convert and bank blood cells from healthy volunteers into stem cells (iPSCs) at a current good manufacturing practice (cGMP) facility within the Discovery and Innovation building on the Mayo FLorida campus. After comprehensive validation, we will bank those cGMP-iPSCs as a resource available to Mayo Clinic investigators and also to outside investigators as appropriate. Those bio-specimens could be unique resources to develop new protocols for production of clinical grade iPSC-derived cells, cell-derived products such as extracellular vesicles, and tissues to support Investigational New Drug (IND) and related clinical trials.

To compare the effect of senolytic drugs on cellular senescence, physical ability or frailty, and adipose tissue-derived MSC functionality in patients with chronic kidney disease. Primary Objectives: To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on clearing senescent adipose-derived MSC in patients with CKD. To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on improving adipose-derived MSC functionality in patients with CKD. Secondary Objective: To assess the short-term effect of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on ...

The investigators propose to study the safety of autologous mesenchymal stromal cell transfer using a biomatrix (the Gore Bio-A Fistula Plug) in a Phase I study using a single dose of 20 million cells. 20 patients (age 12 to 17 years) with Crohns perianal fistulas will be enrolled. Subjects will undergo standard adjuvant therapy including drainage of infection and placement of a draining seton. Six weeks post placement of the draining seton, the seton will be replaced with the MSC loaded Gore fistula plug as per current clinical practice. The subjects will be subsequently followed for fistula response and closure ...

The purpose of this study is to test the safety of this novel cell, combination- based regenerative therapy for use in patients with symptomatic focal cartilage defects of the knee.

This study aims to evaluate the safety of intramyocardial delivery of autologous umbilical cord blood-derived mononuclear cells during Fontan surgical palliation and measure surrogate markers of myocardial protection within a non-randomized study design to obtain prospective data from treatment and control populations.

The purpose of this study is to engage a cohort of patients who are avid information seekers about stem cells to assess their beliefs, online information sources and their credibility, and views on the credibility and persuasiveness of advertisements and warning messages available on the internet; we will use this data along with health behavior theories to develop communication messages aimed at inoculating patients against misinformation, correcting misconceptions, and providing evidence-based information about stem cell procedures.

Group 1: The primary purpose of this study is to evaluate the safety and tolerability of an autologous dendritic cells (DC) vaccine delivered by intra-tumoral injection in patients with primary liver cancer treated with high-dose conformal external beam radiotherapy (EBRT).

Group 2: The primary purpose of this study is to estimate the progression-free survival rate at 2 years post-registration to see if treatment is efficacious compared to historical data

The purpose of this study is to determine the safety and efficacy of intrathecal treatment delivered to the cerebrospinal fluid (CSF) of mesenchymal stem cells in ALS patients every 3 months for a total of 4 injections over 12 months. Mesenchymal stem cells (MSCs) are a type of stem cell that can be grown into a number of different kinds of cells. In this study, MSCs will be taken from the subject's body fat and grown. CSF is the fluid surrounding the spine. The use of mesenchymal stem cells is considered investigational, which means it has not been approved by ...

This study is an extension to re-treat partial and non-responders from the previously approved Phase 1 MCS-AFP protocols IRB #12-009716 (Crohn's Disease perianal fistulas) and 15-003200 (cryptoglandular perianal fistulas).

The investigators propose to study the safety of autologous mesenchymal stromal cell transfer using a biomatrix (the Gore® Bio-A®; Fistula Plug) in a Phase I study using a single dose of 20 million cells. Twenty adult patients (age 18 years or older) with refractory, complicated perianal fistulizing Crohn's disease will be enrolled. Subjects will undergo standard adjuvant therapy including drainage of infection and placement of a draining seton with continuation of pre-existing anti-Crohn's therapy. Six weeks post placement of the draining seton, the seton will be replaced with the MSC loaded Gore® Bio-A® fistula plug as per current clinical practice. ...

In this proposal, we will generate hiPSCs from AA patients and use our TREE-based approaches to introduce AA-associated variants into isogenic hiPSCs. In turn, we will use these isogenic hiPSC lines in a 3-D cortical model to address the following hypothesis-testing questions: (1) Does the presence of specific ABCA7 variants modulate disease-related phenotypes in a hiPSC-based system? (2) Are the risk modifying effects of the ABCA7 variants mediated through cell-autonomous or non-autonomous mechanisms? (3) Do these ABCA7 variants exert their effects through modulation of Aβ processing, secretion, and uptake? (4) What is the effect of these ABCA7 variants ...

The purpose of this study is to determine the safety and practical treatment use of STEM cells collected from a patient's own fat tissue, expanded in laboratory culture, and injected to treat symptoms of mild to severe knee osteoarthritis.

The purpose of this study is to assess the safety and effectiveness of a Stem cell transfer using a biomatrix (The Gore Fistula Plug) in patients with persistent symptoms of post-surgical gastrointestinal leaks despite current standard radiologic and endoscopic treatments.  The subjects will be followed for fistula response and closure for 18 months. This is an autologous product (derived from the patient) and used only for the same patient.

The purpose of this study is to determine whether AVB-114 compared to standard of care treatment is effective in inducing remission of the treated complex perianal fistula in subjects with Crohn’s Disease. It also aims to assess clinical and radiologic components of fistula remission, safety of treatment, disease activity, patient Quality of Life, and patient care journey, between AVB-114 and standard of care treatment.

The purpose of this study is to assess neurodevelopmental and psychosocial outcomes (i.e., executive function, social cognition, psychosocial adjustment, adaptive skills) in children with hypoplastic left heart syndrome (HLHS) who underwent right-ventricle-directed delivery of autologous umbilical cord derived mononuclear cells during staged cardiac surgical palliation, and to compare their outcomes to a matched sample of children with HLHS who did not receive autologous umbilical cord derived mononuclear cells during surgery.

The purpose of this study is to assess the safety, tolerability, optimal dosing, effectiveness signals reflecting kidney repair, and markers of mesenchymal stem cells (MSC) function that relate to response to allogenenic adipose tissue-derived MSC in patients with Chronic Kidney Disease (CKD).

Will injection(s) of autologous culture-expanded AMSCs be safe and efficacious for treatment of painful Hip OA, and if so, which dosing regimen is most effective?

The purpose of this study is to determine the safety of using an autologous mesenchymal stromal cell (MSC) coated fistula plug in people with fistulizing Crohn's disease. Autologous means these cells to coat the plug come from the patient.

This study will evaluate the safety of intramuscular administration of PLX-R18 (allogenetic ex-vivo explanded placental adherent stromal cells) in subjects who have with incomplete hematopoietic recovery after hematopoietic stem cell transplantation.

The purpose of this study is to evaluate the safety and effectiveness of CD34+ cell intracoronary injections for treating coronary endothelial dysfunction (CED).

Ulcerative Colitis (UC) is a chronic inflammatory disease affecting the mucosal lining of the colon and rectum and the incidence is increasing, but the etiology remains unknown. Patients may require a proctocolectomy due to refractory disease. Prior to an operation, UC is treated with antibiotic therapy, immunomodulatory therapy and immunosuppressive agents. While there is an increasing number of approved biologics for the treatment of UC, there are many patients that still suffer from refractory disease. Thus, alternative mechanisms of therapy are desperately needed.

Treatments that have the potential to reduce mucosal inflammation could alleviate the pathology of luminal UC. This trial ...

The objective of this study is to generate a panel of iPSCs from 30 subjects who do not have a personal history of major neuropsychiatric disorders.  

State-of-the-art induced pluripotent stem cells (iPSC) technology has become a powerful biomedical research tool and it clearly holds great potential for application to neuropsychiatric research.

The purpose of this study is to determine the success of mesenchymal stem cells, developed from the patient's own fat tissue, for reducing hemodialysis arteriovenous fistula failure when applied during the time of surgical creation.

The purpose of this study is to collect adipose tissue from patients undergoing elective surgery, or from healthy volunteers, test the donors to assure that they comply with all regulatory aspects required of healthy donors, expand and test mesenchymal stromal cells (MSC), and bank them for future use.

The current proposal aims to test the feasibility of immune function analysis for Tai Chi Easy (TCE) intervention in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT) with concurrent exploration of health related quality of life (HRQOL).

The purpose of this study is to evaluate quality of life over time in patients treated with CAR-T therapy compared with autologous and allogeneic stem cell transplant.

The purpose of this study is to determine the effectiveness of MB-CART2019.1 cells administered following a conditioning lymphodepletion regimen in diffuse large B cell lymphoma (DLBCL) subjects who failed at least two lines of therapy as measured by objective response rate (ORR) at one month.

This phase Ib/II trial studies how well dendritic cell therapy after cryosurgery in combination with pembrolizumab works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Vaccines made from a person's white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells. Cryosurgery, also known as cryoablation or cryotherapy, kills tumor cells by freezing them. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving dendritic cell therapy after cryosurgery in combination with pembrolizumab may work better in treating patients ...

This is a double-blind, sham-controlled clinical study to evaluate the safety and feasibility of AMI MultiStem therapy in subjects who have had a heart attack (Non-ST elevation MI).

The purpose of this study is to evaluate safety, tolerability, pharmacokinetics, and effectiveness of SER-155 in adults undergoing hematopoietic stem cell transplantation to reduce the risk of infection and graft vs. host disease.

The purpose of this study is to compare the efficacy and safety of maribavir to valganciclovir for the treatment of cytomegalovirus (CMV) infection in asymptomatic hematopoietic stem cell transplant recipients.

The purpose of this study is to determine the safety of using an autologous mesenchymal stromal cell (MSC) coated fistula plug in people with rectovaginal fistulizing Crohn's disease. Autologous means that these cells that coat the plug come from you. You will be in this study for two years. There is potential to continue to monitor your progress with lifelong regular visits as part of your standard of care. All study visits take place at Mayo Clinic and Rochester, MN. The study visit schedule is as follows: Visit 1 (Week -6) - Screening visit: exam under anesthesia and surgery to ...

The purpose of this study is to evaluate the cellular composition of PRP produced by the Arthrex Angel System.

The purpose of this study is evaluate the safety of allogeneic adipose derived mesenchymal stem cell (AMSC) use during hemodialysis arteriovenous fistula and arterial bypass creation and its effectiveness on improving access maturation and primary anastomotic patency.

The purpose of this study is to evaluate the side effects of vaccine therapy in treating patients with glioblastoma that has come back. Vaccines made from a person's white blood cells mixed with tumor proteins from another person's glioblastoma tumors may help the body build an effective immune response to kill tumor cells. Giving vaccine therapy may work better in treating patients with glioblastoma.

The purpose of this trial is to evaluate the cosmetic role of novel anti-aging regenerative skin care product, human platelet extract (HPE), on skin rejuvenation. 

Skin aging is a natural part of human aging process caused by intrinsic and extrinsic factors, such as genetics, cellular metabolism, chronic light exposure and other toxins.  Cosmetological care for facial skin aging includes daily skin care, correct sun protection and aesthetic non-invasive procedures. 80 participants over the age of 40 years with moderate photoaging (dyschromic facial skin with fine lines and wrinkles) will be recruited from Mayo Clinic Center for Aesthetic Medicine and ...

The purpose of this study is to collect adiopose tissue to derive mesenchymal stem cells.

Although survivorship recommendations have been developed in areas such as lymphoma and stem cell transplant, the long-term effects of CAR-T therapy are unknown. In addition, relatively little is known about the psychosocial impact of CAR-T on survivors and their caregivers. Due to the intensive nature of CAR-T treatment and its unique side effects, including neurotoxicity in the acute setting and infections and financial burden in the long-term setting, a longitudinal study that assesses these issues in a quantitative and qualitative fashion is required. Consideration of both patient and caregiver needs is important for the provision of appropriate and ...

The purpose of this study is to compare standard-dose combination chemotherapy to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving ...

The study aims to characterize patient factors, such as pre-existing comorbidities, cancer type and treatment, and demographic factors, associated with short- and long-term outcomes of COVID-19, including severity and fatality, in cancer patients undergoing treatment. The study also is aimed to describe cancer treatment modifications made in response to COVID-19, including dose adjustments, changes in symptom management, or temporary or permanent cessation. Lastely, evaluate the association of COVID-19 with cancer outcomes in patient subgroups defined by clinico-pathologic characteristics.

The purpose of this study is to assess the feasibility and safety of delivering adipose mesenchymal stem cells (AMSCs) to kidney allografts.

The purpose of this study is to assess the safety, effectiveness, and overall benefit of FCR001 cell therapy in de novo living donor renal transplantation.

The primary objective of the United States Food and Drug Administration (FDA) for this study is to demonstrate non-inferiority in subjects who received an allogeneic BMT for subjects randomized to Rezafungin for Injection compared to subjects randomized to the standard antimicrobial regimen (SAR) for fungal-free survival at Day 90 (±7 days).

The primary objective of the European Medicines Agency (EMA) for this study is to demonstrate superiority in subjects who received an allogeneic BMT randomized to Rezafungin for Injection compared to subjects randomized to the SAR for fungal-free survival at Day 90 (±7 days).

This randomized phase III trial studies rituximab after stem cell transplant and to see how well it works compared with rituximab alone in treating patients with in minimal residual disease-negative mantle cell lymphoma in first complete remission. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving chemotherapy before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. ...

The purpose of this research study is to evaluate a treatment regimen called IRD which will be given to participants after their stem cell transplant in an effort to help prolong the amount of time the participants are disease-free after transplant. IRD is a three-drug regimen consisting of ixazomib, lenalidomide (also called Revlimid), and dexamethasone. After 4 cycles of IRD, the participants will be randomized to receive maintenance therapy either with ixazomib or lenalidomide. 09/23/2019: Upon review of the interim analysis that suggested inferior progression-free survival in the ixazomib maintenance arm, there will be no further randomizations into the ...

This randomized phase III trial studies ibrutinib to see how well it works compared to placebo when given before and after stem cell transplant in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Before transplant, stem cells are taken from patients and stored. Patients then receive high doses of chemotherapy to kill cancer cells and make room for healthy cells. After treatment, the stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Ibrutinib is a ...

The primary purpose of this study is to identify the therapeutic effect of Adipose-Induced Regeneration (AIR) in radiation-induced skin injury of post-mastectomy breast cancer patients.

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Masks Strongly Recommended but Not Required in Maryland, Starting Immediately

Due to the downward trend in respiratory viruses in Maryland, masking is no longer required but remains strongly recommended in Johns Hopkins Medicine clinical locations in Maryland. Read more .

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Institute for Basic Biomedical Sciences

Stem cell research at johns hopkins institute of basic biomedical sciences.

Stem Cells

Researchers at the IBBS are studying stem cells to figure out how they can give rise to a complex body, how cells of the body can revert back to stem cells and how this knowledge can be used to develop therapies for diseases and injuries.

Stem cells are cells that don’t have an identity but have the potential to develop into many types of cells for many purposes, liking building a complete organism, healing a wound or replacing old, worn-out cells in a tissue.

Embryonic stem cells can become any of the cells in the body and can form entire animals.

Not all stem cells come from embryos, adult stem cells are found throughout the body too. These cells don’t have the ability to become any cell in the body, but can transform into many different cell types. For instance, there are stem cells in our bone marrow that can become fat cells, cartilage cells or bone cells, but they can’t become eye cells or skin cells. Researchers have also figured out how to make adult cells, like a skin cell, turn back into cells with the properties of embryonic stem cells, called induced pluripotent stem cells or iPS cells for short.

Matunis stem cells

Erika Matunis ,  in the Department of Cell Biology , studies in fruit flies how testis stem cells decide to stay stem cells and not become other cell types, like sperm. She has also discovered how cells that are turning into other cell types can revert back to stem cells if the permanent reservoir of stem cells is depleted and she is exploring the mechanism of how this happens. Her research, learning more about the most fundamental aspects of stem cell biology, helps all stem cell researchers better understand the cells they work with.

Jennifer Elisseeff ,  of the Department of Biomedical Engineering , studies the differences between embryonic stem cells and adult stem cells. She has found that embryonic stem cells are better at forming new tissues, whereas adult stem cells are better at secreting therapeutic molecules that promote healing of damaged tissue. Elisseeff is particularly interested in the factors released by stem cells that can help a tissue heal. She uses this information in the development of biosynthetic (part-natural and part-man-made) materials used for therapies. One of the materials her lab has developed is a bio-adhesive—essentially a glue that can be used in the body that is made of part synthetic and part natural components. The glue is used in conjunction with stitches to help prevent leakage of blood or fluids, but it’s flexible enough to allow cells to move in and heal the incision. Also, Elisseeff is collaborating with the military to develop a treatment for soft tissue facial reconstruction for people who have suffered severe trauma. They are developing tissue blueprints that can be transplanted in the face—or any other place in the body for that matter— that would allow a person’s own cells to move into a region to heal and restructure the tissue.

Warren Grayson ,  of the Department of Biomedical Engineering , takes stem cells from fat and bone marrow as well as stem cells that have the potential to become many different cell types, known as pluripotent stem cells, and coaxes them to regenerate bone or skeletal muscle in the lab. He does this by incubating stem cells in biosynthetic structures to give the cells a structured three-dimensional volume to grow in, and then places these either in bioreactors that provide heat, nutrients, movement, mechanical stress or control of any other condition like oxygen concentration to guide the stem cell to become a specific cell type or within a defect in animals to study the regenerative process. He hopes to one day be able to take a person’s own stem cells and grow tissues, like bone or muscle, to be implanted into their body to replace damaged tissue. Using a person’s own cells and tissues will reduce the likelihood that the transplanted tissue will be rejected by the immune system.

Related Links :  Stem Cell Research at Johns Hopkins

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Stem Cell Therapy: From Idea to Clinical Practice

Regenerative medicine is a new and promising mode of therapy for patients who have limited or no other options for the treatment of their illness. Due to their pleotropic therapeutic potential through the inhibition of inflammation or apoptosis, cell recruitment, stimulation of angiogenesis, and differentiation, stem cells present a novel and effective approach to several challenging human diseases. In recent years, encouraging findings in preclinical studies have paved the way for many clinical trials using stem cells for the treatment of various diseases. The translation of these new therapeutic products from the laboratory to the market is conducted under highly defined regulations and directives provided by competent regulatory authorities. This review seeks to familiarize the reader with the process of translation from an idea to clinical practice, in the context of stem cell products. We address some required guidelines for clinical trial approval, including regulations and directives presented by the Food and Drug Administration (FDA) of the United States, as well as those of the European Medicine Agency (EMA). Moreover, we review, summarize, and discuss regenerative medicine clinical trial studies registered on the Clinicaltrials.gov website.

1. Introduction

Despite the progress in medical science, there still exist various diseases in the world for which there is no suitable treatment. People affected by incurable disorders typically use treatment methods intended to decrease the somatic and psychological symptoms and, in these situations, the physician offers treatment methods only to manage the disease, not treat it. Therefore, researchers are attempting to develop new treatment methods to not only control the symptoms of, but also to treat those diseases for which no cure is available at present.

Regenerative medicine is considered a promising new source of treatment for untreatable diseases in modern science [ 1 ]. Regenerative medicine is a multidisciplinary field including cell biology, genetic, biomechanics, material science, and computer science [ 2 , 3 ], the ultimate target of which is returning normal function to defective cells and tissues [ 4 ]. Since the discovery of stem cells and the spread of awareness regarding their unique properties, they have been defined as therapeutic agents for organ and tissue repair, and so are widely considered good candidates for regenerative medicine, due to their many potential applications [ 5 ]. Regenerative medicine is now regarded as an alternative to traditional drug-based treatments by researchers who study its potential applications in various diseases, including degenerative diseases, among others [ 6 , 7 , 8 , 9 , 10 ]. The main concept of regenerative medicine is implied tissue/organ regeneration using cells and, to reach this target, different kinds of cells have been used. However, various studies have indicated that cell therapy is restricted by a few limitations. In recent years, different alternatives have been introduced for cell therapy in order to resolve these limitations, including the improved application of stem cells for the restoration of tissue, such as the combination of cells with scaffolds, cell cultures with suitable biochemical properties, gene editing, and the immunomodulation of stem cells, as well as the use of stem cell derivatives [ 11 , 12 , 13 , 14 , 15 ]; however, the use of these alternatives clinically may be postponed, as more preclinical studies are required due to their status as newer technologies [ 16 ].

Stem cells are a group of immature cells that have the potential to build and recover every tissue/organ in the body due to their unique proliferative, differentiation, and self-renewal abilities [ 17 ]. Stem cells provide therapeutic effects which improve physical development by regenerating damaged cells to assist in organ recovery. Relying on the natural abilities of stem cells, researchers have used their biological mechanisms for stem-cell-based therapy. The mechanisms of action through which stem cells can promote the regeneration of tissue are diverse, including (1) inhibition of inflammation cascades [ 18 , 19 ], (2) reduction of apoptosis [ 20 , 21 ], (3) cell recruitment [ 22 , 23 ], (4) stimulation of angiogenesis [ 24 , 25 ], and (5) differentiation [ 26 ]. The cause of a disease is a vital consideration in selecting the proper stem cell mechanism and in the regeneration of tissue/organs using stem cells. Many examinations must be carried out to determine the main mechanisms involved in treatment when these cells are to be used in clinical practice, and the convergence of stem cell therapeutic mechanisms and disease mechanisms is expected to increase the chance of developing cures through stem cell applications.

From 1971 to 2021, 40,183 research papers were published regarding stem-cell-based therapies. All of these studies were conducted around discoveries and for the goal of “Stem Cell Therapy” based on the therapeutic efficacy of stem cells [ 27 ]. As basic stem cell research has soared over the past few years, “translation research”, a relatively new field of research, has recently greatly developed, making use of basic research results to develop new treatments. Although many articles on stem-cell-based therapies are published annually and their number increases every year, the number of clinical trial studies has not increased rapidly. Furthermore, among these studies, only a small portion of them can receive full regulatory approval for verification as treatment methods. Although one reason for this difference is due to the need for various prerequisite preclinical studies before carrying out a clinical trial study, the main reason is due to the sharply defined guidelines which prevent the translation of many preclinical studies to clinical trials.

In this review, we provide a general overview regarding the translation of stem cell therapies from idea to clinical service. Understanding the step-by-step knowledge underlying the translation of ideas to medical services is the first step in introducing a new treatment method. In this review, we divide this pathway into four levels, including idea evaluation, preclinical studies, clinical trial studies, and clinical practice. We focus not only on understanding each level’s requirements, but also discuss how an idea is assessed during the transition from one level to the next and, finally, move on to marketing.

2. From Idea to Preclinical Study

If a researcher has an idea regarding regenerative medicine using stem cells that inspires their use in a study, it must first be evaluated. During the evaluation step, it is important to select the target disease and make sure that the mechanism causing the disease is understood. Disease-related mechanisms refer to the cellular and molecular processes by which a particular disorder is caused [ 28 , 29 ], and stem-cell-based therapies are considered a treatment method intended to compensate for the disruption caused by such mechanisms in order to finally restore the defective tissue. Multiple mechanisms cause diseases [ 30 , 31 , 32 ]; however, stem cells, with their tremendous differentiation, self-renewal, angiogenesis, anti-inflammation, anti-apoptotic, and immunomodulatory potentials, as well as their capacity for induction of growth factor secretion and cell signaling, can affect these mechanisms [ 33 , 34 , 35 , 36 , 37 ].

After subject evaluation, preclinical studies should be carried out to determine whether the idea has any potential to treat the disease, and the safety of the final product should be assessed in an animal model of the target disease [ 38 , 39 , 40 ]. Preclinical studies are composed of in vitro and in vivo studies. In vitro experiments are performed with biological molecules and cells based on various hypotheses and, during the in vitro evaluation, a new treatment method is assayed in this controlled environment [ 39 ]. In contrast, during in vivo studies, as controlling all biological entities is impossible, the new product may be affected by various factors and thus present different effects. The general purpose of a preclinical study is to present scientific evidence supporting the performance of a clinical study, and the following are required for a decision to move forward to clinical study: (i) the feasibility and establishment of the rationale (e.g., validation, separation of active ingredients in vitro, and determination of its mechanism in vivo), (ii) establishment of a pharmacologically effective capacity (e.g., secure initial dose verification), (iii) optimization of administration route and usage (e.g., safe administration method, repeated administration, and interval verification), (iv) identification and verification of the potential activity and toxicity (e.g., toxicity analysis according to single and repetitive testing), (v) identification of the potential for special toxicity (e.g., genetic, carcinogenic, immunological, and neurotoxic analyses), and (vi) determination of whether to continue or discontinue development of the treatment [ 41 , 42 ].

3. From Preclinical Study to Clinical Trial

In principle, any idea regarding stem cell therapy should be assessed using comprehensive studies (i.e., in vitro and in vivo) before a clinical trial is considered, and the results of these studies should be proved by competent authorities. It can be easy during an in vitro study to create manipulative biological environments such as through the use of genetic mutation, drug testing, and pharmaceuticals, and it is easy to observe changes through the application of manipulated variables through living cells [ 43 , 44 , 45 ]. However, given the many associated variables, such as molecular transport through circulating blood and organ interactions, it is hard to say whether such a study can completely mimic the in vivo environment [ 43 , 44 , 45 ]. Before application in patients, in vivo experiments are conducted after in vitro experiments in order to overcome these weaknesses.

Many researchers use rodents for in vivo studies, due to their anatomical, physiological, and genetic similarities to humans, as well as their other unique advantages including small size, ease of maintenance, short life cycle, and abundant genetic resources [ 46 ]. The strength of in vivo studies is that they can supplement the limitations of in vitro studies, and the outcomes of their applications can be inferred in humans through the use of human-like biological environments. To establish in vivo experiments for stem cell therapies, the most correlated animal model should be selected depending on the specific safety aspects to be evaluated. Where possible, cell-derived drugs made for humans should be used for proof-of-concept and safety studies [ 47 ]. Homogeneous animal models can also be utilized as the most correlated systems in proof-of-concept studies [ 48 ].

Furthermore, in vivo studies require ethical responsibilities and obligations to be upheld according to experimental animal ethics. In other words, unnecessary and unethical experiments must be avoided. Summing up the above, we can see that both in vitro and in vivo approaches are used in preclinical studies, which should be carried out before clinical trial applications based on various interests.

Several factors must be considered in different in vitro and in vivo studies, including cell type determination, cell dose specification, route of administration, and safety and efficiency.

3.1. Stem Cell Source Determination

As expectations rise for regenerative treatment through the application of stem cell therapies, the number of applications of various types and stem cell sources has increased, and stem cell therapies have diversified from autologous to allogenic to iPSCs. These stem cell treatments can vary in risk, depending on the cell manufacturing process [ 49 ], among other factors, and in clinical experience, such that all types of stem cell treatments must be evaluated on the same basis [ 50 ]. Therefore, the strengths and weaknesses of each type of stem cell should be identified in order to determine the maximum therapeutic effect of stem cells in various diseases. This will enable us to build disease-targeted stem cells by applying the appropriate stem cells to the appropriate diseases. Below, we briefly discuss the characteristics of various stem cells.

3.1.1. Mesenchymal Stem Cells (MSCs)

MSCs are lineage-committed cells that divide into mesenchymal systems, primarily fatty cells, chondrocytes, and osteocytes [ 51 ]. It is well known that MSCs can be differentiated into dry cells, nerve cells, glioma cells, and skeletal muscle cells under proper in vitro culture conditions [ 52 , 53 , 54 , 55 , 56 , 57 ]. MSCs are primarily derived from myeloid and adipose tissues [ 58 , 59 ]. At present, MSCs are also isolated from many other tissues, such as the retina, liver, gastric mucosa, tendon, cartilage, placenta, cord blood, and blood [ 60 , 61 , 62 , 63 ]. The biggest characteristics of MSCs are their immunosuppressive functions, which prevent the proliferation of activated T cells through immunosuppressive cytokine secretion and suppression of programmed cell death signaling [ 64 , 65 ]. Due to this role, they have been spotlighted as a potential treatment for immune-related inflammation and disease. The initial clinical application of MSCs was in a case of patients with severe graft versus host disease (GVHD), and these cells have since been well applied in clinical practice, as evidenced through various studies [ 66 , 67 , 68 ].

MSCs have a variety of characteristics according to their organ of origin [ 69 ]. BM-MSCs, which are isolated from bone marrow, are useable in both autologous and allogenic contexts, and can perform stromal functions. However, the process of cell isolation from bone marrow is not only accompanied by the risk of pain and infection, but also has a lower efficiency of collection than other MSC sources. Furthermore, these cells have a longer doubling time (DT) in comparison to MSCs derived from other sources (approximately 60 h) [ 70 ]. Compared to BM-MSCs, AD-MSCs are not only easy to collect, but are also 100 to 500 times more efficient to harvest and have a shorter DT (approximately 20 h) [ 71 ]. However, these are adipose-derived stem cells that have a strong characteristic of adipogenic differentiation, such that they can be suggested as a valid alternative to BM-MSCs, but their nature must be considered regarding proper culture and body environment. Furthermore, there are concerns that these factors may affect the efficacy of treatment, as the amount of cytokines secreted is significantly lower when compared to BM-MSCs [ 72 ]. MSCs extracted from the umbilical cord (UC-MSCs) have come into the spotlight to compensate for these issues: UC-MSCs not only have the advantage of being easily collected compared to other stem cells, but also avoid ethical or donor age issues. They have superior proliferation and differentiation capabilities compared to BM-MSCs and AD-MSCs, and their DT has been reported as 24 h [ 69 , 73 ]. UC-MSCs are currently a subject of concern, as although they are easy to store frozen for a long time (e.g., in a cord blood bank), the cell survival rate and success rate during extraction are not high, due to exposure to cryogenic protectors during cryogenic storage [ 73 ]. Furthermore, as the cells are isolated from other organs, they have limited self-renewal capacity, and their senescence is faster than in other stem cells in long-term cultivation [ 66 , 74 ].

3.1.2. Hematopoietic Stem Cells (HSCs)

HSCs can be differentiated into cells from all hematopoietic systems present in the bone marrow and chest glands, namely myeloid cells and lymphocytes. HSCs can be obtained at good levels from adult bone marrow, the placenta, and cord blood. They can cause immunological problems such as transplant rejection. Nevertheless, they have been shown to be an effective treatment method in various diseases, including leukemia, malignant lymphoma, and regenerative anemia, as well as congenital metabolism, congenital immunodeficiency, nonresponsive autoimmune disease, and solid cancer to date. Furthermore, HSCs are the only stem cell type approved for stem cell treatment by the Food and Drug Administration (FDA) [ 75 , 76 ].

3.1.3. Embryonic Stem Cells (ESCs)

ESCs have established cell lines that can be maintained through in vitro culture. They are pluripotent cells that can be differentiated into almost any type of cell present in the body, and can be differentiated in vitro by adding external factors to the culture medium or by genetic modification. However, they may form teratomas, which are composed of various forms of cells derived from the endoderm, mesoderm, and exoderm, when transplanted into an acceptable host [ 77 ].

3.1.4. Induced Pluripotent Stem Cells (iPSCs)

iPSCs are artificially created stem cells. These cells are made by reprogramming adult somatic cells such as fibroblast cells. They share many of the characteristics of ESCs, including self-renewability, pluripotent differentiation, and malformed species performance. Unfortunately, these cells have little scientific evidence regarding changes in cell-specific regulatory pathways, gene expression, and epigenetic regulation. These characteristics pose a risk of tissue chimerism or cell dysfunction [ 78 ].

In summary, although the FDA-approved stem cell type is HSCs from healthy donors, a variety of issues have been raised, including a lack of donors and immune rejection. Therefore, we need to understand the characteristics of stem cells in order to handle them accordingly and overcome their disadvantages while maximizing their advantages. As stem cells derived from various sources have different characteristics, capabilities, potential, and efficiency, selecting the right source of stem cells that is appropriate for the target can be effective in assuring treatment efficiency.

3.2. Cell Dose Specification

The effective range of administration (i.e., dosage) of stem cells or stem-cell-derived products used in treatment should be determined through in vivo and in vitro studies. The safe and effective treatment capacity must be identified and, where possible, the minimum effective capacity must also be determined. When administered to vulnerable areas such as the central nervous system and myocardium, it has been reported that conducting normal dosage determination tests is unlikely. Thus, if the results of nonclinical studies can safety demonstrate treatment validity, it may be appropriate to conduct early human clinical trials with doses that may indicate therapeutic effects [ 79 ].

Will a high cell dose have better effects, considering only the effectiveness of stem cells? We answer this question below. An increasing dose of CD34 + cells (0.5 × 10 5 per mouse) has been shown to have positive effects, stimulating multilineage hematopoiesis at early stages and increasing the magnitude of reconstitution at post-transplant stages. Furthermore, improved T-cell reconstitution was correlated with higher cell doses of stem cells, compared to lower cell doses [ 80 ]. However, a few studies related to acute myeloblastic leukemia (AML) have reported that high doses of HSCs were correlated with restored function and rapid hematological and immunological recovery, but these results were not unconditional. In this study, a higher dose of HSCs (≥7 × 10 6 /kg) resulted in poorer outcomes and a higher relapse rate than the lower dose of HSCs (<1 × 10 6 /kg) [ 81 ]. In preclinical studies on heart disease, Golpanian et al. have demonstrated, through comparison of some preclinical studies for optimized cell dose, the therapeutic effects of stem cell types (i.e., allogenic and autologous MSCs), as well as the proper cell dose of stem cells and route of administration (direct epicardial and intravenous) in heart disease. Their results showed that the total number of cells used was different, but were inconsistent with the hypothesis that a higher number of cells would have higher therapeutic efficacy [ 82 ]. Therefore, these conclusions suggest that the currently reported data do not provide a decisive answer, such that sufficient and detailed early-stage studies may be needed before proceeding with clinical trials.

3.3. Route of Administration

Stem cells have been extensively studied under various disease conditions, depending on their type and characteristics. At this time, the route of administration should not be overlooked in favor of the number of stem cells transplanted. Several reports have shown that engraftment ability typically has a lower rate of reaching target organs relative to the number of transplanted cells, and does not have a temporary longer duration [ 83 , 84 ].

The methods of stem cell administration can largely be divided into local and systemic transmission. Local transmission involves specific injections through various manipulations and direct intra-organ injections, such as intraperitoneal (IP), intramuscular, and intracardiac injections. Systemic transmission uses vascular pathways, such as intravenous (IV) and intra-arterial (IA) methods. According to the publications in the literature, IV is the most common method, followed by intrasplenic and IP [ 85 , 86 , 87 ]. In a liver disease model, IV was shown to be not only suitable for targeting the liver, but also showed better liver regeneration effects than other routes of administration [ 85 , 88 ]. Intracardial injection showed better cell retention in heart disease, while intradermal injection showed better treatment in skin diseases [ 89 , 90 ]. Hence, we can determine that, in the context of these various diseases, the routes of administration should be different depending on the target organ. Many researchers have suggested that intravascular injection is a minimally invasive procedure, but it also poses a risk of clogged blood vessels, such that direct intravascular injection increases the risk of requiring open-air operations [ 91 ]. Clinical trials have reported that the number of cells and treatment efficacy under the same conditions, as in preclinical studies, are not significant, but also differ in significance depending on the route of administration [ 92 , 93 ]. Therefore, researchers should continue to study which cells are appropriate for a given route of administration—even within the same disease—based on many precedents [ 82 ]. In addition, researchers should explore the appropriate routes of administration for safer and more effective therapeutic effects.

3.4. Manipulation of Cell Transplantation for Safety and Efficiency Improvement of Administration

All medical treatments have benefits and risks. It is not particularly safe to apply these unproven stem cell treatments to patients. As expectations for regenerative treatment through stem cell therapies increase, the application of various administration pathways, including through the spinal cord, subcutaneous, and intramuscular, as well as the stem cell therapies themselves, have been diversifying, from autologous to homogenous to iPS. These stem cell treatments can vary in risk, depending on the cell type manufacturing process among other factors, and they differ in clinical experience, such that all types of stem cell treatments must be evaluate on the same basis. Furthermore, it should only be in limited and justified contexts that stem cells which can proliferate and have all-purpose differentiation remain in a final product.

Unfortunately, the only safe stem cells that have been employed in regenerative medicine so far are omnipotent stem cells, such as HSCs and MSCs, which are isolated from their self-origin [ 94 ]. Unfortunately, potential clinical applications using iPSCs and ESCs face many hurdles, as they present higher risk, including the possibility of rejection, teratoma formation, and genomic instability [ 95 ]. Hence, many researchers have attempted to overcome stem cell tracking for safety assessment. To check the engraftment and the remaining amount of stem cells, they have been labeled using BrdU, CM-Dil, and iron oxide nanoparticles, and visualized using Magnetic resonance imaging (MRI) [ 84 , 96 , 97 ].

A close analysis of the distribution patterns of administrative sites and target organs is required, as well as whether a distribution across the body is expected, and the organ that the cells are predicted to be distributed through should undergo a full-term analysis, including evaluation at administrative sites. To date, studies have reported assessments in the brain, lungs, heart, spleen, testicles, ovaries, kidneys, pancreas, bone marrow, blood, and lymph nodes, including areas of administration [ 98 ].

Some researchers have carried out the detection of transplanted UC-MSCs delivered by IV injection in the lung, heart, spleen, kidney, and liver. According to their results, the transplanted cells were not detected in other organs, except the lung and liver, for 7 days. In the lung and liver, the detected cells persisted at least 7 days after the transplant [ 99 ]. Furthermore, in a study comparing BM-MSCs and UC-MSCs in terms of cell tracking, they reported on the persistence of stem cells according to the route of administration used. In the results of the comparison of intracardiac and intravenous routes, the transplanted stem cells were detected in the lung for 10 days, but the signal disappeared after 21 days [ 100 ]. In other research, the stem cells were transplanted with using a biomaterial scaffold. The AD-MSCs were transplanted with hyaluronic acid/alginate hydrogel through intradermal injection, and could be detected by CM-Dil staining for 30 days [ 101 ]. These studies may show that the transplanted cells localized to the damaged organs through their homing ability, but the results of these previous studies seem to indicate that the residual volume and the residual date vary significantly depending on the target disease, organs, and type of stem cells. The cell residual means the survival of the cell, which represents the risk of formation of tumors. To overcome the problem of teratoma formation, the following results have been reported: According to one study, ESCs showed the following rates of teratoma formation: 100% under the kidney capsule, 60% intratesticular, 25–100% subcutaneous, and 12.5% intramuscular. To overcome this problem, the investigators performed a co-injection with Matrigel into an animal model. According to their results, subcutaneous implantation of ESCs in the presence of Matrigel appeared to be the most efficient, reproducible, and easiest approach for preventing teratoma formation, other than only using ESCs [ 102 ]. Moreover, cellular products derived from iPSCs have higher potential as potential cell sources in personalized medicine [ 103 ]. Their applicability is currently limited due to concerns regarding the potential risk of serious transplant-related side effects, such as tumor formation due to residual pluripotent cells [ 104 ]. Hence, a recent study reported the establishment of an optimized tool for therapeutic intervention that allows for controlled specific and selective ablation of iPSCs through the use of LVCAGs–transgenic iPSCs [ 104 ].

Unlike MSCs, which are generally considered immune-tolerant as an immunomodulator, transplantation of ESCs and HSCs requires close examination of the matching of histocompatibility antigen (HLA) between the donor and beneficiary [ 105 , 106 ]. Although homogeneous mesenchymal stem cells are known to have immunogenicity in immune-active rodent models and are quickly removed from the peripheral blood, studies have shown that a few MSCs remain for weeks to months. Therefore, it is recommended to conduct a study to assess the persistence of MSCs in the cell preparations administered, in order to assess the risk of stem cell removal. Therefore, for stem cell therapies that have undergone extensive in vitro manipulation such as long-term cell culture—including those derived from ESCs and iPSCs—both oncogenicity and genetic stability must be evaluated before clinical research begins. Furthermore, we must constantly review and study the latest research on safety, as well as the effects of regeneration using stem cells, and discuss and study the potential of regenerative medicine [ 107 , 108 , 109 , 110 , 111 ].

As discussed earlier, in vitro and in vivo preclinical studies are the direction of current research, and encompass the tasks that need to be completed. If we reinforce the current strengths and weaknesses based on the preceding content, we are already a step closer to developing stem cell treatments.

4. From Clinical Trial to Clinical Practice

Before a treatment is applied in humans (i.e., patients), preclinical study must involve checking whether the effect of treatment will be positive or negative and, if there are any negative effects, the researcher must check the safety possibilities at every step. Due to concerns relating to treatment using stem-cell-based products, deciding whether preclinical studies are sufficient for translating to clinical trials raises several issues that must be assessed by competent authorities. An application for a clinical trial should be submitted to the Food and Drug Administration (FDA), the European Medicine Agency (EMA), or another organization, based on the country [ 112 ].

The FDA is responsible for certifying clinical trial studies for stem-cell-based products in the United States [ 113 ]. If a new drug is introduced to a clinical investigator which has not been approved by the FDA, an Investigational New Drug (IND) application may need to be submitted [ 114 ]. The IND application includes data from animal pharmacology and toxicology studies, clinical protocols, and investigator information [ 115 ]. A lack of preclinical support (e.g., in vitro and in vivo studies) can lead to required modification or disapproval. If the FDA has announced that an IND requires modifications (meaning that the application is intended to secure approval but has not yet been approved), the results of the preclinical studies were deemed insufficient or inadequate for translation to clinical trial study, such that further study must be completed, after which an amended IND should be submitted.

The FDA has published guidelines for the submission of an IND in the Code of Federal Regulations (CFR). These regulations are presented in 21 CFR part 210, 211 (Current Good Manufacturing Practice (cGMP)), 21 CFR part 312 (Investigational New Drug Application), 21 CFR 610 (General Biological Product Standards), and 21 CFR 1271 (Human Cells, Tissues, and Cellular and Tissue-Based Products) [ 116 , 117 , 118 ]. These guidelines have been issued for the development of stem cell products with the highest standards of safety and potential effective translation to clinical trial studies.

The FDA issued 21 CFR parts 210 and 211to ensure the quality of the final products [ 119 ]. The 21 CFR part 210 contains the minimum current good manufacturing practice (cGMP) considered at the stages of manufacturing, processing, packing, or holding of a drug, while the 21 CFR part 211 contains the cGMP for producing final products. The 21 CFR 211 includes FDA guidelines for personnel, buildings and facilities, equipment, and control of components, process, packaging, labeling, holding, and so on, all of which are critical for pharmaceutical production [ 116 , 117 , 118 , 119 , 120 , 121 ]. The requirements for IND submission and conducting clinical trial studies, reviewed by the FDA in the 21 CFR part 312 (Investigational New Drug Applications), includes exemptions that are described in detail in 312.2 (general provisions). Such exemptions do not require an IND to be submitted, but other studies must present an IND based on 21 CFR part 312. The section, 21 CFR part 312, provides different information, including the requirements for an IND, its content and format, protocols, general principles of IND submission, and so on. In addition, the FDA describes the administrative actions of IND submission, the responsibilities of sponsors and investigators, and so on, in this section [ 116 , 117 , 122 ]. The 21 CFR part 610 contains general biological product standards for final product characterization. The master cell bank (MCB) or working cell bank (WCB) used as a source for stem-cell-based final products must be tested before the release or use of the product in humans. The MCB and WCB should be tested for sterility, mycoplasma, purity, identity, and potency, among other tests based on the final products (e.g., viability, stability, phenotypes), before use at the clinical level. The FDA provides all required information regarding general biological product standards in this section, including release requirements, testing requirements, labeling standards, and so on [ 116 , 117 , 123 , 124 ]. The 21 CFR part 1271 focuses on introducing the regulations for human cells, tissues, and cellular and tissue-based products (HCT/P’s), in order to ensure adequate control for preventing the transmission of communicable disease from cell/tissue products. Current Good Tissue Practice (GTP) is a part of 21 CFR part 1271, where the purpose of GTP is to present regulations for the establishment and maintenance of quality control for prevention of introduction, transmission, or spread of communicable diseases, including regulations for personnel, procedures, facilities, environmental control, equipment, and so on [ 125 , 126 , 127 , 128 ].

The EMA is an agency in the European Union (EU) which is responsible for evaluating any investigational medical products (IMPs) in order to make sure that the final product is safe and efficient for public use. When planning to introduce a new drug for a clinical trial in Europe, one may be required to submit clinical trial applications to the EMA for IMPs. Clinical trial applications for IMPs include summaries of chemical, pharmacological, and biological preclinical data (e.g., from in vivo and in vitro studies) [ 129 ]. The EMA has presented different regulations to support the development of safe and efficient products for public usage, including Regulation (EC) No. 1394/2007, Directive 2004/23/EC, Directive 2006/17/EC, Directive 2006/86/EC, Directive 2001/83/EC, Directive 2001/20/EC, and Directive 2003/94/EC.

Regulation (EC) No. 1394/2007 defines the criteria for regulation regarding ATMPs. Advanced therapy products (ATMPs) are focused on gene therapy medicinal products (GTMP), somatic cell therapy medicinal products (sCTMP), tissue-engineered products (TEP), and combined ATMPs, which refers to a combination of two different medical technologies. Regulation (EC) No. 1394/2007 includes the requirements to be used in development, manufacturing, or administration of ATMPS [ 130 , 131 , 132 ]. Directive 2004/23/EC, Directive 2006/17/EC, and Directive 2006/86/EC define standards for safety and quality, as well as technical requirements for donation, procurement, testing, preservation, storage, and distribution of tissue and cells intended for human applications [ 133 , 134 , 135 ]. Directive 2001/83/EC applies to medicinal products for human use [ 136 ]. Directive 2001/20/EC presents the regulations for the implantation of products in clinical trials in the EU [ 137 ]; however, this directive will be replaced by regulation (EU) No. 536/2014. Regulation (EU) No. 536/2014 was adapted by the European Parliament in 2014, and provides regulation for clinical trials on medical products intended for human use. The new EU regulation comes into effect on 31 January 2022 and aims to coordinate all clinical trials performed throughout the EU, using clinical trials submitted into CTIS (Clinical Trials Information System). The definition of regulation (EU) No. 536/2014 as a homogeneous regulation serves an important role in the EU, as all member states of the EU can be involved in multicenter clinical trials using international coordination, thus allowing larger patient populations [ 138 ]. Directive 2003/94/EC provides Good Manufacturing Practice (GMP) Guidelines in relation to medicinal products or IMPs intended for human use [ 139 ]. All process and application requirements for the IMP application are present in the regulations and directives of the EMA. After presenting an IND/IMP to the regulatory authority responsible for clinical trial oversight (FDA or EMA), the application will be reviewed in accordance with the FDA/EMA criteria and, if assured of the protection of humans enrolled in the clinical study, the application will be approved by the investigational review boards (IRBs) in the United States or Ethics Committees (ECs) in the European Union. Clinical trial studies are composed of different steps where, at each step, products are assessed using different quality and quantity measurements by the responsible agency. An efficient clinical trial study should address the safety and efficiency of new stem cell products in each of the different steps, and it is important to complete each step based on defined instructions and regulations, as the results of previous steps are needed to move forward.

Almost all clinical trial studies that have been approved for testing in humans have been registered online ( https://www.clinicaltrials.gov/ accessed 12 December 2021). Our search on this website revealed more than 6500 records for interventional studies registered using “Stem Cells” up to December 2021. The recorded clinical trials can be analyzed from different aspects.

Recruiting status: The recruiting status of these studies indicated that 18% of these studies were ongoing (recruitment) and 42% were completed ( Figure 1 ). Although completed, suspended, terminated, and withdrawn studies are all terms used for studies that have ended, each is used to describe a different status. Completed studies are those that have ended normally and the participants were completely enrolled in the study. Suspended, terminated, and withdrawn studies are studies that stopped early; however, the participant enrolment status differs between them. A suspended study may start again, but nobody can continue to participate in terminated or withdrawn studies [ 140 , 141 ].

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Status of clinical trials using stem cells.

Type of disease: Stem-cell-based therapy is a new approach for the treatment of various diseases in different clinical trial studies. Blood and lymph diseases are the most common diseases that have benefited from this new approach ( Figure 2 ). Blood and lymph diseases refer to any type of disorder related to blood and lymph deficiency or abnormality, such as anemia, blood protein disorder, bone marrow disease, leukemia, hemophilia, thalassemia, thrombophilia, lymphatic disease, lymphoproliferative disease, thymoma, and so on. In addition, various clinical trial studies have been performed using stem cells to treat immune system disease; neoplasm, heart, and blood disease; and gland- and hormone-related disease ( Figure 2 ). However, this does not mean that all of these studies had great results, nor does it mean that all of these studies introduced a new treatment method; some of these clinical trial studies were only intended to increase treatment efficiency, compare different types of treatment methods, or analyze various parameters after the administration of stem cells into the body.

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Diseases considered in clinical trials using stem cells.

Autologous vs. Allogenic: Stem-cell-based products for use in clinical trial studies can be divided into two categories: autologous and allogeneic stem cells. In autologous stem cell therapy, the stem cells are collected from the patient’s own body. Culture-expanded autologous stem cells are autologous stem cells that are expanded before transplantation, and can be divided into two groups: modified and unmodified expanded autologous stem cells. If autologous stem cells were transplanted to the donor immediately after collection, this is a nonexpanded autologous stem cell treatment. The use of these cells usually has fewer restrictions for receiving clinical trial authorization. The classification of allogenic stem cells is similar to that of autologous stem cells, except that allogeneic stem cells are collected from a healthy donor. The use of these cells requires more prerequisite tests, in order to check the donor’s health. Allogenic stem cells have been used more than autologous stem cells in the clinical trial studies (46.34% vs. 44.51%), as shown in Figure 3 .

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Applied stem cell types in clinical trials using stem cells.

Phase: Clinical trial studies are conducted in different phases. In each phase, the purpose of study, the number of participants, and the follow-up duration may differ. A new phase of clinical trials should not be started unless the results of the completed phase(s) have been reviewed by competent authorities, in order to that certify the results of the completed phase(s) are valid for authorization of the start a new phase of the clinical trial. For this purpose, at the end of each phase of a clinical trial study, competent authorities evaluate whether the new drug is safe, efficient, and effective for the treatment of the target disease ( Figure 4 ).

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Status of clinical phase within clinical trials using stem cells.

Early Phase I emphasizes the effects of the drug on the human body and how the drug is processed in the body.

Phase I of a clinical trial is carried out to ensure that a new treatment is safe and to determine how the new medicine works in humans. The FDA has estimated that about 70% of the studies pass this phase.

In Phase II, the accurate dose is determined and initial data on the efficiency and possible side effects are collected. The FDA has estimated that roughly 33% of the studies move to the next phase.

Phase III evaluates the safety and effectiveness of products. The result of this phase is submitted to the FDA/EMA for new product approval, which allows manufacturing and marketing of the drug. The FDA has estimated that 25%–30% of the drugs pass at this phase.

Phase IV take place after the approval of new products and is carried out to determine the public safety of the new product [ 142 , 143 , 144 ].

The number of participants and the duration: A new stem cell product is eligible for marketing after completing successful clinical trial phases. As the new product has been used on volunteers and the effects/side effects of the drug have also been followed for a long time throughout the different phases, it is now possible to make a decision regarding its introduction to the market for public use. The number of participants and the duration of long-term follow-up in each study and each phase differ ( Figure 5 and Figure 6 ). The number of volunteers that participate in each phase of a clinical trial study varies, as each phase has a different target. The FDA has recommended 20–80, 100–300, and several hundred to thousands of volunteers for Phase I, Phase II, and Phase III, respectively [ 144 , 145 ]. Although the FDA has defined a range for enrolments per phase, the number of participants can vary depending on the type of disease. The number of participants for clinical studies in rare diseases will be lower than when studying common diseases. Searching for stem cells in clinicaltrial.gov, studies can be found with only one participant (e.g., {"type":"clinical-trial","attrs":{"text":"NCT02235844","term_id":"NCT02235844"}} NCT02235844 , {"type":"clinical-trial","attrs":{"text":"NCT02383654","term_id":"NCT02383654"}} NCT02383654 , {"type":"clinical-trial","attrs":{"text":"NCT03979898","term_id":"NCT03979898"}} NCT03979898 , and {"type":"clinical-trial","attrs":{"text":"NCT01142856","term_id":"NCT01142856"}} NCT01142856 ). The sponsor/investigator must provide the FDA with strong documentation regarding the selection of such a number of volunteers. The volunteers for each clinical trial study, before attending, should be informed about the enrolment criteria of each study, possible side effects, and the advantages of the study.

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Enrolment of clinical trials using stem cells.

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The duration of each clinical trial study using stem cells.

Age of participants: Roughly 190,000 people participated in all the completed clinical trial studies using stem cells that had been registered. Each clinical study was performed in different age groups, which differed among the various studies depending on the type of drug, type of disease, and sponsor decision, as shown in Figure 7 .

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The age of patients participating in clinical trials using stem cells.

Number of clinical trial studies: The number of clinical trial studies increased gradually from 2000 to 2014, although it fluctuated after 2014 but did not change significantly ( Figure 8 ). The reason for this increase in 2014 is not clear, but it may have been related to the introduction of the first advanced medicinal therapy product containing stem cells (Holoclar) by the EMA in 2014–2015 [ 146 ].

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The proportion of clinical trials using stem cells by year: ( A ) the proportion of new clinical trial studies using stem cells by year (green bar) and the proportion of registration results accordingly (orange color line); ( B ) the proportion of completed registered clinical trial studies using stem cells by year (blue bar) and the updated results of completed clinical trial studies using stem cells by year (orange line).

Place of study: According to economic website reports, the cell therapy market has grown significantly in recent years, and it is expected to grow more in the coming years; therefore, many countries have begun research in this field. Our data from clinicaltrial.gov showed that the United States has conducted the most clinical trials using stem cells ( Figure 9 ). Government agencies, industry, individuals, universities, and private organizations have all invested in stem-cell-based therapy. The number of stem-cell-based companies has rapidly increased in recent years, and a brief overview of the submitted clinical trial studies indicated that the studies were mostly aimed at introducing therapeutic products for clinical applications. Therefore, we can expect the introduction of stem-cell-based products to the market.

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The registered and completed clinical trial studies using stem cells according to participating countries: ( A ) top 10 participating countries with registered clinical trials using stem cells; and ( B ) top 10 countries based on the completion of registered clinical trials using stem cells.

As indicated above, translational research from the laboratory to clinical services has many layers which must be passed through, each with its own requirements and measurements. Therefore, the only way to introduce a new stem-cell-based product onto the market is for competent authorities to make sure that the discovery is safe and effective for its intended human use, and that the product has successfully passed all of the clinical trial stages.

5. Challenges and Future Directions

One of the most important issues regarding the introduction of a new product for use in humans through a clinical trial is evaluation of its safety. Although many clinical trials have been performed using stem cells for the treatment of various diseases, as stem-cell-based therapies are one of the newest groups of therapeutic products in medicine, it is very hard to introduce new products based on stem cells onto the market, as many different parameters must be evaluated. There are several concerns regarding stem-cell-based therapies, including genetic instability after long-term expansion, stem cell migration to inappropriate regions of the body, immunological reaction, and so on. However, all challenges depend on the type of stem cell (e.g., embryonic stem cell, adult stem cell, iPS), type of disease, route of administration, and many other factors. Almost all researchers in the field of stem cell therapy believe that despite stem cells having great potential to treat disease through their intrinsic potential, unproven stem-cell-based therapies that have not been shown to be safe or effective may be accompanied by very serious health risks. In order to receive clinical trial approval from a competent regulatory authority, different tests must be performed for each study phase, and the results of one study should not be generalized to another study. The FDA and EMA have defined different regulations to ensure that stem-cell-based products are consistently controlled through the use of different preclinical studies (in vitro and in vivo). Based on these preclinical data, the FDA and EMA have the authority to approve a clinical trial study, as discussed in this review.

Another challenge that researchers and companies face is the duration of a clinical trial study before a stem-cell-based product can be introduced onto the market. At present, hematopoietic progenitor cells are the only FDA-approved product for use in patients with defects in blood production, while other stem-cell-based products used in clinical trials have not yet been introduced to the market.

In the past few years, several clinical trials have been conducted using stem cells, most of which have indicated the safety and high efficiency of stem-cell-based therapies. An attractive future option for regenerative medicine is the use of cell derivatives, including exosomes, amniotic fluid, Wharton’s jelly, and so on, for the treatment of diseases. Recently, the safety and efficiency of these products have been evaluated and optimized in preclinical studies. In addition, regenerative medicine using modified stem cells and combinations of stem cells with scaffolds and chemicals to overcome stem cell therapy challenges and increase the associated efficiency are two important future directions of research. However, establishing a safe method for stem cell modification and moving this technology toward clinical trial studies requires many preclinical studies.

The regenerative medicine market is developing and, due to encouraging findings in preclinical studies and predictable economic benefits, competition has increased between companies focused on the development of cell products. Therefore, government agencies, industries, individuals, universities, and private organizations have invested heavily into the development of the regenerative medicine market in recent years, such that we can be more hopeful about the future of stem-cell-based therapies.

6. Conclusions

In recent years, regenerative medicine has become a promising treatment option for various diseases. Due to their therapeutic potential, including the inhibition of inflammation or apoptosis, cell recruitment, stimulation of angiogenesis, and differentiation, stem cells can been seen as good candidates for regenerative medicine. In the last 50 years, more than 40,000 research papers have focused on stem-cell-based therapies. In this review study, we present a general overview of the translation of stem cell therapy from scientific ideas to clinical applications. Multiple mechanisms causing disease could be reversed by stem cells, due to their tremendous therapeutic potential. However, preclinical studies including in vitro and in vivo experiments are necessary to evaluate the potential of stem-cell-based treatments. Through preclinical research, it is possible to present scientific evidence and optimal treatment options for subsequent clinical studies. Before starting a clinical trial based on preclinical data, the application must be approved by a relevant regulatory administration, such as the FDA, EMA, or another organization. If the application is for the use of a new drug (including stem cells) which has never been tested before, the submission of an IND is required for FDA approval. Approximately 50% of clinical trials using stem cells take 2 to 5 years to complete. To minimize possible side effects, every new stem cell product should be approved for clinical marketing only after completing Phase I–IV clinical trials successfully. Interestingly, the number of stem-cell-based companies aimed at introducing clinical applications has rapidly increased in recent years. Therefore, it may be possible to find stem-cell-based products on the clinical market in the near future. As described in this paper, there are several steps that should be carried out on the path from the laboratory to the clinical setting. To develop new stem-cell-based medicine for the clinical market, researchers should follow the guidelines suggested by the relevant authorities. Through these well-controlled development processes, researchers can achieve safe and effective stem-cell-based therapies, thus brings their research ideas into the clinical field.

Author Contributions

All authors have read and agreed to the published version of the manuscript.

This review funded by National Institutes of Health grant: R01HD087417-01A1, R01HD094378-01, R01HD094380-01, R01HD100367-01, R01HD100563, R01HD100563.

Conflicts of Interest

The author has no conflicts of interest to declare.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Stem cells: what they are and what they do.

Stem cells offer promise for new medical treatments. Learn about stem cell types, current and possible uses, and the state of research and practice.

You've heard about stem cells in the news, and perhaps you've wondered if they might help you or a loved one with a serious disease. Here are some answers to frequently asked questions about stem cells.

What are stem cells?

Stem cells as the body's master cells

Stem cells: The body's master cells

Stem cells are the body's master cells. All other cells arise from stem cells, including blood cells, nerve cells and other cells.

Stem cells are a special type of cells that have two important properties. They are able to make more cells like themselves. That is, they self-renew. And they can become other cells that do different things in a process known as differentiation. Stem cells are found in almost all tissues of the body. And they are needed for the maintenance of tissue as well as for repair after injury.

Depending on where the stem cells are, they can develop into different tissues. For example, hematopoietic stem cells reside in the bone marrow and can produce all the cells that function in the blood. Stem cells also can become brain cells, heart muscle cells, bone cells or other cell types.

There are various types of stem cells. Embryonic stem cells are the most versatile since they can develop into all the cells of the developing fetus. The majority of stem cells in the body have fewer abilities to give rise to cells and may only help maintain and repair the tissues and organs in which they reside.

No other cell in the body has the natural ability to generate new cell types.

Why is there such an interest in stem cells?

Researchers are studying stem cells to see if they can help to:

  • Increase understanding of how diseases occur. By watching stem cells mature into cells in bones, heart muscle, nerves, and other organs and tissue, researchers may better understand how diseases and conditions develop.

Generate healthy cells to replace cells affected by disease (regenerative medicine). Stem cells can be guided into becoming specific cells that can be used in people to regenerate and repair tissues that have been damaged or affected by disease.

People who might benefit from stem cell therapies include those with leukemia, Hodgkin disease, non-Hodgkin lymphoma and some solid tumor cancers. Stem cell therapies also might benefit people who have aplastic anemia, immunodeficiencies and inherited conditions of metabolism.

Stem cells are being studied to treat type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, heart failure, osteoarthritis and other conditions.

Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine.

Test new drugs for safety and effectiveness. Before giving drugs in development to people, researchers can use some types of stem cells to test the drugs for safety and quality. This type of testing may help assess drugs in development for toxicity to the heart.

New areas of study include the effectiveness of using human stem cells that have been programmed into tissue-specific cells to test new drugs. For the testing of new drugs to be accurate, the cells must be programmed to acquire properties of the type of cells targeted by the drug. Techniques to program cells into specific cells are under study.

Where do stem cells come from?

There are several sources of stem cells:

Embryonic stem cells. These stem cells come from embryos that are 3 to 5 days old. At this stage, an embryo is called a blastocyst and has about 150 cells.

These are pluripotent (ploo-RIP-uh-tunt) stem cells, meaning they can divide into more stem cells or can become any type of cell in the body. This allows embryonic stem cells to be used to regenerate or repair diseased tissue and organs.

  • Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow or fat. Compared with embryonic stem cells, adult stem cells have a more limited ability to give rise to various cells of the body.

Adult cells altered to have properties of embryonic stem cells. Scientists have transformed regular adult cells into stem cells using genetic reprogramming. By altering the genes in the adult cells, researchers can make the cells act similarly to embryonic stem cells. These cells are called induced pluripotent stem cells (iPSCs).

This new technique may allow use of reprogrammed cells instead of embryonic stem cells and prevent immune system rejection of the new stem cells. However, scientists don't yet know whether using altered adult cells will cause adverse effects in humans.

Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells had better heart function and survival time.

Perinatal stem cells. Researchers have discovered stem cells in amniotic fluid as well as umbilical cord blood. These stem cells can change into specialized cells.

Amniotic fluid fills the sac that surrounds and protects a developing fetus in the uterus. Researchers have identified stem cells in samples of amniotic fluid drawn from pregnant women for testing or treatment — a procedure called amniocentesis.

Why is there controversy about using embryonic stem cells?

The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research and include recommendations for the donation of embryonic stem cells. Also, the guidelines state that embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.

Where do these embryos come from?

The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in women's uteruses. The stem cells are donated with informed consent from donors. The stem cells can live and grow in special solutions in test tubes or petri dishes in laboratories.

Why can't researchers use adult stem cells instead?

Progress in cell reprogramming and the formation of iPSCs has greatly enhanced research in this field. However, reprogramming is an inefficient process. When possible, iPSCs are used instead of embryonic stem cells since this avoids the ethical issues about use of embryonic stem cells that may be morally objectionable for some people.

Although research into adult stem cells is promising, adult stem cells may not be as versatile and durable as are embryonic stem cells. Adult stem cells may not be able to be manipulated to produce all cell types, which limits how adult stem cells can be used to treat diseases.

Adult stem cells are also more likely to contain irregularities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, researchers have found that adult stem cells are more adaptable than was first thought.

What are stem cell lines, and why do researchers want to use them?

A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don't become specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.

What is stem cell therapy (regenerative medicine), and how does it work?

Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next chapter in organ transplantation and uses cells instead of donor organs, which are limited in supply.

Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells.

The specialized cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the heart muscle. The healthy transplanted heart muscle cells could then contribute to repairing the injured heart muscle.

Researchers have already shown that adult bone marrow cells guided to become heart-like cells can repair heart tissue in people, and more research is ongoing.

Have stem cells already been used to treat diseases?

Yes. Doctors have performed stem cell transplants, also known as bone marrow transplants, for many decades. In hematopoietic stem cell transplants, stem cells replace cells damaged by chemotherapy or disease or serve as a way for the donor's immune system to fight some types of cancer and blood-related diseases. Leukemia, lymphoma, neuroblastoma and multiple myeloma often are treated this way. These transplants use adult stem cells or umbilical cord blood.

Researchers are testing adult stem cells to treat other conditions, including some degenerative diseases such as heart failure.

What are the potential problems with using embryonic stem cells in humans?

For embryonic stem cells to be useful, researchers must be certain that the stem cells will differentiate into the specific cell types desired.

Researchers have discovered ways to direct stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. Research is ongoing in this area.

Embryonic stem cells also can grow irregularly or specialize in different cell types spontaneously. Researchers are studying how to control the growth and development of embryonic stem cells.

Embryonic stem cells also might trigger an immune response in which the recipient's body attacks the stem cells as foreign invaders, or the stem cells might simply fail to function as expected, with unknown consequences. Researchers continue to study how to avoid these possible complications.

What is therapeutic cloning, and what benefits might it offer?

Therapeutic cloning, also called somatic cell nuclear transfer, is a way to create versatile stem cells independent of fertilized eggs. In this technique, the nucleus is removed from an unfertilized egg. This nucleus contains the genetic material. The nucleus also is removed from the cell of a donor.

This donor nucleus is then injected into the egg, replacing the nucleus that was removed, in a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This process creates a line of stem cells that is genetically identical to the donor's cells — in essence, a clone.

Some researchers believe that stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because cloned cells are less likely to be rejected once transplanted back into the donor. And it may allow researchers to see exactly how a disease develops.

Has therapeutic cloning in people been successful?

No. Researchers haven't been able to successfully perform therapeutic cloning with humans despite success in a number of other species.

Researchers continue to study the potential of therapeutic cloning in people.

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  • Stem cell basics. National Institutes of Health. https://stemcells.nih.gov/info/basics/stc-basics/#stc-I. Accessed March 21, 2024.
  • Lovell-Badge R, et al. ISSCR guidelines for stem cell research and clinical translation: The 2021 update. Stem Cell Reports. 2021; doi:10.1016/j.stemcr.2021.05.012.
  • AskMayoExpert. Hematopoietic stem cell transplant. Mayo Clinic; 2024.
  • Stem cell transplants in cancer treatment. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant/. Accessed March 21, 2024.
  • Townsend CM Jr, et al. Regenerative medicine. In: Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 21st ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed March 21, 2024.
  • Kumar D, et al. Stem cell based preclinical drug development and toxicity prediction. Current Pharmaceutical Design. 2021; doi:10.2174/1381612826666201019104712.
  • NIH guidelines for human stem cell research. National Institutes of Health. https://stemcells.nih.gov/research-policy/guidelines-for-human-stem-cell-research. Accessed March 21, 2024.
  • De la Torre P, et al. Current status and future prospects of perinatal stem cells. Genes. 2020; doi:10.3390/genes12010006.
  • Yen Ling Wang A. Human induced pluripotent stem cell-derived exosomes as a new therapeutic strategy for various diseases. International Journal of Molecular Sciences. 2021; doi:10.3390/ijms22041769.
  • Alessandrini M, et al. Stem cell therapy for neurological disorders. South African Medical Journal. 2019; doi:10.7196/SAMJ.2019.v109i8b.14009.
  • Goldenberg D, et al. Regenerative engineering: Current applications and future perspectives. Frontiers in Surgery. 2021; doi:10.3389/fsurg.2021.731031.
  • Brown MA, et al. Update on stem cell technologies in congenital heart disease. Journal of Cardiac Surgery. 2020; doi:10.1111/jocs.14312.
  • Li M, et al. Brachyury engineers cardiac repair competent stem cells. Stem Cells Translational Medicine. 2021; doi:10.1002/sctm.20-0193.
  • Augustine R, et al. Stem cell-based approaches in cardiac tissue engineering: Controlling the microenvironment for autologous cells. Biomedical Pharmacotherapy. 2021; doi:10.1016/j.biopha.2021.111425.
  • Cloning fact sheet. National Human Genome Research Institute. https://www.genome.gov/about-genomics/fact-sheets/Cloning-Fact-Sheet. Accessed March 21, 2024.
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NIH Stem Cell Information

Stem cell basics, i. introduction: what are stem cells, and why are they important.

Stem cells have the remarkable potential to renew themselves. They can develop into many different cell types in the body during early life and growth. Researchers study many different types of stem cells. There are several main categories: the “pluripotent” stem cells (embryonic stem cells and induced pluripotent stem cells) and nonembryonic or somatic stem cells (commonly called “adult” stem cells). Pluripotent stem cells have the ability to differentiate into all of the cells of the adult body. Adult stem cells are found in a tissue or organ and can differentiate to yield the specialized cell types of that tissue or organ.

Pluripotent stem cells

Early mammalian embryos at the blastocyst stage contain two types of cells – cells of the inner cell mass, and cells of the trophectoderm. The trophectodermal cells contribute to the placenta. The inner cell mass will ultimately develop into the specialized cell types, tissues, and organs of the entire body of the organism. Previous work with mouse embryos led to the development of a method in 1998 to derive stem cells from the inner cell mass of preimplantation human embryos and to grow human embryonic stem cells (hESCs) in the laboratory. In 2006, researchers identified conditions that would allow some mature human adult cells to be reprogrammed into an embryonic stem cell-like state. Those reprogramed stem cells are called induced pluripotent stem cells (iPSCs).

Adult stem cells

Throughout the life of the organism, populations of adult stem cells serve as an internal repair system that generates replacements for cells that are lost through normal wear and tear, injury, or disease. Adult stem cells have been identified in many organs and tissues and are generally associated with specific anatomical locations. These stem cells may remain quiescent (non-dividing) for long periods of time until they are activated by a normal need for more cells to maintain and repair tissues.

II. What are the unique properties of all stem cells?

Stem cells have unique abilities to self-renew and to recreate functional tissues.

Stem cells have the ability to self-renew.

Unlike muscle cells, blood cells, or nerve cells—which do not normally replicate— stem cells may replicate many times. When a stem cell divides, the resulting two daughter cells may be: 1) both stem cells, 2) a stem cell and a more differentiated cell, or 3) both more differentiated cells. What controls the balance between these types of divisions to maintain stem cells at an appropriate level within a given tissue is not yet well known.

Discovering the mechanism behind self-renewal may make it possible to understand how cell fate (stem vs. non-stem) is regulated during normal embryonic development and post-natally, or misregulated as during aging, or even in the development of cancer. Such information may also enable scientists to grow stem cells more efficiently in the laboratory. The specific factors and conditions that allow pluripotent stem cells to remain undifferentiated are of great interest to scientists. It has taken many years of trial and error to learn to derive and maintain pluripotent stem cells in the laboratory without the cells spontaneously differentiating into specific cell types.

Stem cells have the ability to recreate functional tissues.

Pluripotent stem cells are undifferentiated; they do not have any tissue-specific characteristics (such as morphology or gene expression pattern) that allow them to perform specialized functions. Yet they can give rise to all of the differentiated cells in the body, such as heart muscle cells, blood cells, and nerve cells. On the other hand, adult stem cells differentiate to yield the specialized cell types of the tissue or organ in which they reside, and may have defining morphological features and patterns of gene expression reflective of that tissue.

Different types of stems cells have varying degrees of potency; that is, the number of different cell types that they can form. While differentiating, the cell usually goes through several stages, becoming more specialized at each step. Scientists are beginning to understand the signals that trigger each step of the differentiation process. Signals for cell differentiation include factors secreted by other cells, physical contact with neighboring cells, and certain molecules in the microenvironment.

III. How do you culture stem cells in the laboratory?

How are stem cells grown in the laboratory?

Growing cells in the laboratory is known as “cell culture.” Stem cells can proliferate in laboratory environments in a culture dish that contains a nutrient broth known as culture medium (which is optimized for growing different types of stem cells). Most stem cells attach, divide, and spread over the surface of the dish.

The culture dish becomes crowded as the cells divide, so they need to be re-plated in the process of subculturing, which is repeated periodically many times over many months. Each cycle of subculturing is referred to as a “passage.” The original cells can yield millions of stem cells. At any stage in the process, batches of cells can be frozen and shipped to other laboratories for further culture and experimentation.

How do you “reprogram” regular cells to make iPSCs?

Differentiated cells, such as skin cells, can be reprogrammed back into a pluripotent state. Reprogramming is achieved over several weeks by forced expression of genes that are known to be master regulators of pluripotency. At the end of this process, these master regulators will remodel the expression of an entire network of genes. Features of differentiated cells will be replaced by those associated with the pluripotent state, essentially reversing the developmental process.

How are stem cells stimulated to differentiate?

As long as the pluripotent stem cells are grown in culture under appropriate conditions, they can remain undifferentiated. To generate cultures of specific types of differentiated cells, scientists may change the chemical composition of the culture medium, alter the surface of the culture dish, or modify the cells by forcing the expression of specific genes. Through years of experimentation, scientists have established some basic protocols, or “recipes,” for the differentiation of pluripotent stem cells into some specific cell types.

stem cell research studies

What laboratory tests are used to identify stem cells?

At various points during the process of generating stem cell lines, scientists test the cells to see whether they exhibit the fundamental properties that make them stem cells. These tests may include:

  • Verifying expression of multiple genes that have been shown to be important for the function of stem cells.
  • Checking the rate of proliferation.
  • Checking the integrity of the genome by examining the chromosomes of selected cells.
  • Demonstrating the differentiation potential of the cells by removing signals that maintain the cells in their undifferentiated state, which will cause pluripotent stem cells to spontaneously differentiate, or by adding signals that induce adult stem cells to differentiate into appropriate cell phenotypes.

IV. How are stem cells used in biomedical research and therapies?

Given their unique regenerative abilities, there are many ways in which human stem cells are being used in biomedical research and therapeutics development.

Understanding the biology of disease and testing drugs

Scientists can use stem cells to learn about human biology and for the development of therapeutics. A better understanding of the genetic and molecular signals that regulate cell division, specialization, and differentiation in stem cells can yield information about how diseases arise and suggest new strategies for therapy. Scientists can use iPSCs made from a patient and differentiate those iPSCs to create “organoids” (small models of organs) or tissue chips for studying diseased cells and testing drugs, with personalized results.

Cell-based therapies

An important potential application is the generation of cells and tissues for cell-based therapies, also called tissue engineering. The current need for transplantable tissues and organs far outweighs the available supply. Stem cells offer the possibility of a renewable source. There is typically a very small number of adult stem cells in each tissue, and once removed from the body, their capacity to divide is limited, making generation of large quantities of adult stem cells for therapies difficult. In contrast, pluripotent stem cells are less limited by starting material and renewal potential.

To realize the promise of stem cell therapies in diseases, scientists must be able to manipulate stem cells so that they possess the necessary characteristics for successful differentiation, transplantation, and engraftment. Scientists must also develop procedures for the administration of stem cell populations, along with the induction of vascularization (supplying blood vessels), for the regeneration and repair of three-dimensional solid tissues.

To be useful for transplant purposes, stem cells must be reproducibly made to:

  • Proliferate extensively and generate sufficient quantities of cells for replacing lost or damaged tissues.
  • Differentiate into the desired cell type(s).
  • Survive in the recipient after transplant.
  • Integrate into the surrounding tissue after transplant.
  • Avoid rejection by the recipient's immune system.
  • Function appropriately for the duration of the recipient's life.

While stem cells offer exciting promise for future therapies, significant technical hurdles remain that will likely only be overcome through years of intensive research.

Note: Currently, the only stem cell-based products that are approved for use by the U.S. Food and Drug Administration (FDA) for use in the United States consist of blood-forming stem cells (hematopoietic progenitor cells) derived from cord blood. These products are approved for limited use in patients with disorders that affect the body system that is involved in the production of blood (called the “hematopoietic” system). These FDA-approved stem cell products are listed on the FDA website . Bone marrow also is used for these treatments but is generally not regulated by the FDA for this use. The FDA recommends that people considering stem cell treatments make sure that the treatment is either FDA-approved or being studied under an Investigational New Drug Application (IND), which is a clinical investigation plan submitted and allowed to proceed by the FDA.

V. How does NIH support stem cell research?

NIH conducts and funds basic, translational, and clinical research with a range of different types of stem cells. NIH-supported research with human pluripotent stem cells is conducted under the terms of the NIH Guidelines for Human Stem Cell Research . NIH awards are listed in various categories of stem cell research through the NIH Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC) . NIH also supports a major adult stem cell and iPSC research initiative through the Regenerative Medicine Innovation Project .

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A Fasting-Refeeding Paradigm Rejuvenates Old Stem Cells

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Feeding after fasting could provide an answer to combatting the effects of old age on the blood stem cells that  often lead to life-threatening blood cancer, greater susceptibility to infections, and can even contribute to degenerative disorders in the elderly, according to a study in mice led by researchers in the Columbia Stem Cell Initiative .

Emmanuelle Passegué

As with all stem cells, the body’s blood-forming stem s cells become less effective with age or fail to work at all. Blood-forming stem cells not only create red blood cells, but also all the cells of our immune system, and their decline leads to a whole host of problems for the aging body.

The new study indicates that there is a way to turn back the clock to a younger time and rejuvenate these blood stem cells, restoring their ability to regenerate and fight off age-related diseases.

Led by Emmanuelle Passegué , director of the Columbia Stem Cell Initiative, the researchers found that a cellular recycling process known as autophagy must be activated in old blood stem cells for the cells to survive and function in aged animals.

They identify chronic inflammation in the bone marrow microenvironment as the stressor that drives both metabolic impairment and compensatory autophagy activation in old blood stem cells. They further demonstrate that autophagy is an essential survival response in the context of inflammatory signaling and map out the molecular circuitry involved in the autophagy activation process in this context.

And though autophagy helps old blood stem cells survive the stresses of aging, these old stem cells do not have the same capacity as young stem cells to create the blood’s full repertoire of cells. That youthful capacity can be nearly restored, the researchers discovered, with a 24-hour fasting period followed by refeeding.

The findings are important, says Passegué, whose 2017 Nature paper was the first to identify autophagy in aging blood stem cells, because they help scientists better understand what causes stem cell aging and they identify a way to re-awaken the blood-forming function of aged stem cells, which could prevent harmful age-related conditions in the elderly.

The new study shows that chronic inflammation impairs blood-forming stem cells in old mice, but cells that respond with autophagy can adapt and protect themselves. Feeding after fasting, which triggers transient autophagy, boosts the stem cells' regenerative potential. Figure by Melissa Proven.

Rejuvenation requires resumption of eating

Although previous studies had found that fasting alone can induce autophagy, the new research shows that the resumption of feeding is necessary to fully rejuvenate blood stem cell function. These rejuvenated old stem cells were  reset in their metabolism and  were almost as proficient as young stem cells at regenerating the blood system upon transplantation and creating new red blood cells, white blood cells, and platelets, which are crucial for preventing anemia and infections.

“Even though the same fasting and refeeding process would be impractical to use directly on people because the equivalent fasting period will be much too long, these findings in mice help us identify the pathways that mimic the effect of fasting and refeeding to rejuvenate old blood stem cells,” Passegué says.

The findings of the new study also provide more evidence to support the idea that fasting can improve cancer therapy by helping blood stem cells enhance a weakened immune system.

Understanding the biological causes of aging stem cells will also provide a better understanding of tissue repair and regeneration, stem cell therapy, and metabolic diseases like coronary artery disease, diabetes, and stroke.

“It doesn’t mean that we will begin living to 200,” says Passegué “But we are in a new frontier, and I think over the next decade we should be able to develop therapeutics that could slow down or stop stem cell deterioration so we can lead healthier lives as we grow old.”

More information

Emmanuelle Passegué, PhD, is also the Alumni Professor of Genetics & Development at Columbia University Vagelos College of Physicians and Surgeons.

Co-first authors Paul V. Dellorusso (Columbia) and Melissa A. Proven (Columbia) contributed equally to this work.

Other authors: Fernando J. Calero-Nieto (Cambridge University), Xiaonan Wang (Cambridge), Carl A. Mitchell (Columbia), Felix Hartmann (Stanford University), Meelad Amouzgar (Stanford), Patricia Favaro (Stanford), Andrew DeVilbiss (University of Texas Southwestern Medical Center), James W. Swann (Columbia), Theodore T. Ho (University of California San Francisco), Zhiyu Zhao (UT Southwestern), Sean C. Bendall (Stanford), Sean Morrison (UT Southwestern), and Berthold Göttgens (Cambridge).

The research was supported through grants from the NIH (F31HL151140, TL1DK136048, F31HL160207, R01AG073599, R35HL135763, and P30CA013696), the European Molecular Biology Organization (ALTF-2021-196), Damon Runyon Cancer Research Foundation (DRG-2493-23 postdoctoral fellowships), predoctoral fellowships from the American Heart Association and Hillblom Center for the Biology of Aging predoctoral fellowships, Wellcome (grant 206328/Z/17/Z and core funding to the Cambridge Stem Cell Institute), Cancer Research UK (grant C1163/A21762), Glenn Foundation Research Award, Leukemia & Lymphoma Society Scholar Award, and Milky Way Research Foundation Award (CU21-0225).

Emmanuelle Passegué is a member of the Cell Stem Cell advisory board.

Single-cell sequencing advances in research on mesenchymal stem/stromal cells

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  • Published: 14 May 2024

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stem cell research studies

  • Qingxi Long   ORCID: orcid.org/0000-0002-0795-403X 1 ,
  • Pingshu Zhang 1 , 2 ,
  • Ya Ou 1 , 2 ,
  • Qi Yan 1 &
  • Xiaodong Yuan   ORCID: orcid.org/0000-0002-2612-2781 1 , 2  

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Mesenchymal stem/stromal cells (MSCs), originating from the mesoderm, represent a multifunctional stem cell population capable of differentiating into diverse cell types and exhibiting a wide range of biological functions. Despite more than half a century of research, MSCs continue to be among the most extensively studied cell types in clinical research projects globally. However, their significant heterogeneity and phenotypic instability have significantly hindered their exploration and application. Single-cell sequencing technology emerges as a powerful tool to address these challenges, offering precise dissection of complex cellular samples. It uncovers the genetic structure and gene expression status of individual contained cells on a massive scale and reveals the heterogeneity among these cells. It links the molecular characteristics of MSCs with their clinical applications, contributing to the advancement of regenerative medicine. With the development and cost reduction of single-cell analysis techniques, sequencing technology is now widely applied in fundamental research and clinical trials. This study aimed to review the application of single-cell sequencing in MSC research and assess its prospects.

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This study was supported by grants from Performance-Based Subsidy for the Key Laboratory of Neurobiological Functioning in Hebei Province (20567622H), Medical Science Research Program of Hebei Province (20210526), and Hebei Province Medical Technology Monitoring Program (GZ2023049).

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Qingxi Long outlined the review, designed the figures, collected the literature, and wrote the manuscript. Xiaodong Yuan, Pingshu Zhang and Ya Ou provided the necessary financial support. Wen Li and Qi Yan coordinated the revision and manuscript preparation. We analyzed the literature. All authors read and approved the final manuscript.

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ScienceDaily

Stem cells provide new insight into genetic pathway of childhood cancer

Scientists have discovered a new insight into the genetic pathway of childhood cancer, offering new hope for tailored treatments.

Researchers from the University of Sheffield have created a stem cell model designed to investigate the origins of neuroblastoma, a cancer primarily affecting babies and young children.

Neuroblastoma is the most common childhood tumour occurring outside the brain, affecting the lives of approximately 600 children in the European Union and the United Kingdom each year.

Until now, studying genetic changes and their role in neuroblastoma initiation has been challenging due to the lack of suitable laboratory methods. A new model developed by researchers at the University of Sheffield, in collaboration with the St Anna Children's Cancer Research Institute in Vienna, replicates the emergence of early neuroblastoma cancer-like cells, giving an insight into the genetic pathway of the disease.

The research, published in Nature Communications , sheds light on the intricate genetic pathways which initiate neuroblastoma. The international research team found that specific mutations in chromosomes 17 and 1, combined with overactivation of the MYCN gene, play a pivotal role in the development of aggressive neuroblastoma tumours.

Childhood cancer is often diagnosed and detected late, leaving researchers with very little idea of the conditions that led to tumour initiation, which occurs very early during fetal development. In order to understand tumour initiation, models which recreate the conditions that lead to the appearance of a tumour are vital.

The formation of neuroblastoma usually starts in the womb when a group of normal embryonic cells called 'trunk neural crest (NC)' become mutated and cancerous.

In an interdisciplinary effort spearheaded by stem cell expert Dr Ingrid Saldana from the University of Sheffield's School of Biosciences and computational biologist Dr Luis Montano from the St Anna Children's Cancer Research Institute in Vienna, the new study found a way in which to use human stem cells to grow trunk NC cells in a petri dish.

These cells carried genetic changes often seen in aggressive neuroblastoma tumours. Using genomics analysis and advanced imaging techniques, the researchers found that the altered cells started behaving like cancer cells and looked very similar to the neuroblastoma cells found in sick children.

The findings offer new hope for the creation of tailored treatments that specifically target the cancer while minimising the adverse effects experienced by patients from existing therapies.

Dr Anestis Tsakiridis, from the University of Sheffield's School of Biosciences and lead author of the study, said: "Our stem cell-based model mimics the early stages of aggressive neuroblastoma formation, providing invaluable insights into the genetic drivers of this devastating childhood cancer. By recreating the conditions that lead to tumour initiation, we will be able to understand better the mechanisms underpinning this process and thus design improved treatment strategies in the longer term.

"This is very important as survival rates for children with aggressive neuroblastoma are poor and most survivors suffer from side effects linked to the harsh treatments currently used, which include potential hearing, fertility and lung problems."

Dr. Florian Halbritter, from St. Anna Children's Cancer Research Institute and second lead author of the study, said: "This was an impressive team effort, breaching geographic and disciplinary boundaries to enable new discoveries in childhood cancer research."

This research supports the University of Sheffield's cancer research strategy. Through the strategy, the University aims to prevent cancer-related deaths by undertaking high quality research, leading to more effective treatments, as well as methods to better prevent and detect cancer and improve quality of life.

  • Lung Cancer
  • Breast Cancer
  • Skin Cancer
  • Brain Tumor
  • Prostate Cancer
  • Colon Cancer
  • Stem cell treatments
  • Cervical cancer
  • Colorectal cancer
  • Breast cancer
  • Prostate cancer

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Materials provided by University of Sheffield . Note: Content may be edited for style and length.

Journal Reference :

  • Ingrid M. Saldana-Guerrero, Luis F. Montano-Gutierrez, Katy Boswell, Christoph Hafemeister, Evon Poon, Lisa E. Shaw, Dylan Stavish, Rebecca A. Lea, Sara Wernig-Zorc, Eva Bozsaky, Irfete S. Fetahu, Peter Zoescher, Ulrike Pötschger, Marie Bernkopf, Andrea Wenninger-Weinzierl, Caterina Sturtzel, Celine Souilhol, Sophia Tarelli, Mohamed R. Shoeb, Polyxeni Bozatzi, Magdalena Rados, Maria Guarini, Michelle C. Buri, Wolfgang Weninger, Eva M. Putz, Miller Huang, Ruth Ladenstein, Peter W. Andrews, Ivana Barbaric, George D. Cresswell, Helen E. Bryant, Martin Distel, Louis Chesler, Sabine Taschner-Mandl, Matthias Farlik, Anestis Tsakiridis, Florian Halbritter. A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations . Nature Communications , 2024; 15 (1) DOI: 10.1038/s41467-024-47945-7

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Enhanced anti-tumor efficacy with multi-transgene armed mesenchymal stem cells for treating peritoneal carcinomatosis

  • Yoon Khei Ho   ORCID: orcid.org/0000-0001-5696-1407 1 , 2 , 3 , 4 ,
  • Jun Yung Woo 1 , 2 ,
  • Kin Man Loke 1 , 2 ,
  • Lih-Wen Deng 1 , 2 &
  • Heng-Phon Too 1 , 2  

Journal of Translational Medicine volume  22 , Article number:  463 ( 2024 ) Cite this article

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Mesenchymal stem cells (MSCs) have garnered significant interest for their tumor-tropic property, making them potential therapeutic delivery vehicles for cancer treatment. We have previously shown the significant anti-tumour activity in mice preclinical models and companion animals with naturally occurring cancers using non-virally engineered MSCs with a therapeutic transgene encoding cytosine deaminase and uracil phosphoribosyl transferase (CDUPRT) and green fluorescent protein (GFP). Clinical studies have shown improved response rate with combinatorial treatment of 5-fluorouracil and Interferon-beta (IFNb) in peritoneal carcinomatosis (PC). However, high systemic toxicities have limited the clinical use of such a regime.

In this study, we evaluated the feasibility of intraperitoneal administration of non-virally engineered MSCs to co-deliver CDUPRT/5-Flucytosine prodrug system and IFNb to potentially enhance the cGAS-STING signalling axis. Here, MSCs were engineered to express CDUPRT or CDUPRT-IFNb. Expression of CDUPRT and IFNb was confirmed by flow cytometry and ELISA, respectively. The anti-cancer efficacy of the engineered MSCs was evaluated in both in vitro and in vivo model. ES2, HT-29 and Colo-205 were cocultured with engineered MSCs at various ratio. The cell viability with or without 5-flucytosine was measured with MTS assay. To further compare the anti-cancer efficacy of the engineered MSCs, peritoneal carcinomatosis mouse model was established by intraperitoneal injection of luciferase expressing ES2 stable cells. The tumour burden was measured through bioluminescence tracking.

Firstly, there was no changes in phenotypes of MSCs despite high expression of the transgene encoding CDUPRT and IFNb (CDUPRT-IFNb). Transwell migration assays and in-vivo tracking suggested the co-expression of multiple transgenes did not impact migratory capability of the MSCs. The superiority of CDUPRT-IFNb over CDUPRT expressing MSCs was demonstrated in ES2, HT-29 and Colo-205 in-vitro . Similar observations were observed in an intraperitoneal ES2 ovarian cancer xenograft model. The growth of tumor mass was inhibited by ~ 90% and 46% in the mice treated with MSCs expressing CDUPRT-IFNb or CDUPRT, respectively.

Conclusions

Taken together, these results established the effectiveness of MSCs co-expressing CDUPRT and IFNb in controlling and targeting PC growth. This study lay the foundation for the development of clinical trial using multigene-armed MSCs for PC.

Peritoneal carcinomatosis (PC) is represented by advanced metastases of digestive-tract and gynaecological cancer cells to the peritoneal lining, resulting in malignancy in the peritoneal cavity. It is considered a terminal disease due to high recurrence and poor prognosis with overall survival (OS) of 3–6 months. Patients may receive vigorous combinatorial treatment consisting of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), which has been reported to improve OS to 15–70 months [ 1 , 2 , 3 ]. Nonetheless, even after treatment, a significant number of patients develop recurrence, resulting in an overall 5 year survival ranging from 11 to 19% in PC patients [ 4 , 5 , 6 , 7 ]. Unfortunately, CRS and HIPEC involve major procedures with considerable mortality and morbidity [ 8 ]. Benefits of the iterative procedures may be limited with patients already compromised by late-stage cancer [ 5 , 9 ]. Despite the lack of survival benefits, systemic chemotherapy is the standard treatment for recurrences after CRS and HIPEC [ 4 , 10 ]. Intraperitoneal regional treatments to achieve continuous high local concentrations of multimodal cytotoxic agents is a critical factor to improve clinical outcome for patients with recurring PC.

The rationale of intraperitoneal administration is to maximize the chemotherapeutic dosage delivered directly into the peritoneal tumour nodules while minimizing systemic toxicity [ 11 , 12 ]. For the same intent, stem cells have been explored as cellular vehicles for delivery of therapeutic agents in targeting peritoneal cancers [ 13 , 14 , 15 , 16 ]. Although yet to be fully elucidated, MSCs have been widely accepted as a promising vehicle due to their inert immunogenicity and natural tumour-trophic properties [ 17 , 18 , 19 ]. Furthermore, engineered MSCs could potentially serve as biofactories to provide continuous therapeutics to the tumour milieus. We and others have reported prolonged and sustained expression of therapeutic genes in engineered stem cells for more than 7 days [ 20 , 21 ]. Proof-of-concept and acceptable levels of safety have already been reported in multiple phase I trials for peritoneal cancer treatment where MSCs were engineered to deliver various therapeutic agents including enzyme for prodrug conversion [ 22 ], interferon beta (IFNb) [ 23 ], and oncolytic virus (NCT02068794).

Prodrug systems offer a safer option compared to traditional chemotherapy because the non-toxic prodrugs are converted into active drugs locally, avoiding systemic toxicities [ 24 , 25 ]. We developed a highly efficient cationic polymer-based transfection method to engineer MSCs to express a therapeutic transgene—cytosine deaminase uracil phosphoribosyl-transferase fused to a green fluorescent protein (GFP) reporter. These engineered cells showed strong anti-cancer potency in in-vitro, in subcutaneous laboratory models [ 20 , 26 ] and in companion animals with naturally occurring cancers [ 27 ]. The non-toxic prodrug (5-flucytosine, 5FC) is converted by CD into 5-flurouracil (5FU) that disrupts the nucleotide biosynthesis, leading to apoptosis [ 28 , 29 ]. Interestingly, emerging evidence suggests the full therapeutic potential of 5FU is through the involvement of the cGAS-STING pathway. This signalling cascade reaction elicits the production of type I IFNs from cancer cells, leading to the activation of innate immunity and long-lasting anti-tumour effects [ 30 , 31 ]. Lee et al. has shown that the cGAS-STING pathway plays a critical role in converting immunologically “cold” peritoneal tumours to immunologically favourable phenotypes in a type I IFN-dependent manner, resulting in the eradication of tumour and ascites [ 32 ].

Recent findings showed that STING signalling is habitually defective in ovarian cancer [ 33 , 34 ], colorectal cancer [ 35 , 36 ] and gastric cancer [ 37 ] and is often associated with poor prognosis. Exogeneous type I IFN treatment may potentially be a way to overcome STING deficiency and enhance the therapeutic efficacy of 5FU. Apart from the critical role in modulating immune responses [ 38 ], Type I IFN is also known to have a direct effect on cancer cells [ 39 ] and can potentiate 5FU cytotoxicity by inducing S-phase accumulation and apoptosis [ 40 , 41 , 42 , 43 ]. In clinical studies, recombinant IFNs in combination with 5FU have been shown to be effective in some [ 44 , 45 , 46 , 47 ], but not in others [ 48 , 49 ]. Significant challenges limiting the clinical benefits include the issues of systemic toxicities and short half-life of recombinant IFNb [ 41 , 50 ]. Thus, systemic treatment will unlikely attain therapeutically meaningful local concentrations necessary to synergise with 5FU effects. An interesting approach is the use of MSCs as an effective targeting vehicle to deliver a 5FU prodrug and IFNb to tumor sites, thereby increasing the local therapeutic concentrations [ 51 , 52 ]. In the present study, we showed that non-viral engineered MSCs co-expressing CD prodrug system and IFNb is a promising approach to treat PC.

Cell culture

Human adipose tissue-derived MSCs from a single donor (#100225) were purchased from Essent Biologics (Centennial, CO). The MSCs were cultured in complete culture media consisting of α-MEM supplemented with human platelet lysate (Mill Creek Life Sciences, USA). To maintain experimental consistency, only MSCs between passages 3–5 were used in this study. Cancer cell lines A549 (human lung adenocarcinoma; ATCC CCL-185) was maintained in DMEM supplemented with 10% FBS (HyClone), HT-29 (human colorectal adenocarcinoma; kindly provided by Johnny Ong Chin-Ann, National Cancer Centre Singapore) in McCoy’s 5A medium supplemented with 10% FBS, whereas Colo-205-LUC-GFP (human colon carcinoma; GeneCopoeia SCL-C05-HLG) and ES2-LUC-tdT (human ovarian clear cell carcinoma; kindly provided by Deng Lih Wen, National University of Singapore) were maintained in RPMI 1640 media supplemented with 10% FBS. All cell cultures were maintained in a humidified incubator at 37 °C in 5% CO 2 .

Construction of the plasmid

A multi-cistronic vector encoding CDUPRT-IFNb was cloned into an existing expression vector bearing CDUPRT as previously described [ 20 ]. All plasmids were purified using the E.Z.N.A Plasmid DNA Maxi Kit (Omega Bio-Tek).

Transfection and expression analysis

Transfection was carried out in 6-well plate format. Plasmid complex, at a total volume of 20 μL/cm 2 , consist of 250 ng/cm 2 DNA, 1.1 µL/cm 2 Polyethylenimine MAX (Polyscience; 1 mg/mL) and DPBS, was incubated at room temperature for 15 min. The plasmid complex was then added dropwise into MSCs (150000 cells/cm 2 in 6-well plates) supplemented with 500 ng/mL Lipofectamine ™ 2000 Transfection Reagent (ThermoFisher Scientific) and 0.5 μM Vorinostat (Histone deacetylase inhibitor; HDACi, BioVision) in complete medium. The culture media was replaced with fresh media at 24 h post-transfection. Then, cells were further incubated for 24 h before analysis. Cell images were taken with EVOS FL Cell Imaging System (Thermo Fisher Scientific) equipped with a GFP (Ex470/Em510) fluorescent light cube. For flow cytometric analyses, cells were washed by DPBS, trypsinized using TrypLE Express. Percentage of fluorescent positive cells was quantified by Attune NxT Flow Cytometer system (ThermoFisher Scientific), and the raw data was analysed using non-modified MSCs as the negative control at < 0.8%, using Invitrogen Attune NxT software (Version 3.1.2, ThermoFisher Scientific).

Trilineage differentiation

A trilineage differentiation assay was used to evaluate the trilineage differentiation potential of MSCs to give rise to chondrocytes, osteoblasts and adipocytes using a commercially available differentiation media (StemPro ™ Differentiation Kits, Thermo Fisher Scientific). For chondrogenic differential assay, cells were plated at a density of 10 6 cells/well in ultra-low attachment 96-wellplate and then induced using the chondrogenic differentiation media after 24 h. The differentiation media were replaced twice weekly. After 23 days, differentiation was assessed by Alcian Blue solution staining of sulfated proteoglycans. For osteogenic and adipogenic differential assays, cells were plated at a density of 100,000 cells/well in 24well-plates and replaced with corresponding differentiation media the next day. After 16 days, adipogenic differentiation was assessed by Oil Red O solution staining of oil droplets. For osteogenic differentiation, differentiation was assessed by Alizarin red S solution staining of calcium deposits at day 23 post induction. Images were taken at 4 × objective for chondrogenesis and 20 × objective for both osteogenesis and adipogenesis using a Nikon Eclipse Ts2-FL microscope (Nikon Instruments Inc., NY, USA).

Immunophenotyping

Flow cytometry analysis of the cells was performed using 4% formaldehyde fixed cells and stained according to the manufacturer’s protocol. Briefly, the cells were washed with DPBS and detached with TrypLE Express. Then the cells were fixed in 4% formaldehyde for 15 min at room temperature, washed twice with DPBS and resuspended at a concentration of 1 × 10 6 cells in 100 µL staining buffer. The cells were stained with antibodies to CD73 (APC, Invitrogen, clone AD2), CD90 (APC, Miltenyi Biotec, clone REA897), CD105 (APC, Invitrogen, clone SN6), CD14 (PE, Miltenyi Biotec, clone REA599), CD19 (PE, Miltenyi Biotech, clone REA675), CD34 (APC, Invitrogen, clone 4H11), CD45 (APC, Invitrogen, clone HI30), HLA-DR (PE, Miltenyi Biotec, clone REA805) and corresponding isotypic controls (PE and APC, Miltenyi Biotec, clone REA293; APC, Invitrogen, clone P3.6.2.8.1). The cells were incubated in the dark for 15 min, washed, resuspended in DPBS, and analysed immediately. The immunophenotyping analysis was performed using a CytoFLEX LX flow cytometer (Beckman Coulter). At least 10,000 events were acquired in each sample and analyzed using the Attune ™ NxT Software (Version 3.1.2, Thermo Fisher Scientific).

In-vitro studies

Coculture experiment.

500 cells/well for Colo-205-LUC-GFP, 2000 cells/well for HT29 and ES2-LUC-tdT were seeded in 96-well plates. Four hours later, CDUPRT_MSCs or CDUPRT-IFNb_MSCs were plated to the cancer cell culture at a ratio of 1 MSC to 1, 6, 12, 25, 50, 100, and 200 cancer cells. After overnight attachment of the cells, the medium was replaced with fresh cancer cell medium supplemented with or without 150 μg/mL 5FC (TCI Chemicals). Five days later, cell viability was measured by MTS assay with at least five biological replicates for each condition.

Mitochondrial membrane potential and apoptosis assay

CDUPRT_MSC or CDUPRT-IFNb_MSC were co-cultured with ES2 at a ratio of 1 MSC to 1 cancer cell. Two days after the addition of 150 μg/mL 5FC, all cells were harvested and stained with TMRE (biotium) or annexin-V (PE Annexin V Apoptosis Detection Kit with 7-AAD, Tonbo Biosciences) according to the manufacturer’s instructions. Percentage of fluorescent positive cells was quantified by Attune NxT Flow Cytometer system (ThermoFisher Scientific), and the raw data was analysed using Invitrogen Attune NxT software (Version 3.1.2, ThermoFisher Scientific).

Migration assay

Migration assay was performed using 24-transwell plates (Corning) with 8.0 µm pore size inserts (Corning). A total of 200,000 cancer cells were seeded in the lower chamber with complete medium. Four hours later, the complete medium was discarded and washed twice with DPBS and replaced with serum free medium. A total of 100,000 MSCs were seeded in the upper chamber with serum free medium. After 48 h, MSCs were fixed in 4% formaldehyde. Unmigrated MSCs were removed using a Q-tip and migrated MSCs that penetrated the porous membrane were stained with Hoechst 33342 (5 µg/mL), documented with a fluorescence microscope (EVOS M7000 Imaging System, Thermo Fisher Scientific) and quantified using EVOS Analysis software (Version 1.5.1479.304, Thermo Fisher Scientific).

In-vivo studies

Five to six-week-old female athymic nude (CrTac:NCr-Foxn1 nu ) mice (InVivos) were purchased and all animal experiments were carried out in accordance with relevant guidelines and regulations. General anesthesia in mice was performed by isoflurane inhalation. The research protocol was reviewed and approved by the National University of Singapore, Institutional Animal Care and Use Committee (IACUC; protocol number R18-1383).

In-vivo tumour tropism

To develop in-vivo model of tumour tropism, 1 × 10 6 ES2-LUC-tdT cells suspended in 100 µL of Plasma-Lyte were injected intraperitoneally into the lower right quadrant of the abdomen. All mice including the control mice without ES2-LUC-tdT were treated with MSCs overexpressing Renilla luciferase injected into the peritoneal cavity and monitored for 21 days. Tumour tropism of MSCs was monitored using an in vivo imaging system (IVIS ® Spectrum In Vivo Imaging System, PerkinElmer) after substrate injection (ViviRen ™ , Promega; 1 mg/kg per mouse). The images were analyzed using the Living Image software (PerkinElmer). All mice were euthanized at experimental endpoint.

In vivo cytotoxic effect of CDUPRT_MSC/5FC and CDUPRT-IFNβ_MSC/5FC

To develop in vivo model of peritoneal carcinomatosis, a total of 1 × 10 6 ES2-LUC-tdT cells were suspended in 100 µL of Plasma-Lyte and carefully injected into the peritoneal cavity using an insulin syringe. Three days after tumour cell implantation, mice were divided into three groups, unmodified MSC, CDUPRT_MSC and CDUPRT-IFNb_MSC. For treatment, 1 × 10 6 MSCs suspended in 100 μL of Plasma-Lyte were injected intraperitoneally into the abdomen. One day post-MSC administration, mice were treated intraperitoneally with 500 mg/kg/day of 5FC for four consecutive days. A total of two treatment cycles were administered. Mice were anaesthetized by isoflurane inhalation, and tumor growth was monitored using an in vivo imaging system (IVIS ® Spectrum In Vivo Imaging System, PerkinElmer) after luciferin injection (D-Luciferin, PerkinElmer; 50 mg/kg per mouse). The photon flux of each mouse was measured using Living Image software (PerkinElmer). Organs were isolated after the mice were euthanized at the end of the experiment.

Statistical analysis

All experiments were repeated at least thrice. Parametric Student t -test was used for statistical analysis using Excel (Microsoft). For the in-vitro coculture studies (Fig.  4 ), the qPCR study (Additional file: 8) and the THP1 assay (Additional file: 9), the data was analyzed using Graphpad Prism. Statistical significance was categorized as p < 0.05 and data were reported as mean ± SD.

Sustainable and high expression of dual therapeutic proteins by non-virally engineered allogeneic MSCs

Next, We assessed the transfection efficiency and quality of adipose tissue-derived MSCs after transfected with plasmids encoding either the therapeutic transgene, CDUPRT or CDUPRT- IFNb. Specifically, a “self-cleaving” 2A peptide was used for the coexpression of IFNb downstream of CDUPRT [ 53 ]. The CDUPRT transgene (also referred to as the “prodrug system”) is tagged with GFP, serving as a reporter (Fig.  1 A). In compliance with the Food and Drug Administration (FDA) guidelines (21 CFR 1271.85) the MSCs were screened and cleared of the various pathogens and cultured in xenofree media to avoid the risks of exposure to animal derived pathogens [ 54 ].

figure 1

Modification of MSC to overexpress CDUPRT and IFNb. A A multi-cistronic vector encoding CDUPRT-IFNb (construct 2) was cloned into an existing expression vector bearing CDUPRT. B Representative images of MSCs transfected with CDUPRT and CDUPRT-IFNb on day 1 post transfection. C Transfection efficiency and ( D ) cell viability of cells on day 1, 2, and 4 post-transfection. All bar charts and line graphs are represented as mean ± SD of biological triplicates (n = 3). Statistical significance was measured using a two-tailed Students’ t-test to compare the CDUPRT and CDUPRT-IFNb groups. A p-value of less than 0.05 was considered significant. (*p < 0.05, **p < 0.01, ***p < 0.001)

Optimization of transfection parameters (DNA and polymer amount) for both the constructs were guided by design of experiments (DOE). Leveraging on the non-viral transfection method developed in our previous study [ 55 ], an optimal condition of the modification of MSCs was identified (Additional file 1). At DNA/polymer ratio of 250 ng/1.1 µL per cm 2 for both CDUPRT and CDUPRT-IFNb plasmids, more than 80% of the population expressed the transgenes on day 1 after transfection, and this did not adversely affect cell viability. It is worthy to note that cell morphology was unaffected by the high transgene expression (Fig.  1 B). Cells and conditioned media were collected to determine protein expression and secretion of CDUPRT and IFNb by western blot and ELISA, respectively. Western blot analysis confirmed expression of CDUPRT in the cytosol, and IFNb was secreted into the culture medium (Additional file 2). IFNb concentration in the culture medium was 494.5 ± 10.4 ng/mL for the CDUPRT-IFNb group, which was significantly higher than that in the CDUPRT or native group (p < 0.01) (Additional file: 3). The conditioned media collected from the cells transfected with CDUPRT-IFNb was subjected to an established functional assay [ 56 ]. Upregulation of interferon-stimulated genes (ISGs) in a A549 cell line model confirmed the activity of IFNb secreted by the engineered MSCs (Additional file: 4).

As we intend for modified MSCs to serve as biofactories for sustainable delivery of therapeutic agents at the peritoneal cancer site, prolonged intracellular transgene expression is essential. Hence, we examined the duration of expression for the intended therapeutic agents. Notably, the high intracellular CDUPRT expression, as indicated by GFP + expression was retained over a period of 4 days post transfection (Fig.  1 C).

Engineered MSCs retain genetic stability and immunomodulatory properties

Genetic stability is an essential quality control measure for cell therapy [ 57 ]. To ensure the genetic stability of the engineered MSCs, the karyotypes of the engineered MSCs expressing CDUPRT or CDUPRT-IFNb were analysed and compared against unmodified, native MSCs. All three MSC types displayed a normal human karyotype with no detectable cytogenetic changes (Additional file: 5). With unmodified MSCs as reference, the modified MSCs were assessed according to the criteria as stipulated by the International Society for Cell and Gene Therapy (ISCT) [ 58 ]. MSC identity was validated as > 95% population expressing CD73, CD90, CD105, and < 2% of the cells expressing CD14, CD19, CD34 and CD45 (Fig.  2 A). Notably, the engineered MSCs showed a negligible expression of Human Leukocyte Antigen-DR (HLA-DR), confirming that the MSCs retain low immunogenicity despite the high expression of CDUPRT or IFNb (Fig.  2 A). It was also gratifying to note that MSCs transfected with CDUPRT-IFNb retained their chondrogenic, osteogenic, and adipogenic differentiation potential (Fig.  2 B), like our previous observations with MSC engineered to express CDUPRT [ 20 ].

figure 2

Highly modified CDUPRT-IFNb_MSC retain MSC phenotypic markers and trilineage differentiation potential. A Modified and unmodified MSCs were collected and analysed using immunophenotyping for the expression of positive (CD73, CD90 and CD105) and negative (CD14, CD19, CD34, CD45 and HLD-DR) makers. Respective isotype controls were used as the negative gates for flow cytometry analysis. B CDUPRT-IFNb modified cells were also subjected to trilineage differentiation. Chondrogenic, osteogenic, and adipogenic differentiation was carried out using respective differentiation medium (top panel). Images on the bottom panel represent the undifferentiated controls after staining with respective solutions. Adipogenic differentiation was assessed after 16 days using Oil Red O to stain for oil droplets. Chondrogenic and osteogenic differentiation were assessed after 23 days using Alcian Blue to stain for sulphated proteoglycans present in chondrocytes, and Alizarin Red S to stain for calcium deposits, respectively

Engineered MSCs migrate and effectively target PC cells in vitro and in vivo

The migratory ability of MSCs toward tumours makes them a highly attractive vehicle for the delivery of therapeutic proteins to target cancers. For the treatment to be successful, the migratory potential of highly modified MSCs need to be intact. To that end, we assessed the tumour tropism of modified MSCs in-vitro and in-vivo . Relative to a no-cancer control, we found that MSCs modified with CDUPRT or CDUPRT-IFNb were able to selectively migrate towards Colo-205 and ES2 cancer cells (Fig.  3 A). An in-vivo model of peritoneal carcinomatosis was established via peritoneal injection of ES2 stably expressing firefly luciferase. MSCs modified to express Renilla luciferase were injected into the peritoneal cavity and monitored for 21 days. Interestingly, we observed that the modified MSCs colocalised with the tumours as early as 6 h post-injection and remained in the mice for > 2 weeks. As time progressed, the Renilla luciferase signal spread along the abdomen, indicative that the MSCs were able to track and spread along with the tumours as they progressed. By day 21, the majority of the modified MSCs had cleared from the mice (Fig.  3 B). In line with other studies [ 59 , 60 ], MSCs found to be associated with tumours were detectable for significantly longer durations compared to non-tumour bearing mice.

figure 3

Modified MSCs exhibit efficient tumour tropism in-vitro and in-vivo. A CDUPRT_MSC or CDUPRT-IFNb_MSC were subjected to Boyden chamber assays using ES2 or Colo-205. At the end of the assay, the cells were fixed in 4% paraformaldehyde. The unmigrated cells were removed using a Q-tip and migrated cells on the flipside of the insert were stained with Hoechst 33342 and quantified manually. A total of 3 images per insert were obtained from 3 replicate wells per condition. The fold-difference was calculated using a negative control with no cancer cells within the bottom chamber. The data is presented as mean fold-difference ± SEM from triplicate (n = 3) wells. B In-vivo tumour tropism was evaluated using a nude mouse model with 1 × 10 6 ES2 cancer cells injected into the peritoneal cavity. Once the tumours were established, MSCs overexpressing Renilla luciferase (rLUC) were injected into the peritoneal cavity and monitored at the indicated time periods

MSCs expressing CDUPRT-IFNb is superior in targeting PC cell lines in vitro

Next, we tested the therapeutic potential of both engineered MSCs on various PC cell lines. When we co-cultured Colo-205, HT-29, and ES2 cell lines with MSCs expressing CDUPRT or CDUPRT-IFNb in the presence of the prodrug 5FC, we observed a significant reduction in cell viability (Fig.  4 ). With 2% of engineered MSCs, a ~ 70% reduction in cell number was observed in all 3 PC cell lines. Remarkably, MSCs expressing CDUPRT-IFNb exhibited enhanced potency compared to CDUPRT when 0.5% engineered MSCs were present in the coculture. Notably, Colo-205 colorectal carcinoma cells co-cultured with MSCs modified with CDUPRT-IFNb at a ratio of 1 MSCs to 200 cancer cells (0.5% engineered MSCs) showed a killing efficiency of approximately 60%, double the percentage of killing of cells modified with CDUPRT alone (p < 0.05, Fig.  4 A).

figure 4

CDUPRT-IFNb_MSCs are highly effective against multiple cancer cell lines. A Colo-205, B HT-29, and C ES2 were co-cultured with CDUPRT-IFNb_MSC or CDUPRT_MSC at 1 MSC to 1, 6, 12, 25, 50, 100, and 200 cancer cells. After one day in co-culture, cultures were supplemented with 150 μg/mL 5FC. Five days later, cell viability was quantified by standard MTS assay. Cells co-cultured with CDUPRT_MSC and CDUPRT-IFNb_MSC at different ratios without 5FC treatment were used as the respective controls to calculate cancer killing efficacy using the formula: % Killing = 1-(sample/control) * 100%. All graphs were represented as mean ± SD from at least five biological replicates (n = 5). Statistical significance was measured using an unpaired Students’ t-test. A p-value of less than 0.05 was considered significant. (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001)

We next demonstrated the in vitro conversion of 5FC to 5FU by the engineered MSCs. High-performance liquid chromatography/electrospray ionization/tandem mass spectrometry analysis of the culture media 1 day after addition of 5FC in the MSC cultures suggested a conversion of 5FC to 5FU at approximately 0.02 µM/engineered MSC/day (Additional file 6). A concentration increase of 5FU in the supernatant was detected with increasing number of engineered MSCs in the presence of 100 µg/mL of 5FC. At 1 CDUPRT_MSC to 50 cancer cells, 1 µM of 5FU/day generated in this condition resulted in ~ 70% cell reduction (Fig. 4). To gain insight into the MSC treatment efficacy relative to 5FU alone, we further determined the dose response of 5FU in ES2 cell line. Here, 75% reduction of ES2 was measured in the presence of 12.5 µM of 5FU (Additional File: 7). The stronger potency with engineered MSCs is likely due to the close proximity release of 5FU to the cancer population, supporting the notion of local drug delivery for effective cancer treatment [ 61 , 62 ].

To further investigate the potential anti-cancer mechanisms with the CDUPRT-IFNb modified MSCs, we stained the cells on the second day of the coculture study with tetramethylrhodamine ethyl ester perchlorate (TMRE) and annexin-V to examine the changes in mitochondrial membrane potential and apoptosis, respectively. ES2 and HT29 cells undergo significantly greater mitochondrial perturbation in the presence of IFNb, potentially contributing to the increased apoptosis compared to other conditions (Fig.  5 ). This is consistent with another report that similarly showed mitochondrial perturbation in other ovarian cell lines when cocultured with MSC overexpressing IFNb [ 16 ]. IFN has been shown to trigger cell death via TRAIL [ 63 ], which acts as an effector of mitochondrial perturbation [ 64 , 65 ]. To corroborate these findings, qPCR analysis indicated an increment in the expression of TRAIL, DR5 and ISGs (Additional file: 8) in ES2 exposed to the conditioned media of CDUPRT-IFNb_MSC + 5FC treatment, which was significantly higher than that observed with CDUPRT_MSC + 5FC treatment. While the current study focuses on exploring the use of MSCs to deliver 5FU and IFNb, it is interesting to note that a preliminary study using the monocytic cell line THP1 showed that IFNb overexpression led to an enhancement in immune cell polarization (Additional file: 9). This aspect is currently being pursued in greater detail.

figure 5

CDUPRT-IFNb_MSC with 5FC disrupts mitochondrial potential and increases apoptosis. CDUPRT_MSC or CDUPRT-IFNb_MSC were co-cultured with ( A ) ES2 or ( B ) HT29 at a ratio of 1 MSC to 1 cancer cells. Two days after the addition of 5FC, all cells were harvested and stained with TMRE or annexin V. The graph represents the percentage of cells positive for TMRE and annexin V presented as mean ± SD from at least three biological replicates (n = 3). Unstained controls were used as the negative gate. Statistical significance was measured using a two-tailed Students’ t-test relative to the CDURPT_MSC + 5FC condition. A p-value of less than 0.05 was considered significant. (***p < 0.001)

In vivo evaluation of anticancer efficiency of the engineered MSCs

Extending the study, we next injected MSCs expressing CDUPRT or CDURPT-IFNb intraperitoneally into a laboratory mice model for peritoneal carcinomatosis. A similar administration route for engineered MSCs with IFNb is currently under phase I clinical trial for treatment of patients with ovarian cancer [ 23 ]. Female nude mice (CrTac:NCr-Foxn1 nu ) bearing peritoneal human ES2-tdTomato/Luc tumours were divided into 3 groups, the first group served as a control using native MSCs, while the other 2 groups were treated with CDUPRT or CDUPRT-IFNb expressing MSCs to compare the co-delivery of 5FU and IFNb. One day after the cells were injected peritoneally, 5FC was administered daily for 4 consecutive days to enable the conversion to 5FU. The treatment cycle of MSCs and 5FC was repeated on day 7 and the study was terminated at Day 14 due to the accumulation of excessive ascites in the control group.

To ensure a non-biased assessment of the therapeutic efficacy, the mice were grouped to ensure comparable average tumour burden prior to the start to treatment. The tumour burden was tracked by weekly measurement of bioluminescence reading. Significant suppression of tumour growth was observed in the treatment groups but not in the control group (Fig.  6 ). Remarkably, animals treated with CDUPRT-IFNb modified MSCs experienced minimal tumour progression compared to the control group treated with unmodified MSCs. Mice treated with cells modified with CDUPRT but not CDUPRT-IFNb experienced a slight increase in tumour burden (Fig.  6 A, B). All mice were observed every 2 days post-treatment and scored for any debilitating signs of pain and stress, including laboured breathing, obvious illness, hunched posture, and the ability to remain upright. None of these adverse signs were detected throughout the experiment. However, two mice in the control group were shown to have developed ascites, a commonly observed symptom of end-stage PC, at day 14. Additionally, none of the mice experienced significant loss of weight throughout the experiment (Fig.  6 C). At experimental endpoint, the internal organs of the mice were extracted and imaged individually for any signs of luciferase expressing ES2 tumours. Metastases were detected in the heart, lungs, pancreas, kidneys, spleen, and liver in the control group but was less apparent in the treatment groups. Further analysis of the internal organs confirmed the greater therapeutic potential of CDUPRT-IFNb expressing MSCs over its counterparts in suppressing cancer metastasis (Fig.  6 D). In this group, metastasis was only found in liver and not in other organs. In the liver, the tumour burden was significantly lower than the other two groups. Potentially, the therapeutic efficacy could be enhanced by increasing the dose of engineered MSCs or number of treatment cycles.

figure 6

CDUPRT-IFN_MSC exerts a strong tumour suppressive effect in-vivo. The in-vivo model of peritoneal carcinomatosis was established using ES2 by injecting 1 × 10 6 cancer cells into the peritoneal cavity of nude mice. Tumour burden was assessed using bioluminescence and determined to be approximately similar prior to the start of the experiment. A total of two treatment cycles were administered, each consisting of 1 × 10 6 MSCs followed by 4 consecutive days of 500 mg/kg/day 5FC via intraperitoneal injection. The treatment cycles were spaced a week apart. Day 0 indicates the day of injection of MSCs for the first treatment dose. The mice were divided into three groups of four mice (n = 4) each. The mice were treated with unmodified MSC, CDUPRT_MSC or CDUPRT-IFNb_MSC. Tumour burden was assessed on day 7 and day 14. A The bioluminescence readings from each group presented as a box-and-whisker plot. B Bioluminescence images showing tumour burden in mice before treatment and at the end of the study (day 14). C Change in weight of the mice throughout the course of the study. D After the mice were euthanised, internal organs were harvested and examined for metastatic lesions

In the recent years, there has been growing interest in utilizing MSCs as cell vehicles to deliver therapeutic agents for localized solid tumour treatments, including patients with advanced peritoneal cancers [ 66 ]. Particularly, two phase I clinical trials (NCT02530047, NCT02068794) have successfully demonstrated safety and promising clinical benefits with engineered MSCs administered through intraperitoneal infusion in the cohorts of recurrent ovarian cancer patients [ 17 , 19 ]. Leveraging on our non-viral method for MSCs modification, we explored the feasibility of co-delivering a 5FU prodrug system and IFNb for localized cytoreductive effect against peritoneal cancers. Our results demonstrated the highly efficacious therapeutic benefits of the combination of 5FU and IFNb. This paves the path for further development towards investigational new drug studies for the application of a phase I clinical trial. This further requires the use of MSCs that are free of various pathogens and are cultured in xenofree media.

Historically, 5FU has been used as the first-line chemotherapeutic for patients with PC of gastrointestinal and colorectal origin [ 67 , 68 ], and experimentally for advanced ovarian cancer patients [ 69 , 70 , 71 ]. To improve therapeutic outcome, 5FU is delivered intraperitoneally to achieve minimal toxicity, higher drug concentration and prolonged half-life of the drug [ 67 , 71 ]. Nonetheless, some groups have reported that patients receiving intraperitoneal or intravenous administration developed similar adverse effects [ 72 , 73 ] and the half-life of intraperitoneal 5FU remains short (40 min) [ 74 ]. Additionally, the high drug concentration in the peritoneal fluid may not equate to increment in drug penetration into the tumour nodules [ 75 ]. Such a lack of therapeutically meaningful local concentrations of systemically administered 5FU and IFNb has contributed to the failure of randomized human trials [ 41 , 50 ].

Using MSCs to deliver therapeutic agents may circumvent some of these issues as MSCs are known to home and nest onto the tumour site to continually release therapeutic payloads locally [ 17 , 19 , 76 ]. We showed that the homing capacity of the highly overexpressed CDUPRT and CDUPRT-IFNb modified MSCs were comparable, a contrast to a previous report of the reduced migratory property of MSCs post modification [ 77 ]. While other delivery systems rely on paracellular or transcellular transport [ 78 ], MSCs present unique properties in the ability to penetrate deeply into the central region of tumour mass [ 79 , 80 ]. Notably, we found that the MSCs were present along with the tumour as the disease progressed (Fig.  3 B). This property is particularly relevant to the use of MSCs as therapeutic delivery vehicles to target the wide spreading tumour nodules on the surface of the peritoneum.

In addition to tumour penetration, delivery of a high therapeutic payload is critical for achieving high potency in cancer killing. With only 2% therapeutic cells, CDUPRT-modified MSCs achieved significant killing efficiencies of 60, 70, and 80% for HT-29, Colo-205, and ES2 cells, respectively. When the therapeutic cell concentration was reduced further to 1% relative to cancer cells, CDUPRT-IFN modified MSCs demonstrated notably enhanced efficacy, resulting in killing efficiencies of 60% for HT-29, 70% for Colo-205, and a remarkable 95% for ES2.The superior anti-cancer effect of CDUPRT-IFN_MSC in the mice model further supports the notion that multi-transgene armed MSCs is a preferred therapeutic candidate for PC. Intriguingly, with virally engineered neural stem cells expressing CD and IFNb, Choi et al. demonstrated synergistic anti-cancer effect of such combination in some [ 51 , 52 ] but not all [ 81 , 82 , 83 , 84 ] cancer cell lines. Using 100 µg/mL 5FC, only ~ 20% reduction in cell viability was observed at a 2:1 ratio of therapeutic cells to HT-29, and even increasing to a ratio of 6:1 did not improve cancer killing further [ 52 ]. A possible reason for this lack of cytoreductive efficiency is the limited payload of virally engineered cells [ 20 ].

The key to high payload is to maximise number of DNA copies in the cells. While transient transfection enables more than 10 4 copies of DNA per cell [ 55 ], there have been several reports on the FDA’s position on restricting the integration of viral vectors into the host cell genome to fewer than 5 copies in cell and gene therapy productto mitigate the risk of oncogenesis [ 85 ]. This limitation on vector integration into the host genome results in a limited payload within the engineered cells. The high payload ensures the efficient conversion of 5FC to 5FU. We have previously shown that 100 µg/mL of 5FC and 20% CDUPRT engineered MSCs was as potent as 100 µg/mL 5FU in a coculture study with cancer cells [ 20 ]. In addition to the robust conversion of 5FC to 5FU, the expression level of secreted IFNb from our modified MSCs was found to be ~ 500 ng/mL. This represents the highest reported IFNb expression level, contrasting the typical pg/mL range in virally engineered MSC studies [ 86 , 87 , 88 ]. To our knowledge, this is the first report to demonstrate localized 5FU and IFNb treatment delivered by non-virally engineered MSCs.

It has not escaped our notice that this multi-armed MSCs could potentially exert further therapeutic effects through the induction of anti-cancer immunity. Studies are underway to demonstrate its potential effect in modulating the immune response in humanized mice models. Additionally, safety and efficacy studies will be conducted for investigational new drug application. In conclusion, we have shown that MSCs armed with a 5FU prodrug system and IFNb provided higher therapeutic efficacy than the 5FU prodrug system alone.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Abbreviations

  • Mesenchymal stem cells

Cytosine deaminase and uracil phosphoribosyl transferase

Green fluorescent protein

Interferon-beta

  • Peritoneal carcinomatosis

5-Fluorouracil

5-Flucytosine

Overall survival

Cytoreductive surgery

Hyperthermic intraperitoneal chemotherapy

Human Leukocyte Antigen-DR

Tetramethylrhodamine ethyl ester perchlorate

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Acknowledgements

THP-1 assay in Additional file 9 was performed in collaboration with Dr. Song Yuan and A/Prof Liu Haiyan from the Department of Microbiology and Immunology of the National University of Singapore.

This work was supported by the Dean Office, Yong Loo Leen School of Medicine, National University of Singapore [Grant reference number: NUHSRO/2022/075/NUSMed/029/LOA].

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Yoon Khei Ho, Jun Yung Woo, Kin Man Loke, Lih-Wen Deng & Heng-Phon Too

NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

AGeM Bio, Singapore, 119276, Singapore

Yoon Khei Ho

Singapore Innovate, Singapore, 059911, Singapore

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THP and HYK designed the study. HYK, WJY and LKM performed experiments, analysed data, prepared figures and wrote the manuscript. All authors reviewed and edited manuscript. All authors have read and approved the final manuscript.

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Supplementary Information

12967_2024_5278_moesm1_esm.pptx.

Additional file 1: Design of experiment (DOE) for optimisation of non-viral transfection. Human MSCs were modified with increasing amounts of pDNA and polymer. The cells were harvested one day post-transfection and the (A) transfection efficiency and (B) cell viability was determined using flow cytometry. For viability measurements the cells were stained using 7-aminoactinomycin D (7AAD). A quadratic model was obtained using the DesignExpert (v.13) software (StatEase Inc., MN, USA) to obtain the optimized transfection parameters. (C) Images of cells transfection using the 16 conditions tested. Surface response graphs and images were obtained from a representative experiment run. Each DOE experiment was repeated at least thrice (n=3) to validate the results.

12967_2024_5278_MOESM2_ESM.pptx

Additional file 2: Immunoblot analysis of CDUPRT and interferon-beta. MSCs were modified to express CDUPRT and IFNb. One day post transfection, conditioned media and cell lysate were analysed by immunoblotting. 20uL of conditioned media, or 20ug of protein from cell lysate was added to the respective wells. (A) and (B) were probed using anti-human IFNb and (C) using anti-eGFP antibody. Expected size. IFNb = 22.3kDa; CDUPRT-GFP = 68.1kDa; recombinant GFP = 26.2kDa. UT – Untransfected, L – Ladder, D1 – day 1 post-transfect, Ctrl – Control (for IFNb – recombinant human IFNb, Genscript #Z03109; for CDUPRT-GFP – Recombinant eGFP from e.coli). There was no detectable CDUPRT in the conditioned media (data not shown).

12967_2024_5278_MOESM3_ESM.pptx

Additional file 3: Secretion of IFNb. Concentration (ng/mL) of IFNb secreted on day 1 post-transfection from native cells (Control), cells modified with CDUPRT only, and cells modified with CDUPRT-IFNb. Control and CDUPRT samples did not secrete IFNb and were below the detection limit of the assay.

12967_2024_5278_MOESM4_ESM.pptx

Additional file 4: Interferon-β expressed in MSC is functional. (A) Schematic of the assay design for determining IFNb function. (B) MSC were transfected with CDUPRT, CDUPRT-IFNb or IFNb alone and allowed to express IFNb for two days. The supernatant was then collected and directly transferred into well plates containing A549 lung carcinoma cells. The conditioned medium was treated at a 1:1 ratio of conditioned medium to cell culture medium. One day later, the RNA was extracted and MxA, ADAR1 and ISG56 expression were detected using qPCR. All fold-changes were calculated using the ΔΔCT method using the untreated control and RPL19 as a biological normalizer. Here the untreated control refers to A549 cells without any treatment, untransfected control refers to the treatment with conditioned medium from native MSC and 10 ng/mL recombinant human IFNb (Genscript) was used as the positive control. All bars were represented as mean fold-change ±SD of three biological replicates (n=3).

12967_2024_5278_MOESM5_ESM.pptx

Additional file 5: Karyotype of MSCs remain unchanged after modification. Karyotype of (A) non-modified MSCs, (B) CDUPRT modified MSCs, and (C) CDUPRT-IFNb modified MSCs. No abnormalities were observed.

12967_2024_5278_MOESM6_ESM.pptx

Additional file 6: Conversion of 5FC to 5FU. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed on supernatant samples collected from wells containing 0, 50, 750, and 7500 MSCs as indicated. The graph represents the average amount of 5FU detected from biological duplicates (n=2).

12967_2024_5278_MOESM7_ESM.pptx

Additional file 7: 5FU sensitivity of various GBM cell lines. Six replicates of ES2 cell line (2500 cells) were plated. One day later, culture media were replaced with RPMI supplemented with 10% FBS and 5FU (0–100 μM). Cell viability was determined using Crystal Violet assay 48 hours later. The percentage of cell viability was calculated with no treatment control set at 100%.

12967_2024_5278_MOESM8_ESM.pptx

Additional file 8: Differential activation of interferon stimulated genes (ISG) using modified MSCs. MSCs were transfected with CDUPRT, CDUPRT-IFNb. One day post transfection, 100 µg/mL 5FC was added to the transfected MSCs to allow for conversion of 5FC to 5FU for one day. The supernatant was then collected and directly transferred into well plates containing ES2 cells. The conditioned medium was treated at a 1:10 ratio of conditioned medium to cell culture medium. Three days later, the RNA was extracted and TNFSF10 (TRAIL), DR4, DR5, STAT1 and CXCL10 expressions were detected using qPCR. All fold-changes were calculated using the ΔΔCT method using the native control and RPL19 as a biological normalizer. Here, the native control refers to ES2 cells treated with conditioned media from native MSCs. All bars were represented as mean fold-change ± SD of three biological replicates (n=3). Significance was calculated using unpaired Students’ t-test. A p-value of less than 0.05 was considered significant. (*p<0.05, **p<0.01).

12967_2024_5278_MOESM9_ESM.pptx

Additional file 9: Differential activation of immune cells in-vitro using conditioned medium from co-culture of CDUPRT-IFNb_MSC and colorectal cancer cells. CDUPRT-IFNb_MSC and CDUPRT_MSC were co-cultured with (A) COLO 205 or (B) HT-29 colorectal adenocarcinoma cell lines at a ratio of 1 MSC to 5 or 10 cancer cells. One day later, co-cultures were treated with or without 150 µg/mL 5FC. Percentage killing was assessed 5 days post-treatment with 5FC by harvesting and counting of viable cells. Cells co-cultured with CDUPRT_MSC at different ratios without 5FC treatment was used as the respective controls to calculate cancer killing percentage using the formula: Percentage Killing = 1-(sample/control) * 100%. Separately, the co-culture supernatant was collected from COLO 205 at 24 hours and 48 hours after the addition of 5FC for a THP-1 stimulation assay. THP-1 cells were plated onto 96well plates and treated with respective supernatant samples as indicated. After overnight treatment, the cells were harvested and stained for (C) CD80, (D) CD40, (E) CD86, and (F) HLA-DR. All graphs were represented as mean ±SD from at least three biological replicates (n=3). Significance was calculated using two-way ANOVA with Tukey’s correction. A p-value of less than 0.05 was considered significant. (*p<0.05, **p<0.01, ***p<0.001, ****p<0.00001).

Additional file 10.

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Ho, Y.K., Woo, J.Y., Loke, K.M. et al. Enhanced anti-tumor efficacy with multi-transgene armed mesenchymal stem cells for treating peritoneal carcinomatosis. J Transl Med 22 , 463 (2024). https://doi.org/10.1186/s12967-024-05278-5

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Received : 08 November 2023

Accepted : 07 May 2024

Published : 15 May 2024

DOI : https://doi.org/10.1186/s12967-024-05278-5

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Theradaptive secures landmark funding from maryland stem cell research fund (mscrf) to support human clinical trials.

FREDERICK, Md. , May 22, 2024 /PRNewswire/ -- Theradaptive, Inc., a regenerative medicine company developing targeted therapeutics, announced today it has been awarded funding from the Maryland Stem Cell Research Fund (MSCRF) to support human clinical trials for its lead product, OsteoAdapt SP.  OsteoAdapt SP is currently in Phase I/II clinical studies for transforaminal lumbar interbody spinal fusion (TLIF) to treat degenerative disc disease, spondylolisthesis, and retrolisthesis.

Theradaptive was granted an Investigational Device Exemption (IDE) in January 2024 by the U.S. Food and Drug Administration (FDA) to begin its human clinical trial. This $1 million award from the MSCRF Clinical Program will enable Theradaptive to expand its OASIS human clinical study to sites in Maryland . More details can be found at ClinicalTrials.gov: identifier NCT06154005 . Theradaptive also holds three Breakthrough Medical Device designations for various spine indications including TLIF, ALIF, and PLF.

"We are so grateful to the Maryland Stem Cell Research Fund for this generous support as we take OsteoAdapt SP through clinical development,"  said Luis Alvarez , PhD, CEO and Founder of Theradaptive. " This grant will expand our ability to provide patients with limited options a much better alternative by accelerating the development of this ground-breaking technology."

How OsteoAdapt SP is changing biologic implants

OsteoAdapt SP is a biologic-enhanced implant designed to stimulate anatomically precise local bone growth and promote rapid fusion following spinal surgery. It combines a proprietary protein called AMP2 that activates a patient's own stem cells with a resorbable scaffold implant. This implant remodels into bone and completely resorbs, leaving no trace behind. This technology ushers in the next generation of regenerative therapeutics compared to the current standard of care by mitigating side effects and significantly improving safety and efficacy over traditional bone grafts and biologics.

"This funding will benefit us greatly as we work toward making this revolutionary therapy available to patients in need, putting Maryland at the forefront of innovation in regenerative bone repair" said Jonathan Elsner , PhD, Vice President of Clinical Operations. " We appreciate that MSCRF recognizes the importance of this program and look forward to dosing the first patient in the coming months ."

" Our goal is to accelerate the development of promising technologies by providing funding to help them reach patients as quickly as possible," said Ruchika Nijhara, Executive Director of MSCRF. "We are enthusiastic about the potential of OsteoAdapt SP to benefit patients suffering from debilitating spine conditions ."

Theradaptive was spun out of the Massachusetts Institute of Technology in 2017 to commercialize a platform that immobilizes therapeutic proteins on implantable biomaterials. The company's near-term focus is on regenerative treatments for musculoskeletal conditions and spinal fusion surgery.

Clinical sites investigating OsteoAdapt SP in TLIF procedures are currently enrolling patients across the U.S., including Maryland , and in Australia .

Theradaptive plans to file for marketing authorization with the U.S. Food and Drug Administration following successful completion of pivotal clinical studies.

About Theradaptive

Theradaptive, Inc. is a privately held regenerative medicine company developing therapeutic implants that harness the body's own stem cells to regenerate tissues. The company's proprietary AMP2 technology platform enables localized, sustained delivery of therapeutic proteins to trigger highly targeted regenerative responses.

Theradaptive's lead clinical program, OsteoAdapt SP, is an investigational bone graft material designed to improve spinal fusion outcomes. For more information, visit www.theradaptive.com .

Contact: Harry Warne Senior Contributor Flame PR [email protected]

View original content to download multimedia: https://www.prnewswire.com/news-releases/theradaptive-secures-landmark-funding-from-maryland-stem-cell-research-fund-mscrf-to-support-human-clinical-trials-302151884.html

SOURCE Theradaptive

  • Open access
  • Published: 16 May 2024

Human lung cancer-derived mesenchymal stem cells promote tumor growth and immunosuppression

  • Xiaoyan Gao 1 ,
  • Zhengrong Zhang 1 , 2 ,
  • Shuai Cao 3 ,
  • Bo Zhang 1 , 4 ,
  • Qiang Sun 4 ,
  • Gerry Melino 2 , 5 &
  • Hongyan Huang 1  

Biology Direct volume  19 , Article number:  39 ( 2024 ) Cite this article

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The presence of mesenchymal stem cells has been confirmed in some solid tumors where they serve as important components of the tumor microenvironment; however, their role in cancer has not been fully elucidated. The aim of this study was to investigate the functions of mesenchymal stem cells isolated from tumor tissues of patients with non-small cell lung cancer.

Human lung cancer-derived mesenchymal stem cells displayed the typical morphology and immunophenotype of mesenchymal stem cells; they were nontumorigenic and capable of undergoing multipotent differentiation. These isolated cells remarkably enhanced tumor growth when incorporated into systems alongside tumor cells in vivo. Importantly, in the presence of mesenchymal stem cells, the ability of peripheral blood mononuclear cell-derived natural killer and activated T cells to mediate tumor cell destruction was significantly compromised.

Collectively, these data support the notion that human lung cancer-derived mesenchymal stem cells protect tumor cells from immune-mediated destruction by inhibiting the antitumor activities of natural killer and T cells.

Mesenchymal stem cells (MSCs) are fibroblast-like, multipotent progenitor cells that were initially discovered in bone marrow; however, over time, their presence has been confirmed in almost all tissue types, and these cells exhibit the potential for multidirectional differentiation (such as into bone, adipose, cartilage, and muscle cells) as well as the capacity for self-renewal [ 1 , 2 , 3 ]. MSCs can be recruited to the site of tissue injuries where they participate in processes associated with wound repair. Tumors are considered to be "wounds that never heal," and MSCs tend to migrate toward sites of inflammation and tumor microenvironments [ 3 , 4 ]; therefore, many studies have recommended the use of MSCs as therapeutic vectors to target tumors [ 5 , 6 , 7 ]. However, the function of MSCs in cancer remains controversial, and it is essential to clarify their effects within the tumor microenvironment. Several studies have demonstrated that MSCs exert their antitumor effects through several mechanisms, including the inhibition of angiogenesis, the promotion of antitumor immune responses, and the induction of apoptosis in cancer cells [ 8 , 9 , 10 ]. In contrast, several other studies have shown that MSCs can promote tumor growth and metastasis by enhancing tumor cell proliferation, angiogenesis, and metastatic capacity, thereby inducing immunosuppression or inhibiting tumor cell apoptosis [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Possible explanations for the discrepancies between studies could be the variability of MSCs in terms of the tissue and microenvironment from which they were isolated or the fact that some studies have used murine rather than human MSCs. Notably, previous studies have mainly focused on MSC lines or healthy donor-derived MSCs isolated from bone marrow. Only recently has there been growing interest in the effects of tumor-derived MSCs on cancer progression. However, the interactions between tumor-associated MSCs and cancer cells remain obscure and require further investigation.

The aims of this study were to isolate human lung cancer-derived MSCs (hLC-MSCs) to characterize their phenotypes, assess their effects on tumor growth both in vivo and in vitro, and elucidate the mechanisms underlying their tumor-promoting effects.

Materials and methods

Dissociation of tumor-associated mesenchymal cells.

Tumor tissue samples were obtained from two patients with non-small cell lung cancer (NSCLC) who had not received any treatment prior to undergoing surgical resection at Xuanwu Hospital. Written informed consent was obtained according to the guidelines of the Ethics Committee of Capital Medical University. Lung tumor tissues were minced and added to a solution containing a mixture of dispase and collagenase 1A (STEMCELL Technologies Inc, Vancouver, BC, Canada) for digestion. A cell strainer (70 μm; BD Biosciences, Bedford, MA) was used for single-cell isolation and the removal of adipose and other tissues.

Cells and culture conditions

hLC-MSC cell expansion was performed as previously described by Liu et al. [ 18 ]. Briefly, isolated epithelial cells were co-cultivated with irradiated (3,000 rad) Swiss 3T3 fibroblasts (J2 strain) in F medium [3:1 (v/v) Ham’s Nutrient Mixture F-12: Dulbecco's Modified Eagle's Medium (Invitrogen), with 5% fetal bovine serum (FBS), 10 ng/mL epidermal growth factor (Invitrogen, Waltham, MA), 5 μg/mL insulin, 0.4 μg/mL hydrocortisone, 24 μg/mL adenine (Sigma-Aldrich, St. Louis, MO), and 8.4 ng/mL cholera toxin], to which 10 μmol/L Y-27632 (ROCK inhibitor, Tocris Bioscience, Bristol, UK) was added. All cells were cultured in a humidified atmosphere of 5% CO 2 at a temperature of 37 °C and passaged at a ratio of 1:4 after reaching 80%–90% confluence.

Differential trypsinization was performed to separate feeder and epithelial cells during passaging. Briefly, feeder/epithelial co-cultures were rinsed with phosphate-buffered saline (PBS) and incubated with 0.05% trypsin solution at room temperature for 30 s to 1 min, with close monitoring under phase-contrast microscopy. When the feeder cells became rounded and began to detach from the substrate, the cultures were gently tapped to facilitate their detachment and subsequent removal by aspiration, while the epithelial cell colonies remained tightly adherent. The epithelial cells were again rinsed with PBS and trypsinized at 37 °C for 3–5 min. The cells were transferred to a solution of PBS containing 10% serum to neutralize the trypsin and subjected to centrifugation at 500× g . The cell pellets were subsequently resuspended in F medium for passaging. To minimize any potential changes in cellular behavior caused by prolonged culture times, cells at passages P3–P5 were used in this study.

Cell line MC38/CT-26/NIH3T3/A549/HepG2 and its derivatives were routinely maintained in Dulbecco’s Modified Eagle’s Medium (MACGENE Technology Ltd., Beijing, China) supplemented with 10% FBS (Kangyuan Biology, China), and 100 units/mL penicillin plus 100 µg/mL streptomycin (Invitrogen). NK92MI cell line was maintained in RPMI 1640 medium (MACGENE Technology Ltd.) supplemented with 12.5% FBS and 12.5% horse serum (Kangyuan Biology). T cells isolated from peripheral blood and activated were further cultured in RPMI 1640 medium supplemented with 10% FBS supplemented with 100 IU/mL human interleukin 2 (hIL-2). All cells were cultured in a humidified incubator with 5% CO2 at 37 °C.

Constructs and stable cell lines

The luciferase gene was subcloned into a pQCXIP retroviral vector to generate a pQCXIP-luciferase-puro vector. pQCXIP and retroviral helper plasmids vesicular stomatitis virus G (VSV-G) and Gag-Pol-Rev were purchased from Addgene. All constructs were verified using DNA sequencing. More detailed information is provided below.

Stable cell lines were established via viral infection. Retroviruses were packaged into human embryonic kidney 293 T (HEK293T) cells using Lipofectamine 2000 reagent (Invitrogen), as previously described [ 19 , 20 ]. For infection, 1 mL of viral supernatants mixed with 10 μg of Polybrene (Sigma) was added to the target cells in 6-well plates for a period of 12 h, after which the cells were fed with regular media. Virus-infected tumor cells were selected through a 7–14-day exposure to puromycin (2 μg/mL).

Flow cytometric analysis

Cells were detached from the culture plate using TrypLE Express (Invitrogen) before being resuspended in PBS supplemented with 1% bovine serum albumin. The cells were incubated with fluorophore-conjugated antibodies targeting various cluster of differentiation (CD) and human leukocyte antigens (HLA) for 30 min in the dark at 4 °C, including CD14, CD90, CD166, CD144, CD73, CD105, CD45, CD31, CD29, and the HLA-DR isotype. Cell suspensions with isotype-matched immunoglobulins were used as controls. After three washes with PBS, the labeled samples were analyzed using a FACSAria II flow cytometer (BD Biosciences, San Jose, CA).

In vitro assessment of osteogenic differentiation

Cells were cultured in osteo-inductive medium (alpha-Minimum Essential Medium [α-MEM] containing 0.1 μM dexamethasone, 10 mM β-sodium glycerophosphate, 50 μM ascorbic acid, and 10% FBS) for 21 days, with a half-volume change performed every 3 days. Von Kossa staining was performed to detect calcified matrix precipitation. Cells were fixed in neutral formaldehyde solution for 1 h. After washing with deionized water, 2% silver nitrate solution was added for a 10-min reaction at 37 °C in the dark, a 15-min exposure time, and washing in deionized water. The presence of calcified matrix precipitation was assessed using an inverted phase-contrast microscope. Cells in the control group were cultured in α-MEM plus 10% FBS for 3 weeks.

In vitro assessment of adipogenic differentiation

Cells were cultured in adipo-inductive medium (α-MEM containing 1 μM dexamethasone, 200 μM indomethacin, 10 μM insulin, 0.5 mM isobutyl methylxanthine, and 10% FBS), with a half-volume change performed every 3 days. After 3 weeks, the cells were fixed with neutral formaldehyde for 10 min at room temperature; this was followed by staining with Oil Red O and counterstaining of cell nuclei with alum hematoxylin to assess the degree of adipogenesis. Fat droplets were observed using an inverted phase-contrast microscope. The control cells were MSCs cultured in the aforementioned cell expansion medium.

Preparation of cytotoxic T lymphocytes (CTLs)

First, peripheral blood mononuclear cells (PBMCs) were isolated from heparinized venous blood samples collected from healthy adults using Ficoll Histopaque (Sigma Chemical Co., St. Louis, MO) density gradient centrifugation. Subsequently, an EasySep™ Human T Cell Isolation Kit (STEMCELL Technologies Inc.) was used to isolate T cells from the PBMCs. Viable human T cells were seeded in Roswell Park Memorial Institute (RPMI)-1640 complete medium at a density of 1 × 10 6 cells/mL. To activate the T cells, 25 µL/mL of ImmunoCult™ Human CD3/CD28/CD2 T Cell Activator and 100 U/mL of hIL-2 were added to the cell suspension. The cells were subsequently incubated at 37 °C with 5% CO 2 for up to 3 days. To induce T cell expansion after 3 days of activation, the T cells were cultured in RPMI-1640 complete medium containing 100 U/mL of hIL-2 and subcultured once every 2–3 days to maintain a cell density of 1 × 10 6 cells/mL. After 12 days of culture, the CTLs were collected for subsequent experiments.

In vitro assessment of immune cell-induced tumor cell destruction

Tumor cells were plated at a density of 2,000 or 4,000 cells/well in either 96-well flat-bottomed plates or the lower chamber of a transwell system (Corning, NY, USA) in DMEM supplemented with 10% FBS. MSCs were plated at a density of 2,000 or 40,000 cells/well in either 96-well flat-bottomed plates or the upper chamber of a transwell system (Corning, NY, USA) in DMEM supplemented with 10% FBS. The following day, natural killer (NK) or T cells were added to the cultures on top of the tumor cell layer at different effect-to-target ratios in each well in RPMI 1640 medium containing 10% FBS supplemented with hIL-2 to reach a final concentration of 100 IU/mL. Luciferase activity was measured after 24 h and 48 h.

Tumor formation assay

All protocols involving animals were approved by the Animal Care and Use Committee of the Beijing Institute of Biotechnology and performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. To assess the tumor formation capacity, 3 × 10 6 MC38 murine colon adenocarcinoma cells, with or without 3 × 10 6 hLC-MSCs, were suspended in a 100-μL volume at a 1:1 ratio in either standard RPMI 1640 medium alone or medium with Matrigel matrix (BD Biosciences), and transplanted subcutaneously into 4- to 5-week-old C57BL/6N mice. Tumor formation was monitored weekly.

Statistical analysis

All data are presented as the mean with standard deviations (SD) unless stated otherwise. Statistical analyses were performed using SPSS software (version 22.0; IBM Corp., Armonk, NY). For all quantitative measurements, a normal distribution was assumed, and differences between two groups were determined using unpaired, two-tailed Student’s t -tests. Each measurement was based on at least three independent replicates.

Isolation of hLC-MSCs

After 8 days of culture in conditions conducive to the growth of MSCs, the cells that remained adhered to the Petri dish formed several cell colonies (Fig.  1 A-a). Cobblestone-like cell colonies, determined to be primary lung cancer cells, were observed (Fig.  1 A-b), in addition to MSC-like cells that exhibited a long, spindle-shaped morphology and were abundant in all cultures (Fig.  1 A-c). Single-cell suspensions were re-plated to increase the purity of the hLC-MSC clones, and several assays were conducted to confirm the low degree of contamination with other cell types, especially cancer and endothelial cells, to allow for cellular phenotyping (Fig.  1 A-d). Immunophenotyping of the hLC-MSCs was performed based on the immunofluorescent labeling of various molecules, including E-cadherin (a marker of epithelial cells), N-cadherin and vimentin (markers of mesenchymal cells), α-smooth muscle actin (α-SMA) (a fibroblast marker), and cytokeratin 18 (CK18) (a malignant tumor marker). The hLC-MSCs isolated in the present study did not express E-cadherin, whereas they did express N-cadherin, vimentin, α-SMA, and CK18 (Fig.  1 B).

figure 1

Morphology and immunophenotyping of hLC-MSCs. A (a) Representative images of primary cells arising from NSCLC tissues. Magnification, ×40. (b–d) The resultant distinct, purified colonies of epithelial tumors cells (b) or hLC-MSCs (c–d). Magnification ×200. B Representative images of hLC-MSC clones that were subjected to immunocytochemical staining. The hLC-MSCs were negative for E-cadherin and positive for N-cadherin, vimentin, α-SMA, and CK18 expression. Cytoskeletal proteins were stained using phalloidin, and cell nuclei were stained with DAPI. hLC-MSCs human lung cancer-derived mesenchymal stem cells; NSCLC non-small cell lung cancer; α-SMA alpha smooth muscle actin; CK18 cytokeratin 18; DAPI 4’,6-diamidino-2-phenylindole

Surface markers expressed by hLC-MSCs

To determine whether the colony-forming cells (hLC-MSCs) expressed the same characteristic surface antigens as MSCs, flow cytometric analysis was performed, which confirmed that these cells did in fact express a set of MSC markers, including CD90, CD166, CD73, CD29, and CD105 (Fig.  2 ). Antibodies that target several of these antigens are routinely used to characterize expanded mesenchymal cell populations. In contrast, the cells did not express the lipopolysaccharide receptor CD14, the leukocyte common antigen CD45, the endothelial cell marker CD31, or the epithelial cell marker CD144. Moreover, the cells did not express HLA-DR. Collectively, these data confirmed that the isolated MSC-like cells exhibited surface marker expression patterns typically observed in MSCs, which was in accordance with the accepted phenotypic markers for hMSCs described previously [ 21 ].

figure 2

Surface antigens expressed by hLC-MSCs. Surface antigens expressed on hLC-MSCs were analyzed using flow cytometry. The hLC-MSCs were positive for CD90, CD166, CD73, CD29 and CD105, and negative for CD14, CD45, CD31, CD144, and HLA-DR. hLC-MSCs human lung cancer-derived mesenchymal stem cells; CD cluster of differentiation; HLA-DR human leukocyte antigen DR isotype

Multilineage differentiation capacity of hLC-MSCs

True MSCs have the capacity to undergo multipotent differentiation into cells of the adipogenic, osteogenic, and chondrogenic lineages when cultured in specific media [ 1 , 22 , 23 ]. Therefore, the cells were first cultured in a medium containing 1-methyl-3-isobutylxanthine, dexamethasone, insulin, and indomethacin to induce adipogenic differentiation [ 1 ]. After a two-week incubation, the hLC-MSCs had begun to undergo differentiation. In the third week, the hLC-MSCs had clearly differentiated into adipocytes (Fig.  3 A), with lipid droplets with positive Oil Red O staining.

figure 3

Differentiation potential of hLC-MSCs. A Representative images of hLC-MSCs that had differentiated into adipocytes, with positive Oil-Red-O staining of triglycerides. Most hLC-MSCs exhibited positive Oil-Red-O staining after being induced to differentiate into adipocytes for 21 days, whereas the control cells, which were not exposed to conditions conducive to adipocyte development, failed to undergo such differentiation (magnifications: ×200, ×400). B Representative images of hLC-MSCs that had differentiated into osteoblasts based on positive von Kossa staining of calcium deposition after three weeks of exposure to conditions specifically conducive to osteoblast development. The control cells failed to undergo such differentiation, as evidenced by the negative von Kossa staining (magnification: ×200, ×400). hLC-MSCs human lung cancer-derived mesenchymal stem cells

To promote osteogenic differentiation, the hLC-MSCs were cultured in a medium supplemented with dexamethasone, β-glycerophosphate, and ascorbate. Three weeks later, osteogenic differentiation products were detected using von Kossa staining, whereas the cells that had been cultured in normal media did not undergo such differentiation after culturing for 3–4 weeks or longer. Collectively, these data indicated that the isolated hLC-MSCs possessed the capacity to undergo multipotent differentiation under different culture conditions.

hLC-MSCs enhance cancer cell growth in vivo

Some studies have reported that MSCs promote tumor growth, whereas other have shown they suppress it. To evaluate the effect of hLC-MSCs on tumor formation in vivo, MC38 cells, a line of murine colorectal adenocarcinoma cells, were injected into the flanks of immune-competent C57BL/6N mice, either alone or in combination with hLC-MSCs. Tumors formed by the co-injection of MC38 cells and hLC-MSCs were significantly larger than those formed by the injection of MC38 cells alone. To examine the effect of hLC-MSCs on tumor growth in vivo, hLC-MSCs were also injected alone into C57BL/6N mice; this failed to induce tumor formation under the same conditions. After 6 weeks, the mice were euthanized and the tumors were dissected and weighed (Fig.  4 A). The tumor weights in the MC38 + hLC-MSC group were significantly higher than those in the control group injected with tumor cells alone (Fig.  4 B, C). These data demonstrate that the tumor-promoting abilities in mice with normal immunity were a specific property of the admixed MSCs or their derivatives.

figure 4

Human lung cancer-derived mesenchymal stem cells enhance tumor cell growth in vivo. A Representative images showing the formation of tumors in C57BL/N6 mice who were subcutaneously injected with either MC38 cells alone (left) or MC38 cells in combination with hLC-MSCs (right) (n = 6). B , C Tumor weights at the end of the experiment. The data are shown as the mean ± SD. * P  < 0.05; ** P  < 0.01; *** P  < 0.001. MC38 murine colorectal adenocarcinoma cells; hLC-MSC human lung cancer-derived mesenchymal stem cells; SD standard deviation

hLC-MSCs inhibit NK cell-mediated tumor destruction in contact and non-contact systems

Tumor cells were co-cultured with hLC-MSCs (at a 1:1 ratio) or without hLC-MSCs at tumor cell:NK cell ratios of 1:0, 1:1, 1:2, 1:4, and 1:5 in a combined medium containing DMEM with 10% FBS plus MSC-conditioned medium. In the contact systems, as presented in Fig.  5 A, B, hLC-MSCs inhibited the killing efficiency of NK cells in a dose-dependent manner; similar results were observed for the transwell system experiments, as presented in Fig.  8 A, suggesting that soluble factors are involved in this process. To rule out the possibility that the effect of mass was mediating this outcome, the same experiments were repeated with NIH3T3 fibroblast or MRC-5 fetal lung fibroblast cell lines rather than hLC-MSCs at a ratio of 1:1. Little inhibitory effect was observed in either the contact cultures or the transwell systems (data not shown). To confirm that these effects were the result of the inhibition of NK cell-mediated destruction and not due to changes in cellular proliferation, luciferase values were compared with those of the tumor cells in the control group that had not been exposed to NK cells; no significant differences were observed between the tumor cell–MSC co-culture group, the tumor cell–control cell co-culture group, and the tumor cell only group (Figs.  6 A, B and 8 C). Collectively, these results suggest that the attenuation of the ability of NK cells to destroy tumor cells can be attributed to the hLC-MSC co-culture.

figure 5

Human lung cancer-derived mesenchymal stem cells inhibit NK cell-mediated tumor destruction in vitro. Tumor cells were cultured in normal medium for 24 h ( A ) or 48 h ( B ) in the presence or absence of hLC-MSCs at hLC-MSC:NK cell ratios of 1:1, 1:2, and 1:4 in the contact system. The data are expressed as the mean ± SD based on data from three independent replicates. *Statistically significant ( P  < 0.05) difference compared with that of the cultures performed without hLC-MSCs. NK natural killer; hLC-MSCs human lung cancer-derived mesenchymal stem cells

figure 6

hLC-MSCs effects on tumor cell growth in an in vitro contact system. hLC-MSCs did not affect the kinetics of CT-26, MC-38, A549, or HepG2 tumor cells in vitro after 24 h ( A ) or 48 h ( B ) of exposure in the contact system. The histograms show the luciferase activity of the indicated cells cultured for 24 h or 48 h in vitro in the presence or absence of hLC-MSCs (n = 5). * P  ≤ 0.05, ** P  ≤ 0.001, n.s. > 0.05 by Student’s t -test. The error bars represent the SD of three independent experiments. hLC-MSC human lung cancer-derived mesenchymal stem cells; CT-26 an undifferentiated colon carcinoma cell line; MC-38 a murine colon adenocarcinoma cell line; A549 lung carcinoma epithelial cell line; HepG2 a human liver cancer cell line; n.s. not significant; SD standard deviation

hLC-MSCs inhibit T cell-mediated tumor destruction in contact and no-contact systems

Tumor cells were co-cultured with hLC-MSCs (at a 1:1 ratio) or without hLC-MSCs at tumor cell:T cell ratios of 1:0, 1:5, and 1:10 in a combined medium consisting of DMEM with 10% FBS plus MSC-conditioned medium. As presented in Fig.  7 A, hLC-MSCs inhibited the killing efficiency of T cells in a dose-dependent manner. This inhibitory effect was conspicuous when MSCs and cancer cells were in physical contact, and this influence remained significant even when they were cultured separately (Fig.  8 B). In addition, to rule out the possibility that the observed effect was related to mass in both the contact culture and transwell system, hLC-MSCs were replaced with NIH3T3 (or MRC-5) cells, which resulted in the absence of an inhibitory effect. The comparison of luciferase signals confirmed that the observed effects were not a result of changes in tumor cell proliferation (Figs.  7 B, 8 D). Collectively, these results suggest that the compromised T cell-mediated destruction of tumor cells can be attributed to the hLC-MSC co-culture.

figure 7

Human lung cancer-derived mesenchymal stem cells inhibit CTL-mediated tumor cell destruction in vitro. A Tumor cells were cultured in ordinary medium for 24 h in the presence or absence of hLC-MSCs, at hLC-MSC:CTLs ratios of 1:5 and 1:10 in a contact system. The in vitro cell viability ratios of the indicated cells are shown (n = 5). B hLC-MSCs did not affect the kinetics of CT-26, A549 or HepG2 tumor cells in vitro following 24 h of exposure in a contact system. The histograms show the luciferase activity of the indicated cells cultured in the presence or absence of hLC-MSCs (n = 5). The data are expressed as the mean ± SD from three independent replicates. * P  ≤ 0.05, ** P  ≤ 0.001, n.s. > 0.05 by Student’s t -test. The error bars represent SD of three independent experiments. CTL cytotoxic T lymphocytes; hLC-MSCs human lung cancer-derived mesenchymal stem cells; CT-26 an undifferentiated colon carcinoma cell line; A549 lung carcinoma epithelial cell line; HepG2 a human liver cancer cell line; SD standard deviation; n.s. not significant

figure 8

Human lung cancer-derived mesenchymal stem cells inhibit NK-/CTL-mediated tumor cell destructions in vitro. Tumor cells were cultured in ordinary medium for 48 h in the presence or absence of hLC-MSCs at hLC-MSC:CTL ( A ) or hLC-MSC:NK cell ( B ) ratios of 1:5 in a transwell system. The histograms show the viability of the indicated cells cultured for 48 h in vitro in the presence or absence of hLC-MSCs (n = 5). C , D hLC-MSCs did not affect the kinetics of the indicated cells when cultured in a transwell system containing tumor cells for 48 h. The histograms show the luciferase activity of the indicated cells cultured for 48 h in vitro in the presence or absence of hLC-MSCs (n = 5). * P  ≤ 0.05, ** P  ≤ 0.001, n.s. > 0.05 by Student’s t -test. Error bars represent the SD of three independent experiments. NK natural killer; CTL cytotoxic T lymphocyte; hLC-MSCs human lung cancer-derived mesenchymal stem cells; n.s. not significant; SD standard deviation

MSCs have become a focal point of research in regenerative medicine and immunology because of their capacity for self-renewal, their ability to differentiate into multiple cell types, their tendency to be recruited to sites of inflammatory injury, and their immunosuppressive capabilities. During tumorigenesis, non-cancerous tissue-derived MSCs (such as bone marrow-derived MSCs [BM-MSCs]) are recruited to tumor sites where they become integrated into the tumor stroma where they are instructed to adapt to novel features and become tumor-resident MSCs. Therefore, the properties of tissue-resident MSCs are primarily determined by the tissue in which they reside and their physical location within those tissues [ 24 ].

Although numerous studies have investigated the correlation between noncancerous tissue-derived MSCs and tumor cells, transformed tumor-resident MSCs have not been adequately characterized to date in terms of their properties and their roles in modulating tumor growth and progression. The results of the present study indicate that MSCs are commonly present in the tumors of human patients with lung cancer, which is consistent with previous reports that MSCs are present in those with many other types of cancer [ 25 , 26 ]. The study provides clear experimental evidence that indicates the isolated cells were, in fact, MSCs, and not cancer-associated fibroblasts. First, the hLC-MSCs demonstrated the capacity for multipotent differentiation by transforming into adipose and bone tissues when exposed to certain conditions in vitro. The hLC-MSCs also expressed cell surface markers that are commonly expressed on MSCs, such as CD29, CD73, CD90, CD166, and CD105, whereas hematopoietic markers such as CD14, CD31, and CD45 were absent. Additionally, unlike fibroblasts, these cells could be stably maintained in MSC-specific medium for several months without losing their capacity for multipotent differentiation.

Most previous studies that have conducted in vivo tumorigenic experiments in immunodeficient mice involved models or conditions that failed to objectively and accurately reflect the immunosuppressive effects of tumor-associated MSCs on cancer cell growth and proliferation. Thus, in the present study, C57BL/6N immunocompetent mice were used to more adequately reflect real-world conditions. The data strongly support the fact that MSCs exert tumor-promoting activity within the tumor microenvironment, an effect that appears to be at least partially due to their immunosuppressive capabilities. These results are consistent with those of previous studies; for example, in 2012, Ren et al. reported that murine lymphoma-derived MSCs (L-MSCs) exerted a much more pronounced effect on the promotion of tumor growth compared to that of matched BM-MSCs [ 27 ]. Tumor-associated MSCs differ from BM-MSCs in several ways; for instance, an in-depth in vivo analysis revealed that, unlike their BM-MSC counterparts, these L-MSCs produced high levels of the C–C motif chemokine receptor 2 (CCR2) ligands CCL2, CCL7, and CCL12, which promoted the recruitment of macrophages to tumor sites where they underwent a phenotypic shift to the tumor-promoting M2-like phenotype [ 27 ].

It has long been assumed that the primary mechanism through which the immune system achieves tumor cell destruction involves NK cells and major histocompatibility complex class I (MHC-I)-restricted CTLs [ 7 ]. Tumor cells that downregulate MHC-I molecules are protected from CTL-mediated destruction, although they are still susceptible to NK-mediated killing. Recently, human MSCs have been shown to exhibit immunosuppressive properties that affect NK and T-lymphocyte proliferation in an MHC-independent manner, bypassing the species barrier. MSCs may also be capable of inhibiting several functions of naïve and memory T cells, and they express negligible levels of MHC-II molecules, low levels of MHC-I molecules, and no co-stimulatory molecules [ 28 , 29 , 30 , 31 ]. Since MSCs themselves are not inherently immunogenic, they are incapable of eliciting allogeneic T cell responses [ 32 ]; this phenomenon has been reported to be mediated by the production of certain cytokines, such as transforming growth factor beta 1 (TGF-β1) and hepatocyte growth factor (HGF), rather than by the induction of apoptosis [ 17 , 29 , 33 , 34 , 35 ].

To test this assumption, several in vitro experiments were conducted. First, to test whether this effect was caused by direct contact or if it occurred via soluble mediators, tumor cells were co-cultured with hLC-MSCs in direct or transwell systems. Compared with the abundance seen in the blank control or the group involving mixed fibroblast populations, tumor cells in the hLC-MSC group were significantly more abundant, regardless of which co-culture system was used. To test whether this phenomenon was caused by tumor cell proliferation or the suppression of immune cell-mediated tumor destructions, the number of tumor cells was quantified in each group in which the immune cells were absent from the culture; those experiments revealed that the presence of hLC-MSCs had little impact on the proliferation of tumor cells among the different groups and confirmed that hLC-MSCs promoted tumor growth, at least in part, by inhibiting immune cell-mediated tumor cell destruction.

It is important to acknowledge that the present study was a preliminary exploration of the effects of MSCs on tumor cells, and further studies are required to investigate the underlying mechanisms. Both in vivo and in vitro studies have shown that murine BM-MSCs and human placental MSCs can induce tolerance in monocytes and a phenotypic shift in macrophages from an inflammatory phenotype to an immunosuppressive one that is characterized by increased IL-10 production and the expression of co-inhibitory molecules such as B7-H4 [ 36 , 37 ]. Interleukin 6 (IL-6) is significantly enriched in the supernatant of cultured MSCs and exerts an immunosuppressive effect; however, other studies have shown that IL-6 can promote the expression of programmed death-ligand 1 to inhibit anti-tumor immunity [ 38 , 39 ]. Collectively the findings of the present study and those previously conducted suggest that MSCs, tumor cells, and immune cells affect tumor growth and evolution through intricate regulatory mechanisms, which must be systematically investigated to gain a better understanding of the regulatory processes that control tumor growth and metastasis.

Conclusions

The presence of mesenchymal stem cells has been confirmed in some solid tumors, where they serve as important components of the tumor microenvironment; however, their role in cancer has not been fully elucidated, and there have been contradictory findings reported in terms of whether they suppress or promote tumor growth or survival. This study investigated the functions of mesenchymal stem cells isolated from tumor tissues of a patient with non-small cell lung cancer. In vitro and in vivo experiments were performed to determine the characteristics of these isolated cells and their effects on immune cell-mediated destruction of tumor cells. The isolated human lung cancer-derived mesenchymal stem cells displayed the typical morphology and immunophenotype of MSCs, and the results confirmed that they were nontumorigenic and capable of undergoing multipotent differentiation. These isolated cells remarkably enhanced tumor growth when incorporated into systems alongside tumor cells in vivo. Importantly, in the presence of MSCs, the ability of peripheral blood mononuclear cell-derived natural killer cells and activated T cells to mediate tumor cell destruction was significantly compromised. These data support the notion that hLC-MSCs protect tumor cells from immune-mediated destruction by inhibiting the antitumor activities of NK and T cells, which could contribute to poorer outcomes. This study provides a good basis for further exploration of the mechanisms that regulate the interactions and effects between these cell types in various cancers.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Alpha-Minimum Essential Medium

Alpha-smooth muscle actin

Bone marrow-derived mesenchymal stem cells

Chemokine ligand

C-C motif chemokine receptor 2

Cluster of differentiation

Cytokeratin 18

Cytotoxic T lymphocytes

Fetal bovine serum

4’,6-Diamidino-2-phenylindole

Human interleukin 2

Hepatocyte growth factor

Human leukocyte antigen

Human lung cancer-derived mesenchymal stem cells

Major histocompatibility complex class 1

Lymphoma-derived mesenchymal stem cells

Mesenchymal stem cells

Natural killer

Peripheral blood mononuclear cells

Phosphate-buffered saline

Roswell Park Memorial Institute

Standard deviation

Standard error of the mean

Transforming growth factor beta one

Vesicular stomatitis virus G

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This work was supported by Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park (Z211100002921033). 

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Xiaoyan Gao, He Ren, Zhengrong Zhang, Bo Zhang & Hongyan Huang

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Department of Orthopedics, Civil Aviation General Hospital, No.1 Gaojing Street, Chaoyang District, Beijing, 100123, China

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HH and XG designed the experiments; HH, XG, HR and ZZ performed the experiments; XG, SC, GM, QS and HH analyzed the data. XG and BZ wrote the original draft with the help of HH, GM and QS; XG and HH writing–review & editing; HH supervised the study and obtained funding to support the study. All authors have read and approved the final manuscript.

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Gao, X., Ren, H., Zhang, Z. et al. Human lung cancer-derived mesenchymal stem cells promote tumor growth and immunosuppression. Biol Direct 19 , 39 (2024). https://doi.org/10.1186/s13062-024-00479-w

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Revolutionizing Corneal Transplants with Stem Cells

Brian Lett

Corneal transplantation, also known as corneal grafting, is a surgical procedure that involves replacing a damaged or diseased cornea with a healthy cornea from a donor. The cornea is the clear, dome-shaped tissue that covers the front of the eye and plays a crucial role in focusing light onto the retina. When the cornea becomes damaged or diseased, it can lead to vision loss or impairment.

Corneal transplantation is necessary when other treatments, such as medication or contact lenses, are unable to restore vision or alleviate symptoms. It is often performed to treat conditions such as corneal scarring, keratoconus (a progressive thinning and bulging of the cornea), corneal ulcers, and corneal dystrophies.

However, traditional corneal transplantation has its challenges. The availability of donor corneas is limited, and there is a risk of rejection by the recipient’s immune system. Additionally, lifelong immunosuppressive therapy is often required to prevent rejection, which can have its own complications and side effects.

Key Takeaways

  • Corneal transplantation is a surgical procedure that replaces damaged or diseased corneal tissue with healthy donor tissue.
  • Traditional corneal transplantation has limitations, including a shortage of donor tissue and the risk of rejection.
  • Stem cells have the potential to regenerate corneal tissue and improve the success rates of corneal transplants.
  • Different types of stem cells, including limbal stem cells and mesenchymal stem cells, have been used in corneal transplants.
  • Stem cell-based corneal tissue engineering and preclinical studies have shown promising results, and clinical trials are ongoing.

The Challenges of Traditional Corneal Transplantation

Traditional corneal transplantation involves replacing the entire cornea with a donor cornea. While this procedure has been successful in restoring vision for many patients, it has its limitations. One of the main challenges is the risk of rejection. The recipient’s immune system may recognize the transplanted cornea as foreign and mount an immune response against it. This can lead to graft failure and vision loss.

To prevent rejection, recipients of traditional corneal transplants are typically required to take immunosuppressive medications for the rest of their lives. These medications suppress the immune system’s response to the transplanted cornea, but they also increase the risk of infections and other complications.

Another challenge is the limited availability of donor corneas. The demand for corneal transplants far exceeds the supply, resulting in long waiting lists for patients in need. This shortage of donor corneas highlights the need for alternative approaches to corneal transplantation.

The Role of Stem Cells in Corneal Regeneration

Stem cells have emerged as a promising alternative to traditional corneal transplantation. These cells have the unique ability to differentiate into various cell types, including corneal cells. By harnessing the regenerative potential of stem cells, researchers are exploring the possibility of using them to regenerate damaged corneal tissue.

Stem cell-based corneal regeneration offers several advantages over traditional transplantation. First, it eliminates the need for donor corneas, addressing the issue of limited availability. Instead, stem cells can be obtained from the patient’s own body or from a compatible donor, reducing the risk of rejection.

Second, stem cell-based corneal regeneration has the potential to restore normal corneal function and improve visual outcomes. By regenerating the damaged tissue, it may be possible to achieve better integration and functionality compared to traditional transplantation.

Types of Stem Cells Used in Corneal Transplants

There are several types of stem cells that can be used in corneal transplants. These include:

1. Limbal stem cells: Located in the limbus, a region at the edge of the cornea, limbal stem cells are responsible for maintaining and regenerating the cornea’s epithelial layer. These cells have been successfully used in treating conditions such as limbal stem cell deficiency and chemical burns.

2. Corneal stromal stem cells: Found within the stroma, the middle layer of the cornea, corneal stromal stem cells have the potential to differentiate into various cell types within the cornea. They can be isolated from healthy corneas or derived from other sources such as bone marrow or adipose tissue.

3. Induced pluripotent stem cells (iPSCs): iPSCs are adult cells that have been reprogrammed to a pluripotent state, meaning they can differentiate into any cell type in the body. These cells can be generated from the patient’s own cells, eliminating the risk of rejection.

Each type of stem cell has its own characteristics and benefits. Limbal stem cells are particularly useful for treating conditions that primarily affect the corneal epithelium, while corneal stromal stem cells and iPSCs offer broader regenerative potential.

Stem Cell-Based Corneal Tissue Engineering

Stem cell-based corneal tissue engineering involves creating a new cornea using stem cells. This process typically involves three main steps: cell isolation, cell expansion, and tissue fabrication.

First, stem cells are isolated from the patient’s own body or from a compatible donor. This can be done using various techniques, such as biopsy or tissue culture. The isolated stem cells are then expanded in the laboratory to increase their numbers.

Once a sufficient number of stem cells have been obtained, they can be used to fabricate a new cornea. This can be achieved through various methods, such as seeding the stem cells onto a scaffold or using bioengineering techniques to create a three-dimensional corneal tissue.

The fabricated cornea can then be transplanted into the patient’s eye, where it integrates with the surrounding tissues and regenerates the damaged corneal tissue. This approach holds great promise for restoring vision and improving outcomes for patients in need of corneal transplantation.

Preclinical Studies on Stem Cell-Based Corneal Transplants

stem cell research studies

Numerous preclinical studies have been conducted to evaluate the safety and efficacy of stem cell-based corneal transplants. These studies have shown promising results and have provided valuable insights into the potential of this approach.

For example, a study published in the journal Stem Cells Translational Medicine in 2017 demonstrated the successful transplantation of corneal stromal stem cells in a rabbit model. The transplanted cells integrated with the host tissue and regenerated the damaged cornea, leading to improved visual outcomes.

Another study, published in the journal Nature in 2019, reported the successful generation of corneal tissue from iPSCs. The researchers used bioengineering techniques to create a three-dimensional corneal tissue that closely resembled the native cornea. When transplanted into mice, the fabricated cornea integrated with the host tissue and restored corneal function.

These preclinical studies provide strong evidence for the potential of stem cell-based corneal transplants. However, further research is needed to optimize the techniques and ensure their safety and efficacy before they can be translated into clinical practice.

Clinical Trials of Stem Cell-Based Corneal Transplants

Several clinical trials have been conducted to evaluate the safety and efficacy of stem cell-based corneal transplants in humans. These trials have shown promising results and have paved the way for further research and development in this field.

One notable clinical trial was conducted by researchers at the University of Pittsburgh School of Medicine. The trial involved transplanting limbal stem cells derived from deceased donors into patients with limbal stem cell deficiency. The results, published in the journal Science Translational Medicine in 2012, showed that the transplanted cells successfully regenerated the damaged corneal tissue and improved visual outcomes.

Another clinical trial, conducted by researchers at Kyoto University in Japan, involved transplanting corneal stromal stem cells derived from patients’ own bone marrow into patients with corneal scarring. The results, published in the journal Stem Cells Translational Medicine in 2016, demonstrated that the transplanted cells integrated with the host tissue and regenerated the damaged cornea, leading to improved visual outcomes.

These clinical trials provide strong evidence for the safety and efficacy of stem cell-based corneal transplants in humans. However, larger-scale trials are needed to further evaluate the long-term outcomes and potential complications of this approach.

Success Rates and Benefits of Stem Cell-Based Corneal Transplants

The success rates of stem cell-based corneal transplants vary depending on the specific technique used and the underlying condition being treated. However, overall, these transplants have shown promising results in restoring vision and improving outcomes for patients.

One of the main benefits of stem cell-based corneal transplants is the reduced risk of rejection. By using the patient’s own cells or compatible donor cells, the risk of immune rejection is significantly reduced compared to traditional transplantation. This eliminates the need for lifelong immunosuppressive therapy, which can have its own complications and side effects.

Additionally, stem cell-based corneal transplants have the potential to restore normal corneal function and improve visual outcomes. By regenerating the damaged tissue, it may be possible to achieve better integration and functionality compared to traditional transplantation.

Future Directions and Potential Applications of Stem Cell-Based Corneal Transplants

The field of stem cell-based corneal transplants is rapidly evolving, with ongoing research and development aimed at improving techniques and expanding their applications. Some potential future directions and applications include:

1. Personalized medicine: The use of iPSCs allows for the generation of patient-specific corneal tissue, which could potentially eliminate the need for donor corneas altogether. This personalized approach could lead to better outcomes and reduce the risk of rejection.

2. Treatment of complex corneal diseases: Stem cell-based corneal transplants hold promise for treating complex corneal diseases that are difficult to manage with traditional transplantation. For example, they may be used to treat conditions such as corneal scarring, corneal ulcers, and corneal dystrophies.

3. Integration with other regenerative therapies: Stem cell-based corneal transplants can be combined with other regenerative therapies, such as gene therapy or tissue engineering, to further enhance their efficacy and improve outcomes.

4. Development of bioengineered corneas: Researchers are working on developing bioengineered corneas that closely resemble the native tissue in terms of structure and function. These bioengineered corneas could potentially be used as an alternative to donor corneas in transplantation.

The Promise of Stem Cell-Based Corneal Transplants for Vision Restoration

Stem cell-based corneal transplants hold great promise for restoring vision and improving outcomes for patients in need of corneal transplantation. By harnessing the regenerative potential of stem cells, researchers are exploring new approaches to address the limitations of traditional transplantation.

The use of stem cells in corneal regeneration offers several advantages over traditional transplantation, including reduced risk of rejection and improved visual outcomes. Preclinical studies and clinical trials have provided strong evidence for the safety and efficacy of this approach, paving the way for further research and development.

However, more research is needed to optimize the techniques, ensure their long-term safety and efficacy, and expand their applications. Continued investment in stem cell research and development is crucial to unlock the full potential of stem cell-based corneal transplants and bring them closer to widespread clinical use. With further advancements in this field, we can look forward to a future where vision restoration becomes a reality for all patients in need.

If you’re interested in the latest advancements in eye surgery, you may want to check out this informative article on corneal transplant stem cells. It explores how stem cells are being used to revolutionize the field of corneal transplantation, offering hope to those suffering from corneal diseases and injuries. To learn more about this groundbreaking procedure, click here: Corneal Transplant Stem Cells .

What is a corneal transplant?

A corneal transplant is a surgical procedure that involves replacing a damaged or diseased cornea with a healthy one from a donor.

What are stem cells?

Stem cells are undifferentiated cells that have the ability to differentiate into specialized cells and regenerate damaged tissues.

How are stem cells used in corneal transplants?

Stem cells can be used to regenerate the cornea and improve the success rate of corneal transplants. They can be harvested from the patient’s own body or from a donor.

What are the benefits of using stem cells in corneal transplants?

Using stem cells in corneal transplants can improve the success rate of the procedure, reduce the risk of rejection, and speed up the healing process.

Are there any risks associated with using stem cells in corneal transplants?

There are some risks associated with using stem cells in corneal transplants, such as infection, rejection, and abnormal growth of cells.

How long does it take to recover from a corneal transplant using stem cells?

The recovery time for a corneal transplant using stem cells varies depending on the individual and the extent of the procedure. It can take several weeks to several months for the eye to fully heal.

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  • Published: 17 June 2019

Advances in stem cell research and therapeutic development

  • Michele De Luca   ORCID: orcid.org/0000-0002-0850-8445 1   na1 ,
  • Alessandro Aiuti 2 , 3   na1 ,
  • Giulio Cossu 4   na1 ,
  • Malin Parmar   ORCID: orcid.org/0000-0001-5002-4199 5 , 6   na1 ,
  • Graziella Pellegrini 7   na1 &
  • Pamela Gehron Robey 8   na1  

Nature Cell Biology volume  21 ,  pages 801–811 ( 2019 ) Cite this article

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  • Stem-cell therapies

Despite many reports of putative stem-cell-based treatments in genetic and degenerative disorders or severe injuries, the number of proven stem cell therapies has remained small. In this Review, we survey advances in stem cell research and describe the cell types that are currently being used in the clinic or are close to clinical trials. Finally, we analyse the scientific rationale, experimental approaches, caveats and results underpinning the clinical use of such stem cells.

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Acknowledgements

The authors would to thank the following parties, from whose work elements of our figures were modified; F. Aiuti (Fig. 2a ), A. De Luca (Fig. 3a ), and J. Drouin-Ouellet (Fig. 4 ). This work was partially supported by Regione Emilia-Romagna, Asse 1 POR-FESR 2007-13 to M.D.L. and G.P.; Italian Telethon Foundation to A.A.; Division of Intramural Research, National Institute of Dental Research, a part of the Intramural Research Program, the National Institutes of Health, Department of Health and Humman Services (ZIA DE000380 to P.G.R.), the Wellcome Trust (ME070401A1), the MRC (MR/P016006/1) the GOSH-SPARKS charity (V4618) to G.C.

Author information

These authors contributed equally: Michele De Luca, Alessandro Aiuti, Giulio Cossu, Malin Parmar, Graziella Pellegrini, Pamela Gehron Robey.

Authors and Affiliations

Center for Regenerative Medicine “Stefano Ferrari”, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

Michele De Luca

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

Alessandro Aiuti

Vita-Salute San Raffaele University, Milan, Italy

Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Giulio Cossu

Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund, Sweden

Malin Parmar

Lund Stem Cell Center, Lund University, Lund, Sweden

Center for Regenerative Medicine “Stefano Ferrari”, Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy

Graziella Pellegrini

National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA

Pamela Gehron Robey

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Corresponding author

Correspondence to Michele De Luca .

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Competing interests.

M.D.L. and G.P. are members of the Board of Directors of Holostem Terapie Avanzate Srl and consultant at J-TEC Ltd, Japan Tissue Engineering. A.A. is the principal investigator of clinical trials of HSC-GT for ADA-SCID, MLD and Wiskott–Aldrich, sponsored by Orchard Therapeutics. Orchard Therapeutic is the marketing authorization holder of Strimvelis in the European Union. M.P. is the owner of Parmar Cells AB and co-inventor of the US patent application 15/093,927 owned by Biolamina AB and EP17181588 owned by Miltenyi Biotec. M.P. is a New York Stem Cell Foundation Robertson Investigator.

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De Luca, M., Aiuti, A., Cossu, G. et al. Advances in stem cell research and therapeutic development. Nat Cell Biol 21 , 801–811 (2019). https://doi.org/10.1038/s41556-019-0344-z

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Received : 06 August 2018

Accepted : 09 May 2019

Published : 17 June 2019

Issue Date : July 2019

DOI : https://doi.org/10.1038/s41556-019-0344-z

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