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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: 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.
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Stem cells What they are and what they do

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Putting Stem Cell-Based Therapies in Context

Photos of Karen M. Wai, Theodore Leng, and Jeffrey Goldberg

Karen M. Wai, MD, Theodore Leng, MD, MS, and Jeffrey Goldberg, MD, PhD, Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, CA

In recent years, the potential of stem cell-based therapies to treat a wide range of medical conditions has given hope to patients in search of novel treatments or cures. At the same time, thousands of rogue clinics have sprung up across the U.S and around the world, offering stem cell-based therapies before being tested for safety and efficacy. When communicating to the public about stem cell-based therapies, it is important to put any treatment claims in context.

Stem cell-based therapies include any treatment that uses human stem cells. These cells have the potential to develop into many different types of cells in the body. They offer a theoretically unlimited source of repair cells and/or tissues. (For more about stem cells, see https://stemcells.nih.gov .)

Over the past three decades, the Food and Drug Administration (FDA) has approved several stem cell-based products. These include bone marrow transplants, which have been transformational for many cancer patients, and therapies for blood and immune system disorders. 1 Other approved treatments include dental uses for gum and tissue growth and in skin for burns. Since the early 2000s, stem cell-based therapies have been explored in many eye diseases, including age-related macular degeneration and glaucoma. 2 Stem cell-based therapies are also being explored for neurodegenerative diseases such as stroke and Alzheimer’s disease, and for countless other conditions.

Over time, we expect that breakthroughs will continue with stem cell-based therapies for many conditions. However, at this time, rogue clinics, driven by profits, are taking advantage of patients desperate for cures and are claiming dramatic results, often exaggerated in sensational media testimonials. The clinics may mimic legitimate practices. They may extract a patient’s own stem cells, concentrate or modify the cells, and then re-inject them. Some manufacturers offer stem cell-based derived products, such as “biologic eye drops” made with placenta extract or amniotic fluid to treat dry eye. Clinics may provide misleading information and advertise their practice as running clinical trials. However, these clinics almost always work without FDA regulatory approval and outside of legitimate clinical trial approaches.

These unproven, unregulated stem cell treatments carry significant risk. The risks range from administration site reactions to dangerous adverse events. For example, injected cells can multiply into inappropriate cell types or even dangerous tumors. A 2017 report described one Florida clinic that blinded patients with stem cell eye injections. 3

The Pew Charitable Trusts gathered 360 reports of adverse events related to unapproved stem cell therapies, including 20 cases that caused death. 4 Further, adverse events are likely underreported because these products are not FDA approved or regulated. Many unproven stem cell-based therapies cost thousands of dollars to patients and are not covered by insurance. Further, even if patients avoid adverse events from these therapies, they may suffer consequences from delaying evidence-based treatments.

The FDA has made substantial progress toward regulation of stem cell-based therapies. In 2017, it released guidance under the 21 st Century Cures Act that clarifies which stem-cell based therapies fall under FDA regulation. It also better defined how the agency will act against unsafe or unregulated products. 5 As of May 2021, the FDA has more strongly enforced compliance for clinics that continue to market unproven treatments. 6

Despite this increased regulation, rogue clinics are still relatively commonplace. A 2021 study estimated that there are over 2,500 U.S. clinics selling unproven stem cell treatments. 7 Patients at these clinics are often led to believe that treatments are either approved by the FDA, registered with the FDA, or do not require FDA approval. It is important to recognize that there are limits to the FDA’s expanded reach, especially when it is targeting hundreds of clinics at once. Our clinic at Stanford recently cared for a patient who had received stem cell injections behind his eyes, where he developed tumors that ultimately ruined vision in both eyes.

Progress in stem cell science is rapidly translating to the clinic, but it is not yet the miracle answer we envision. With time, stem cell-based therapies will likely expand treatment options. People considering a stem-cell based therapy should find out if a treatment is FDA-approved or being studied under an FDA-approved clinical investigation plan. This is called an Investigational New Drug Application. Importantly, being registered with ClinicalTrials.gov does not mean that a therapy or clinical study has been authorized or reviewed by the FDA. For more information about stem cell therapies, visit www.closerlookatstemcells.org , a resource from the International Society for Stem Cell Research.

As we look hopefully to the future, we need greater awareness of the current limitations of stem cell therapy and the dangers posed by unregulated stem cell clinics. Strong FDA regulation and oversight are important for ensuring that stem cell-based therapies are safe and effective for patients. Accurate communication to the public, careful advocacy by physicians, and education of patients all continue to be crucial.

References :

1 U.S. Food and Drug Administration, “Approved Cellular and Gene Therapy Products,” Sept. 9, 2022, https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products .

2 Stern JH, Tian Y, Funderburgh J, Pellegrini G, Zhang K, Goldberg JL, Ali RR, Young M, Xie Y, Temple S. Regenerating Eye Tissues to Preserve and Restore Vision. Cell Stem Cell . 2018 Sep 6;23(3):453. doi: 10.1016/j.stem.2018.08.014. Erratum for: Cell Stem Cell. 2018 Jun 1;22(6):834-849. PMID: 30193132.

3 Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, Parrott MB, Rosenfeld PJ, Flynn HW Jr, Goldberg JL. Vision Loss after Intravitreal Injection of Autologous "Stem Cells" for AMD. N Engl J Med . 2017 Mar 16;376(11):1047-1053. doi: 10.1056/NEJMoa1609583. PMID: 28296617; PMCID: PMC5551890.

4 The Pew Charitable Trusts, “Harms Linked to Unapproved Stem Cell Interventions Highlight Need for Greater FDA Enforcement,” June 1, 2021, https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2021/06/harms-linked-to-unapproved-stem-cell-interventions-highlight-need-for-greater-fda-enforcement .

5 U.S. Food and Drug Administration, “FDA announces comprehensive regenerative medicine policy framework,” Feb. 2, 2022, https://www.fda.gov/news-events/press-announcements/fda-announces-comprehensive-regenerative-medicine-policy-framework .

6 U.S. Food and Drug Administration, “FDA Extends Enforcement Discretion Policy for Certain Regenerative Medicine Products,” July 7, 2020, https://www.fda.gov/news-events/press-announcements/fda-extends-enforcement-discretion-policy-certain-regenerative-medicine-products .

7 Turner L. The American stem cell sell in 2021: U.S. businesses selling unlicensed and unproven stem cell interventions. Cell Stem Cell . 2021 Nov 4;28(11):1891-1895. doi: 10.1016/j.stem.2021.10.008. PMID: 34739831.

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Published: 14 February 2023

Progress and challenges in stem cell biology

Effie Apostolou 1 ,
Helen Blau 2 ,
Kenneth Chien 3 ,
Madeline A. Lancaster 4 ,
Purushothama Rao Tata 5 ,
Eirini Trompouki 6 ,
Fiona M. Watt 7 ,
Yi Arial Zeng 8 , 9 &
Magdalena Zernicka-Goetz 10 , 11

Nature Cell Biology volume 25 , pages 203–206 ( 2023 ) Cite this article

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Since stem cells were first discovered, researchers have identified distinct stem cell populations in different organs and with various functions, converging on the unique abilities of self-renewal and differentiation toward diverse cell types. These abilities make stem cells an incredibly promising tool in therapeutics and have turned stem cell biology into a fast-evolving field. Here, stem cell biologists express their view on the most striking advances and current challenges in their field.

Effie Apostolou: induced pluripotency — the continued reprogramming revolution

The seminal discovery of pluripotency induction achieved by means of transcription factors or chemical cocktails has revolutionized multiple biomedical fields and shed light on processes including development, aging, regeneration and cancer. Over the past 15 years, many burning questions around reprogramming mechanisms, trajectories and translational limitations have been addressed.

High-throughput functional screens identified critical regulators and barriers of reprogramming, while multimodal omics studies helped with constructing four-dimensional (4D) roadmaps of the complex transcriptional, epigenetic, topological, proteomic and metabolic changes that somatic cells undergo upon loss of their initial identity and acquisition of pluripotency. Parallel studies have also identified potentially detrimental, long-lasting aberrations that are introduced along the way. Moreover, single-cell technologies during cellular reprogramming captured intriguing intermediate and refractory states, reminiscent of early embryonic fates, senescence response, regeneration or tumorigenesis.

Despite this progress, important gaps remain and new questions continually arise. What are the cause-and-effect relationships during the multi-layered molecular chain reaction of reprogramming, and which factors lie at the top of the regulatory hierarchy? How can we reproducibly and deterministically reprogram cell identity, if we know the start and end points, to enable efficient and safe generation of any therapeutically relevant cell type from easily accessible tissues? How can we either avoid or rationally exploit the epigenetic variability of induced pluripotent stem cells? Can we capture, and propagate in vitro, transient intermediate cell states of biomedical relevance? Future studies using advanced engineering approaches for acute and reversible perturbations in defined time windows will be critical to address the functional interconnections of various reprogramming regulators and enable fine-tuning toward end states of interest. Moreover, ongoing single-cell efforts to map the continuum of cell states in early embryos and tissues or synthetic structures will determine more definitively the degree to which reprogramming intermediates recapitulate physiological or pathological transitions. Together with continuously improved computational approaches and modelling, these efforts will enable accurate predictions of critical conditions and cocktails for precise, reproducible and error-free cell fate engineering. These engineered fates can ultimately expand the toolbox for generating complex tissues and organoids for disease modelling and drug screening and for understanding and ameliorating hallmarks of ageing and cancer.

Helen Blau: multiple strategies to augment muscle regeneration and increase strength

Mobility is a major determinant of quality of life. Elderly patients with sarcopenia or patients with heritable muscle-wasting disorders suffer from a debilitating loss of muscle strength for which there is no approved treatment. COVID-19 highlighted the need for strategies to strengthen atrophied diaphragm muscles after ventilator support. Although our knowledge of stem cell function in regeneration has markedly increased, major knowledge gaps and challenges remain.

First, muscle stem cells (MuSCs) are a heterogeneous population that diverges over time and in response to disease or ageing. Targeting the functional subset of MuSCs is an unmet challenge. Second, understanding the role of the microenvironment and the muscle stem cell niche in muscle stem cell behaviour is key. Data are emerging showing that MuSCs respond not only to biochemical but also to biomechanical cues and that the elasticity of the niche matters. This suggests that stiffer fibrotic muscles, characteristic of muscular dystrophy or ageing, will harbour stem cells with impaired regenerative function. The development of hydrogels that can stiffen or soften on demand, while maintaining stem cells in a viable state, could provide new molecular and signalling insights into stem cell mechanosensing mechanisms, how they change with ageing and how they can be overcome. Third, from advances in single-cell and single-nuclei RNA sequencing, we are gaining knowledge of the gene expression patterns of the complex, diverse array of cell types that populate the niche. However, these technologies entail tissue destruction and therefore do not provide spatial information regarding cell–cell interactions that are crucial to maintaining stem cell quiescence and inducing stem cell activation and efficacious regeneration. There is a great need for spatial proteomics and multiplexed imaging modalities that preserve information about cell location and the dynamics of cell–cell interactions characteristic of regeneration, disease and ageing. Finally, inflammation has beneficial roles in wound healing, but is deleterious when chronic, as in aged muscles. Finding ways to rejuvenate muscle form and function remains a major challenge. The discovery of the prostaglandin degrading enzyme 15-PGDH, an immune modulator, as a pivotal molecular determinant of muscle ageing is a notable step in that direction. Remarkably, overexpression of 15-PGDH for one month in young adult mouse muscles induces atrophy and weakness, whereas inhibition of 15-PGDH in aged mouse muscles results in a 15% increase in muscle mass, strength and exercise performance. Solving these challenges will pave the way for new, effective stem cell-targeted therapeutic agents to regenerate and rejuvenate muscle.

Kenneth Chien: heart progenitors rebuild cardiac muscle

Rebuilding the failing human heart with working muscle is the holy grail of regenerative medicine. Although initial therapeutic attempts with non-cardiac cells have proven unfruitful, mouse studies have shown the potential to create de novo cardiomyocyte-like cells in situ by direct reprogramming via gene transfer. A novel class of adult claudin-6 + epicardial progenitors can convert to muscle, contributing to regeneration of the injured vertebrate heart. The studies point to a key role of tight junction proteins in the formation of a honeycomb-like regenerative structure. Although the adult human epicardium lacks these specific progenitors, uncovering their regenerative molecular pathways could identify new signals that can restore the myogenic potential of non-human epicardial cells via conversion to a progenitor state.

Thus far, the most advanced stem cell therapeutic agents are based on human embryonic stem (ES) cells for the generation of either cardiomyocytes or human ventricular progenitors (HVPs) for transplantation in large animals following cardiac injury. Issues of scalability, efficacy, clear evidence of working ventricular muscle grafts, lack of teratoma formation and tissue integration have all been largely addressed, moving both ES-cell-derived cell types toward the clinic with large pharma partners. However, additional issues remain, including safety (arrhythmias), durability (rejection) and the development of clinically tractable in vivo delivery systems. Our work on cardiogenesis over two decades recently led to the discovery of HVPs, which can migrate toward the injury site, prevent fibrosis via fibroblast repulsion, and proliferate to form large human ventricular muscle grafts to improve function in failing pig hearts. Additional work is ongoing, but early returns support the therapeutic potential of HVPs with minimal major side effects, with a two-year projected timeline for a first-time-in-human study. Prevention of rejection with optimal drug regimens, hypoimmune ES cell lines and new tolerization strategies, as well as novel catheters for in vivo delivery, are on the horizon. With these advances, HVPs might eventually provide new hope for patients with near-end-stage heart failure and no other options.

Madeline A. Lancaster: next-generation human neural stem cell models

The field of neural stem cell biology has made great strides in the past decade. What started out with neural stem cells that were cultured ex vivo to generate neurons and glia has evolved into a diverse field of ever-more-complex tools to model not just individual cells, but whole 3D neural tissues in a dish called neural organoids. Such organoids mimic not only the cellular makeup of the developing brain, but also local tissue architecture, with recent methods even demonstrating morphogenetic movements of neurulation.

Organoids and other in vitro models of the nervous system are becoming increasingly complex, for example through the use of so-called assembloids to combine different regions and examine their integration. Neural organoids also enable extensive neuronal maturation, even reaching hallmarks seen in the postnatal brain. However, as these models increase in complexity, so too do the challenges. With increasing size and maturity, the lack of vasculature becomes problematic. Although promising results have come from in vivo transplantation and integration of endothelial cells, vascularization leading to more advanced tissue development remains to be demonstrated. This challenge will likely represent one of the most difficult hurdles not just for the neural organoid community, but for the field of organoids as a whole, and creative approaches will be needed.

Brain organoids are already paving the way to fundamental discoveries in human neurobiology and are providing new understanding of disease pathogenesis. The future will hold new insight into why the human brain is unique, as well as how to prevent and treat various neurological conditions. Organoids may hold the key to these insights, but they cannot be the only tool, and it will be important to use them as complementary approaches alongside more established methods. Marrying in vitro and in vivo approaches will be the key to uncovering fundamental processes of neurobiology and answer age-old questions such as how genetics influence connectivity, how networks of neurons compute and how information is stored in the brain. The brain is still a largely uncharted territory, and powerful techniques combined with creative minds are needed to untangle its mysteries.

Purushothama Rao Tata: phenotypic and functional interrogation of lung biology at single-cell resolution

Lung tissues are relatively quiescent at homeostasis, but they respond rapidly to regenerate lost cells after injury. Early lineage tracing studies in animal models showed that this regeneration is driven predominantly by several ‘professional’ and facultative stem and progenitor cells in different regions of the lung, including basal and secretory cells in the airways and type 2 pneumocytes in the alveoli. These studies also uncovered a remarkable plasticity of some differentiated cell populations that contribute to regeneration following severe injury. More recently, multiple groups have used single-cell omics approaches to catalogue lung cells and their associated molecular signatures in great detail. Remarkably, in the case of the human lung, these efforts have identified previously unknown and uncharacterized cell types located in discrete regions. These cell populations are often quite heterogeneous, and include transitory states enriched in lungs from patients with respiratory disease. Significantly, these cell types are not found in the mouse, the animal model most commonly used for lung research. Consequently, there is an urgent need to develop new experimental tools to test their normal in vivo function and role in regeneration and disease.

To address this problem, efforts are underway by several groups, including our own, to develop genetically engineered ferrets and pigs as new animal models. Similarly, analytical tools are being optimized to infer cell lineages in human lungs based on clonally amplified genetic variants (single-nucleotide polymorphisms or mitochondrial heteroplasmy). In the case of ex vivo organotypic cultures, such as those derived from human induced pluripotent stem cells or primary foetal or adult lung progenitors, there remain many challenges. These include attaining or retaining mature cell types in the correct ratios to match those in normal in vivo lung tissue. To overcome this challenge, collaborative efforts are underway between lung stem cell biologists and bioengineers to generate new scaffolds to reassemble and mimic the cell–cell interactions found in native lung tissue niches. Taken together, these new approaches have the potential to identify the genetic circuits that regulate normal and disease-associated human lung cell states, establish scalable disease models and, ultimately, develop cell-based therapies to treat degenerative lung diseases.

Eirini Trompouki: the time journey of blood stem cells

Haematopoietic stem and progenitor cells (HSPCs) are critical for sustaining lifelong haematopoiesis via their extensive self-renewal and multilineage differentiation capacities. The secrets to how HSPCs acquire these capacities reside in the enigmatic process through which they are generated during an embryonic endothelial-to-haematopoietic transition (EHT). On the other end of the spectrum, age alters HSPCs, resulting in defective haematopoiesis. The most critical problems in HSPC biology relate to these lifetime bookends. Recently, human HSPC development was addressed in a spatial and single-cell manner, revealing that a haematopoietic stem cell (HSC) transcriptional signature is established after the emergence of HSCs along with continuously evolving cell surface markers, while haematopoietic heterogeneity already starts to be established at the haemogenic endothelium stage. Single-cell transcriptomics also led to the identification of a progenitor population that is responsive to retinoic acid and gives rise to haemogenic endothelial cells. Our group and others pinpointed the importance of DNA and RNA sensors in EHT. We and others found that transposable elements and R-loops trigger innate immune sensors to induce sterile inflammation that enhances EHT. Another layer of regulation lies in the interaction between HPSCs and other cells, such as macrophages or T cells, that are proposed to perform quality control of HSPCs during development and adulthood, respectively. Despite this progress, however, we still cannot faithfully recapitulate EHT in vitro and produce the massive quantities of HPSCs required for transplantations and gene therapy. Therefore, I think one of the most important aspects of haematology in the near future will be generating and maintaining good quality and quantity of HSPCs in vitro.

Ageing of HSPCs, on the other hand, is especially relevant because the population of the Earth is continuously ageing. An interesting feature of ageing that is lately gaining more and more attention is clonal haematopoiesis, which has been linked to haematological (and other) diseases. Inflammation, chemotherapy and irradiation have been shown by many groups to be advantageous for mutated clones. It is interesting to speculate that a collection of stressful moments experienced during life are ‘memorized’ by HSPCs and aided by clonality to instigate ageing. It was recently demonstrated that epigenetic memory is a feature not only of immune cells but also of HSCs. Further research needs to show whether every stress in life could be depicted in our genome as ‘memory’ and finally constitute the intricate mechanism of ageing.

Fiona M. Watt: understanding epidermal stem cell biology through data integration

Although mammalian skin contains many different cell types, the best-characterized stem cell population is in the epidermis, the multilayered epithelium that forms the skin surface. Autologous sheets of cultured epidermis were one of the first cell therapies involving ex vivo expansion of stem cells to be validated clinically, dating back to the early 1980s. That approach has been refined over the years, and the life-saving effects of combining cell and gene therapy to treat blistering skin disorders have been demonstrated unequivocally. In parallel with the development of techniques to culture human epidermis, the mouse became a key model for stem cell studies because of the availability of tools to target the different epidermal layers and the demonstration that genetic lesions in humans could be phenocopied in the mouse. With the advent of extensive single-cell RNA sequencing (scRNA-seq) databases for healthy and diseased human skin, it is essential that stem cell researchers use these resources both to validate their experimental models and to design new experiments. We need to look hard at the extent to which mouse models are still appropriate for modelling healthy and diseased human skin.

A very exciting challenge we face is data integration. There are many different axes along which integration can be achieved. One is spatiotemporal — the ability to correlate changes in cell types and states as a function of time and distribution within the skin. I am particularly intrigued by the possibility of correlating macroscopic skin features that are captured by optical coherence tomography with features obtained via spatial transcriptomics. Another example is integrating epidermal datasets from transcriptomics, proteomics, lipidomics and glycomics to gain a more holistic understanding of the nature of the stem cell state. In our enthusiasm for scRNA-seq, we risk ignoring the central dogma that DNA makes RNA that makes protein, and failing to remember the importance of protein modifications and turnover. I believe that by integrating epidermal stem cell responses to different extracellular cues, whether physical or biochemical, we will gain new insights into stem cell function and find switches between cell states that are conserved between tissues.

Yi Arial Zeng: the journey to islet regeneration

The islets of Langerhans are endocrine regions of the pancreas containing hormone-producing cells. β-cells produce and secrete insulin — the hormone that lowers blood glucose levels. Insufficient numbers of functional β-cells are associated with both type 1 and late-stage type 2 diabetes. With 1 in 11 people being diabetic, there is a great need to understand how the adult islet mass is maintained and how β-cells are regenerated to guide new therapies.

Stimulation of in situ islet regeneration is one approach for replenishing β-cells, through the formation of new progenitor-derived β-cells and enhanced proliferation of existing β-cells. Although the existence of islet progenitors in postnatal life has long been debated, recent work using mouse models has reported their existence in adults, leading to exciting opportunities for dissecting the activation mechanisms of these progenitors during homeostasis, regeneration and aging. It is noteworthy that neogenesis from progenitors and β-cell replication are not mutually exclusive: the proliferative β-cell subpopulation could possibly be the progeny of the progenitors, or there could be parallel proliferative pathways. Considering that relatively few insulin-secreting cells are needed to ameliorate hyperglycaemia, in vivo transdifferentiation represents another promising route. It has been reported that pancreatic exocrine cells and gut cells can be transdifferentiated into insulin-secreting cells. Collectively, these approaches aim to offer therapeutic strategies to stimulate in situ regeneration.

Pancreatic islet transplantation from donors is a recognized approach for replacing lost or damaged β-cells. Because of the shortage of donors, ongoing efforts aim to identify a renewable supply of human β-cells. A promising idea involves the differentiation of human pluripotent stem cells into β-like cells, and clinical trials using these β-like cells are underway. However, one may ask whether transplanting only mature β-cells is optimal, as proper glucose regulation requires coordination between various islet cell types. Will it be advantageous to produce whole islets in vitro rather than differentiating cells solely into β-like cells? Murine adult islet progenitors can generate organoids that contain all endocrine cell types of the intact islet and are proven to ameliorate diabetes in murine models. More work will be needed to establish the identity of these progenitors in the human pancreas and to translate the organoid culture system to human cells. As our understanding of islet regeneration matures, therapeutic transplant options will continue to emerge.

Magdalena Zernicka-Goetz: stem cells in modelling embryology

ES cells, derived from the pluripotent epiblast, can host transgenes and be reintroduced back into the embryo to generate a chimeric animal and a pure breeding line in future generations. A stunning application of ES cells in recent years has been their use to generate embryo-like structures in vitro. Several approaches have advanced our quest to recapitulate embryogenesis.

A 2D method using exclusively ES cells cultured as micropatterns offered a powerful route toward understanding how different cell types are established and signal between themselves. A second model, in which large aggregates of ES cells are treated with chemicals and growth factors, generated 3D structures developing many aspects of the segmental body plan, although still lacking body regions, particularly those required for forebrain development.

The importance of extraembryonic signalling was recognized through a series of whole-embryo models. The first such model, built from ES cells alone, pointed to the role of signals normally provided by the extraembryonic primitive endoderm, which can be replaced by the extracellular matrix to polarize ES cells to form a rosette-like structure that undertakes lumenogenesis. The second model, built from ES cells and trophectoderm stem cells, taught us that this interaction alone is sufficient to establish amniotic cavity and posterior embryo identity to induce mesoderm and germ cells. By incorporating a third stem cell type, extraembryonic endoderm cells, we achieved the formation of the anterior signalling centre and anterior–posterior patterning. Recently, additional approaches we and others undertook led to the generation of embryo models that were capable of developing much further to establish brain and heart structures and initiate organogenesis. Such whole-embryo-like models have brought insight into the biophysical and biochemical factors mediating stem cell self-organization and defining the cellular constituents, the chemical environment and the physical context required for embryo assembly.

Despite this progress, challenges remain. Cell fate specification relies on chemical cross-talk within and between lineages. Cell fate decisions must be spatiotemporally coordinated by establishing and interpreting gradients of numerous diffusible signalling proteins. We have much to learn about these combinatorial effects and about how to improve the efficiency with which different cell types combine to form embryo-like structures. A deep understanding of the components of cellular, biochemical and biophysical networks will be crucial to reaching this goal. Computational modelling will allow us to predict and guide self-organizational outcomes through exploitation of the capacity of cell communication to promote self-organization in vivo. It would also be powerful to advance our abilities to culture model embryos and replicate the maternal environment by delivering suitable nutrients to the circulatory system of the developing structure. These problems are also inherent to the assembly of synthetic organs, and I am certain that we will see a cross-talk between these different disciplines of synthetic biology for mutual benefit.

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Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

Effie Apostolou

Donald E. and Delia B. Baxter Foundation Professor for Stem Cell Biology, Stanford University School of Medicine, Stanford, CA, USA

Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

Kenneth Chien

MRC Laboratory of Molecular Biology, Cambridge, UK

Madeline A. Lancaster

Department of Cell Biology and Duke Regeneration Center, Duke University School of Medicine, Durham, NC, USA

Purushothama Rao Tata

IRCAN Institute for Research on Cancer and Aging, INSERM Unité 1081, CNRS UMR 7284, Université Côte d’Azur, Nice, France

Eirini Trompouki

Directors’ Research Unit, European Molecular Biology Laboratory, Heidelberg, Germany

Fiona M. Watt

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

Yi Arial Zeng

School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

Mammalian Embryo and Stem Cell Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

Magdalena Zernicka-Goetz

Stem Cells Self-Organization Group, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

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Correspondence to Effie Apostolou , Helen Blau , Kenneth Chien , Madeline A. Lancaster , Purushothama Rao Tata , Eirini Trompouki , Fiona M. Watt , Yi Arial Zeng or Magdalena Zernicka-Goetz .

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Apostolou, E., Blau, H., Chien, K. et al. Progress and challenges in stem cell biology. Nat Cell Biol 25 , 203–206 (2023). https://doi.org/10.1038/s41556-023-01087-y

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Published : 14 February 2023

Issue Date : February 2023

DOI : https://doi.org/10.1038/s41556-023-01087-y

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Multiple myeloma: Its evolution, treatment and the quest to catch it early

The evolution of multiple myeloma

Cancerous plasma cells — myeloma cells — make proteins that cause the symptoms and complications of multiple myeloma. "When the plasma cells develop mutations and produce a monoclonal protein, this group of conditions is called monoclonal gammopathies," says Dr. Cook.

The earliest phase of monoclonal gammopathies is monoclonal gammopathy of undetermined significance (MGUS) , which doesn't cause symptoms. When a person has MGUS, monoclonal protein, or M-protein, is found in their blood at a level too low to damage the body. "If we detect M-protein in a person's blood, and we aren't concerned about organ damage, we monitor them," says Dr. Cook.

If cancerous plasma cells continue to multiply and produce M-proteins, MGUS evolves into smoldering multiple myeloma. People still don't have symptoms at this phase but have a higher M-protein level in their blood and urine.

People with smoldering multiple myeloma are classified based on their risk of progressing to multiple myeloma: low risk, intermediate risk or high risk. "We may treat some people with high-risk smoldering multiple myeloma, typically as part of a clinical trial, but for the most part, we actively monitor people without treating them," says Dr. Cook.

Multiple myeloma might be suspected when blood tests conducted for another reason raise red flags. "We may see that the protein is quite elevated or that a patient has a lower blood count than usual or an abnormality in their kidney numbers," she says. This prompts a care team to order blood tests to detect M-protein and assess blood chemistry and kidney function, urine tests to detect proteins, imaging tests to identify bone problems, and a bone marrow biopsy to look for myeloma cells.

People with multiple myeloma can experience a variety of symptoms or none. This can make diagnosing the disease a challenge. When a healthcare professional suspects multiple myeloma, they frequently check for specific signs and symptoms. "People with multiple myeloma may have anemia . If the M-proteins deposit in the kidneys and cause them to fail, they will have kidney abnormalities. They may have bone pain and high blood calcium levels caused by bone destruction," says Dr. Cook.

Multiple myeloma treatment options

Treatment for multiple myeloma typically starts with a combination of medications called induction chemotherapy. "Treatment involves plasma-cell directed therapy," says Dr. Cook. "It's usually a combination of three or four drugs: A steroid, an immunomodulating agent (a drug that stimulates the immune system to fight cancer), an antibody ( anti-CD38 ) that targets a surface marker on the cancerous plasma cell, and a proteasome inhibitor that targets the cell's protein manufacturing."

Your care team will also decide if you are a candidate for a bone marrow transplant. "This decision depends on factors like fitness and age — it's a soft cut-off, but generally, we don't transplant patients over 75. There are exceptions, though," says Dr. Cook.

The drugs your care team uses in your induction chemotherapy will depend on your overall health and whether you are a candidate for a bone marrow transplant.

A bone marrow transplant — a stem cell transplant — is a procedure that infuses healthy blood-forming stem cells into your body to regenerate the bone marrow's ability to produce blood cells. Stem cell transplants can pose risks, and some people can have serious complications.

If eligible, people with multiple myeloma typically have a stem cell transplant after about four to six months of induction chemotherapy. Before the transplant, they receive a high dose of a different type of chemotherapy called conditioning chemotherapy.

Dr. Cook uses a garden metaphor to explain how conditioning and stem cell transplants work to treat multiple myeloma. "In myeloma, your bone marrow is akin to a garden overgrown with weeds (the myeloma). You use strong weed killers (the conditioning chemotherapy) to eliminate those weeds, but then the garden is barren. You need to plant seeds to allow the garden to grow. That's what a stem cell transplant does. The reinfusion of stem cells is like planting seeds so your bone marrow can recover faster."

Dr. Cook says other promising treatment options exist if you cannot undergo a bone marrow transplant. "For people who relapse after several types of treatment, CAR-T cell therapy , where people's T cells are engineered to recognize and kill a myeloma cell, offers great response rates and good survival. And we've seen success with new drugs called bispecific antibodies — specially designed antibodies that redirect a patient's T cells (immune cells) to kill myeloma cells," she says.

Radiation therapy may also be an option to treat areas of the body affected by myeloma that are painful or causing other problems, says Dr. Cook.

Research aimed at catching multiple myeloma early

"Being diagnosed early is important because you want to avoid organ damage, renal impairment and bone destruction. If we can detect and diagnose multiple myeloma early, we can prevent that damage," says Dr. Cook.

"MGUS and multiple myeloma are detected most often. It's less common to detect smoldering multiple myeloma," says Dr. Cook. She says researchers are exploring screening options — primarily blood tests — to identify MGUS and smoldering myeloma.

Dr. Cook is working with colleagues on a clinical trial in Rochester, Minnesota, to screen people of East African descent. Other clinical trials are studying people with MGUS and those in higher-risk populations. "There are screening studies focused on Black people and those who have first-degree relatives with myeloma or MGUS," she says.

Dr. Cook is confident that the outlook for people diagnosed with multiple myeloma will continue to improve. "There are so many treatment options being developed," she says. "The field is just forging ahead."

Learn more about multiple myeloma and find a clinical trial at Mayo Clinic.

Join the Blood Cancers and Disorders Support Group on Mayo Clinic Connect , an online community moderated by Mayo Clinic for patients and caregivers.

Also, read these articles:

" CAR-T cell researchers at Mayo Clinic optimistic about future of treating blood cancers ."
" Monoclonal antibody drugs for cancer: How they work "
" Advances in treating multiple myeloma help extend quality of life for patients "
" Investigating dual CAR-T cell therapy for multiple myeloma "
" Is a cancer clinical trial right for me? "
" Multiple myeloma: New, better treatments are improving outcomes "
" What is multiple myeloma? "

After receiving CAR-T cell therapy at Mayo Clinic, Welsh-born John Cadwallader achieved remission and found new hope. He now receives care in the U.K. and is monitored by Mayo in the U.S. and London.

Mayo Clinic's Advanced Care at Home program helped David Elder recover at home from a bone marrow transplant to treat his multiple myeloma.

Learn about CAR-T cell therapy and research at Mayo Clinic to reduce its side effects and expand its use beyond blood cancers.

The Stem Cellar

The official blog of cirm, california's stem cell agency, advancing clinical research for a car t-cell therapy for systemic lupus erythematosus (sle), autoimmune diseases.

Symptoms of Lupus may include pain or swelling in the joints. Image is of swollen hands.

The California Institute for Regenerative Medicine (CIRM) has awarded $7.9 million to Barbara Hickingbottom, MD, of Fate Therapeutics to advance clinical research for FT819, an induced pluripotent stem cell (iPSC)-derived CD19 CAR T-cell therapy for Systemic Lupus Erythematosus (SLE). SLE is a debilitating autoimmune disease and affects more than 200,000 Americans, particularly women of color. FT819 targets B cells with the aim to reset the immune system and provide drug-free remission for patients with autoimmune diseases. Fate manufactures FT819 using a clonal master iPSC line as a renewal cell source, providing a uniform cell therapy product that is mass produced and delivered off-the-shelf to patients. As a result, FT819 is designed to bring the curative potential of cell therapy to large numbers of patients with SLE and other autoimmune diseases.

Anatomical diagram of Lupus Erythematosus symptoms.

“This innovative approach shows great promise in transforming clinical practice for Systemic Lupus Erythematosus, providing a new potential treatment option for individuals and families affected by this challenging disease,” added Dr. Creasey. “CD19 CAR T cell therapy has demonstrated tremendous potential for patients with autoimmune diseases,” said Dr. Hickingbottom. “We look forward to partnering with CIRM to broadly realize this potential with FT819, the industry’s first CAR T-cell therapy manufactured from a clonal master iPSC line to reach clinical investigation.”

Scientists Create Elephant Stem Cells in the Lab

The results could shed light on why the animals rarely get cancer. But the researchers’ ultimate goal of bringing back woolly mammoths is still aspirational.

By Carl Zimmer

When the biotechnology firm Colossal started in 2021, it set an eyebrow-raising goal : to genetically engineer elephants with hair and other traits found on extinct woolly mammoths.

Three years later, mammoth-like creatures do not roam the tundra. But on Wednesday, researchers with the company reported a noteworthy advance : They created elephant stem cells that could potentially be developed into any tissue in the body.

Eriona Hysolli, the head of biological sciences at Colossal, said that the cells could help protect living elephants. For example, researchers could create an abundant supply of elephant eggs for breeding programs. “Being able to derive a lot of them in a dish is important,” she said.

Independent researchers, too, were impressed by the cells, known as induced pluripotent stem cells, or iPSCs. Vincent Lynch, a biologist at the University at Buffalo who was not involved in the research, said iPSCs could help scientists learn about the strange biology of elephants — including why they so rarely develop cancer.

“The ability to study this with iPSCs is very exciting,” Dr. Lynch said. The discovery “opens a world of possibilities to study cancer resistance,” he added.

The data were published online Wednesday but have not yet appeared in a scientific journal.

George Church, a biologist at Harvard Medical School, started trying to resurrect the woolly mammoth more than a decade ago. At the time, geneticists were extracting DNA from the bones of the extinct animals and pinpointing genetic differences between them and their living elephant cousins. Dr. Church reasoned that if he could alter an elephant embryo’s DNA, it would sport some of the traits that allowed woolly mammoths to survive in cold climates.

Moonlighting with Dr. Hysolli, who was a postdoctoral researcher in his lab, and their colleagues, Dr. Church did some preliminary research on editing elephant DNA. But the group struggled with a limited supply of elephant cells.

So the researchers set out to make their own supply, drawing inspiration from the Nobel Prize-winning work of the Japanese biologist Shinya Yamanaka and his colleagues. Dr. Yamanaka figured out how to turn back the clock in adult mouse cells so that they were effectively like the cells in an embryo. With the right combination of chemicals, these iPSCs could then develop into many different tissues, even eggs .

Researchers have made iPSCs of other species, including humans. Some researchers, for example, have made clumps of human neurons that make brain waves .

But elephant cells have proven much harder to reprogram. Dr. Lynch said he had tried to create elephant iPSCs for years with no success. The trouble, he suspected, had to do with a remarkable feature of elephants: They rarely get cancer .

Simple arithmetic suggests that a lot of elephants should get cancer. A single embryonic elephant cell divides many times over to produce the enormous body of an adult animal. With each division, DNA has a chance to mutate. And that mutation may push the new cell toward uncontrolled growth, or cancer.

But elephants have evolved a number of extra defenses against cancer.

Among them is a protein called TP53. All mammals carry a gene for the protein, which causes a cell to self-destruct if it starts showing signs of uncontrolled growth. Elephants have 29 genes for TP53. Together, they may aggressively quash cancerous cells.

These anticancer adaptations may have been what stopped adult elephant cells from being reprogrammed into iPSCs. The changes happening in the cell may resemble the first steps toward cancer, causing the cells to self-destruct.

“We knew p53 was going to be a big deal,” Dr. Church said. He and his colleagues tried to overcome the challenge by obtaining fresh supplies of cells from Asian elephants, which are endangered. While they couldn’t extract tissue samples from those animals, they were able to get the umbilical cords of baby elephants.

The researchers then created molecules to block the production of all p53 proteins in the cells. Combining this treatment with Dr. Yamanaka’s cocktail — as well as with other proteins — they succeeded in making elephant iPSCs.

“They seem to pass all the tests with flying colors,” Dr. Church said. He and his colleagues have coaxed these cells to grow into an embryolike cluster of cells. And the cells have developed into three distinct types found in early mammal embryos.

Colossal is still aiming to hit its grander goal of “ bringing back the woolly mammoth .” Dr. Hysolli and her colleagues plan to change some genes in the stem cells from elephant sequences to woolly mammoth sequences. They will then see if those edits lead to changes in the cells themselves. With this strategy, she said, it may be possible to grow a clump of elephant cells that sprout mammoth hair, for example.

Dr. Lynch is skeptical about the company’s ultimate goal. He argued that modifying a few genes in a living elephant was a far cry from reviving their extinct cousins.

“We know almost nothing about the genetics of complex behavior,” Dr. Lynch said. “So do we end up with a hairy Asian elephant that doesn’t know how to survive in the Arctic?”

Carl Zimmer covers news about science for The Times and writes the Origins column . More about Carl Zimmer

The Mysteries and Wonders of Our DNA

Women are much more likely than men to have an array of so-called autoimmune diseases, like lupus and multiple sclerosis. A new study offers an explanation rooted in the X chromosome .

DNA fragments from thousands of years ago are providing insights into multiple sclerosis, diabetes, schizophrenia and other illnesses. Is this the future of medicine ?

A study of DNA from half a million volunteers found hundreds of mutations that could boost a young person’s fertility and that were linked to bodily damage later in life.

In the first effort of its kind, researchers now have linked DNA from 27 African Americans buried in the cemetery to nearly 42,000 living relatives .

Environmental DNA research has aided conservation, but scientists say its ability to glean information about humans poses dangers .

That person who looks just like you is not your twin. But if scientists compared your genomes, they might find a lot in common .

Abstract 5557: Stem-like T cells maintain latent anticancer activity and underly therapy resistance

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Fang Tao , Sara McElroy , Jacqelyn Nemechek , Irina Pushel , John Szarejko , Santosh Khanal , Todd Bradley , Doug Myers , John M. Perry; Abstract 5557: Stem-like T cells maintain latent anticancer activity and underly therapy resistance. Cancer Res 15 March 2024; 84 (6_Supplement): 5557. https://doi.org/10.1158/1538-7445.AM2024-5557

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Pre-cancerous cells are normally recognized and eliminated by immune cells. Cancer progresses only when this immunosurveillance system fails. Although immunotherapy has driven the most significant and exciting advances in cancer treatment in modern times, current approaches are running into barriers. An emerging area of interest includes evidence for rare but highly potent stem cell-like T cells. Stem-like T cells combine long-term persistence and high potency with immunological memory. Our recent findings reveal insights into the nature and regulation of stem-like T cells and their potential anticancer activity. Minimal residual disease (MRD) underlies therapeutic resistance, dictates treatment escalation, and predicts patient outcomes. We have shown that the Wnt and PI3K pathways promote the transformation of hematopoietic stem cells (HSCs) into chemoresistant leukemia stem cells (LSCs), which form the root of leukemia initiation and post-treatment recurrence. High-throughput screening revealed that LSCs could be targeted by low dose anthracycline treatment. Mechanistically, low dose, but not high dose anthracyclines indirectly target LSCs by inhibiting their unique properties of immune escape, allowing for their elimination by CD8+ T cells. We employed single-cell genomic and proteomic analysis to investigate immunological changes during development of HSCs, LSCs, and their progeny in response to low dose anthracycline treatment. While leukemia progression results in exhaustion of differentiated CD8+ T cells, stem-like T cells accumulate. However, low dose anthracycline treatment reverses this imbalance. Comparing MRD+ and MRD- patient samples, we found that differential proportions of stem-like T cells persist in the bone marrow of leukemia patients. While T cells of MRD- patients recover following chemotherapy induction, T cell recovery is severely attenuated in MRD+ patients. Furthermore, failure of immunological recovery is driven at least partially by a lack of stem-like T cells in MRD+ leukemia patients. Overall, our studies have revealed that low dose anthracyclines, in contrast to high dose, induce opposing, dichotomous effects on LSCs vs. HSCs and stem-like vs. differentiated T cells.

Citation Format: Fang Tao, Sara McElroy, Jacqelyn Nemechek, Irina Pushel, John Szarejko, Santosh Khanal, Todd Bradley, Doug Myers, John M. Perry. Stem-like T cells maintain latent anticancer activity and underly therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5557.

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FDA Approves Lenmeldy for Metachromatic Leukodystrophy

Lenmeldy is the first and only treatment in the U.S. for early onset MLD.

Today the FDA approved Lenmeldy (atidarsagene autotemcel), a hematopoietic stem cell gene therapy for the treatment of children with metachromatic leukodystrophy (MLD), making it the first and only treatment in the U.S. for early-onset forms of the disease.

MLD is a rare disorder caused by a mutation in the gene responsible for encoding the enzyme arylsulfatase A (ARSA). When working properly, the healthy gene produces a protein that helps clean up a cell. Without proper cleanup, fats called sulfatides accumulate and damage the myelin sheath of the cell, which leads to progressive decline of brain and motor function.

Lenmeldy, marketed in Europe as Libmeldy, works by inserting a working copy of the ARSA gene into the genome of the patients’ own stem cells. The repaired cells are then infused back into the patient, where they naturally migrate across the blood-brain barrier into the central nervous system, engraft, and express the functional enzyme.

Lenmeldy is indicated for patients six and under with the late-infantile form of MLD and without clinical manifestations, as well as patients six and under with the early-juvenile form with either early or no clinical manifestations.

The experience of receiving a rare disease diagnosis is difficult enough, and in the case of MLD it’s heartbreaking for a patient’s family to see their loved one gradually lose the ability to walk, talk, eat, and see as the disease progresses. This approval is so exciting because it provides a one-time treatment that will prevent much of the decline brought on by this disease.

The biologics licensing application for Lenmeldy is based on data from 39 pediatric patients with early-onset MLD and compared with data from 49 untreated patients. In clinical trials, treatment with Lenmeldy resulted in preservation of motor function and cognitive development in most patients compared to disease natural history with up to 12 years of follow-up (median 6.76 years).

With more than a cumulative 250 patient-years of follow-up, treatment was generally well-tolerated, with no treatment-related serious adverse events or deaths.

FDA granted its U.S. approval to Orchard Therapeutics.

Dr. Chamberlain is President of ASGCT.

Fda approves first gene therapy to treat severe hemophilia a, fda approves first gene therapy for duchenne muscular dystrophy, fda approves first gene therapy for dystrophic epidermolysis bullosa (deb), fda approves first gene therapy for bladder cancer, register for the 27th annual meeting.

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Efficacy and safety of CD19 CAR-T cell therapy for acute lymphoblastic leukemia patients relapsed after allogeneic hematopoietic stem cell transplantation

Progress in Hematology
Prevention and management of relapse after allogeneic hematopoietic cell transplantation in hematological malignancies
Published: 23 June 2022
Volume 116 , pages 315–329, ( 2022 )

Cite this article

Xing-yu Cao 1 , 2 ,
Jing-jing Li 1 , 2 ,
Pei-hua Lu 1 , 2 na1 &
Kai-yan Liu ORCID: orcid.org/0000-0002-6331-7369 2 , 3 na1

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for B-cell acute lymphoblastic leukemia (B-ALL). Although allo-HSCT can be curative for some B-ALL patients, relapse still occurs in some patients following allo-HSCT. Conventional chemotherapies show poor efficacy in B-ALL patients who have relapsed following allo-HSCT. In the past decade, chimeric antigen receptor T-cell (CAR-T) therapy has shown to be efficacious for B-ALL patients. In particular, autologous CD19 CAR-T therapy results in a high remission rate. However, there are challenges in the use of CD19 CAR-T therapy for B-ALL patients who have relapsed following allo-HSCT, including the selection of CAR-T cell source for manufacturing, post-CAR-T graft-versus-host disease (GVHD) risk, maintenance of long-term efficacy after remission through CAR-T therapy, and whether a consolidative second transplant is needed. In this review, we describe the current status of CAR-T therapy for B-ALL patients who have relapsed following allo-HSCT, the advantages and disadvantages of various CAR-T cell sources, the characteristics and management of GVHD following CAR-T therapy, and the risk factors that may affect long-term efficacy.

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CAR-T bridging to allo-HSCT as a treatment strategy for relapsed adult acute B-lymphoblastic leukemia: a case report

Shupeng Wen, Zhiyun Niu, … Fuxu Wang

A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia

Yongxian Hu, Jiasheng Wang, … He Huang

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Guedan S, Posey AD, Shaw C, Wing A, Da T, Patel PR, et al. Enhancing CAR T-cell persistence through ICOS and 4–1BB costimulation. JCI Insight. 2018. https://doi.org/10.1172/jci.insight.96976 .

Qian LR, Li D, Ma L, He T, Qi FF, Shen JL, et al. The novel anti-CD19 chimeric antigen receptors with humanized scFv (single-chain variable fragment) trigger leukemia cell killing. Cell Immunol. 2016;304–305:49–54. https://doi.org/10.1016/j.cellimm.2016.03.003 .

Myers RM, Li Y, Barz LA, Barrett DM, Teachey DT, Callahan C, et al. Humanized CD19-targeted chimeric antigen receptor (CAR) T Cells in CAR-Naive and CAR-Exposed children and young adults with relapsed or refractory acute lymphoblastic leukemia. J Clin Oncol. 2021;39(27):3044–55. https://doi.org/10.1200/JCO.20.03458 .

Zhao Y, Liu ZF, Wang X, Wu HT, Zhang JP, Yang JF, et al. Treatment with humanized selective CD19CAR-T Cells shows efficacy in highly treated B-ALL Patients who have relapsed after receiving murine-based CD19CAR-T therapies. Clin Cancer Res. 2019;25(18):5595–607. https://doi.org/10.1158/1078-0432.CCR-19-0916 .

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Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492–500. https://doi.org/10.1038/leu.2015.247 .

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Zolov SN, Rietberg SP, Bonifant CL. Programmed cell death protein 1 activation preferentially inhibits CD28CAR-T cells. Cytotherapy. 2018;20(10):1259–66. https://doi.org/10.1016/j.jcyt.2018.07.005 .

Rafiq S, Yeku OO, Jackson HJ, Purdon TJ, van Leeuwen DG, Drakes DJ, et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol. 2018;36(9):847–56. https://doi.org/10.1038/nbt.4195 .

Liu SY, Deng BP, Yin ZC, Lin YH, An LH, Liu D, et al. Combination of CD19 and CD22 CAR-T cell therapy in relapsed B-cell acute lymphoblastic leukemia after allogeneic transplantation. Am J Hematol. 2021;96(6):671–9. https://doi.org/10.1002/ajh.26160 .

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Zhao YL, Liu DY, Sun RJ, Zhang JP, Zhou JR, Wei ZJ, et al. Integrating CAR T-Cell therapy and transplantation: comparisons of safety and long-term efficacy of allogeneic hematopoietic stem cell transplantation after CAR T-Cell or chemotherapy-based complete remission in B-Cell acute lymphoblastic leukemia. Front Immunol. 2021;12:605766. https://doi.org/10.3389/fimmu.2021.605766 .

Gu B, Shi BY, Zhang X, Zhou SY, Chu JH, Wu XJ, et al. Allogeneic haematopoietic stem cell transplantation improves outcome of adults with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia entering remission following CD19 chimeric antigen receptor T cells. Bone Marrow Transplant. 2021;56(1):91–100. https://doi.org/10.1038/s41409-020-0982-6 .

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Cao, Xy., Li, Jj., Lu, Ph. et al. Efficacy and safety of CD19 CAR-T cell therapy for acute lymphoblastic leukemia patients relapsed after allogeneic hematopoietic stem cell transplantation. Int J Hematol 116 , 315–329 (2022). https://doi.org/10.1007/s12185-022-03398-6

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Published: 15 March 2010

Welcome to Stem Cell Research & Therapy

Ann Donnelly 1 ,
Surayya Johar 1 ,
Timothy O'Brien 2 &
Rocky S Tuan 3

Stem Cell Research & Therapy volume 1 , Article number: 1 ( 2010 ) Cite this article

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Welcome to the first issue of the international open access journal Stem Cell Research & therapy , edited by Professor Rocky Tuan, of the University of Pittsburgh, and Professor Timothy O'Brien, of the National University of Ireland, Galway.

Stem Cell Research & Therapy aims to be the major forum for translational research into stem cell therapies. The journal has a special emphasis on basic, translational, and clinical research into stem cell therapeutics, including animal models, and clinical trials.

Stem cell research for therapeutic purposes has largely used adult stem cell sources. Embryonic stem cell research has enormous potential and also has major hurdles to overcome, not the least of which are ethical in nature. Funding for research into embryonic stem cells has also been in a state of transition. The change in US policy and subsequent National Institutes of Health guidelines allowing funding for human embryonic research has moved the use of stem cells of embryonic origin back into the spotlight [ 1 ]. Although legislation throughout the world varies, the international research community is striving to disseminate critical knowledge and useful ideas to aid the progress of our expertise in this area, and our open access policy will promote this.

Why is stem cell research important?

Stem cell research has great potential in the treatment of as-of-yet incurable diseases, including Huntington disease and Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. Other, more chronic conditions such as congestive cardiac failure, diabetes, and osteoarthritis may also respond well to stem cell therapy.

With the knowledge that stem cells can be induced to differentiate into specialized cells and that they can influence the tissues around them, the potential of stem cells as a therapeutic option is great. Recent advances have demonstrated that adult somatic cells, called induced pluripotent stem cells, can be reprogrammed into becoming stem-like in their nature and behavior [ 2 ].

Research is currently focused on calibration of the process of cell reprogramming, ensuring the quality of induced pluripotent stem cells, and modification of the stem cell niche. Future research will increasingly consider quality control of stem cell manufacture, delivery to the target areas, and architectural aids to ensure optimum placement and exposure of the stem cells.

Another important aspect of stem cell therapeutics will be a focus on the bioengineering of materials necessary to deliver and support stem cells on their therapeutic journey. Combinations of stem cell therapy with gene therapy will also expand the therapeutic repertoire as the effectiveness of the stem cell product may be enhanced via genetic modification. Thus, combinations of stem cells, biomaterials, and gene therapy may augment the therapeutic outcome but will result in complex regulatory challenges.

The potential paracrine mode of the therapeutic action of stem cells is worthy of substantial attention. Understanding the mechanism whereby stem cells heal tissue by regulating and interacting with host cells may lead to the development of novel therapeutic paradigms that may not require the stem cell per se as the therapeutic agent.

How and what will we publish?

BioMed Central is launching Stem Cell Research & Therapy to provide a new forum to highlight the growing area of stem cell therapeutics. In this open access journal, our research content will be made freely available upon publication. This means that readers worldwide will have immediate and free access to original research, promoting the immediate and wide distribution of the most current developments in the field [ 3 ]. Under our open access license, authors retain copyright of their article, allowing them, and any third party, to re-use their work as long as the authors are given correct attribution [ 4 ]. To cover the costs of open access, authors of original research are asked to pay an article-processing charge once their article has been accepted for publication. This is a flat fee that includes the use of color figures, unlimited pages, and additional data sets. Indeed, authors can upload both audio and visual files alongside their manuscript at no extra cost. To ensure permanence and high visibility, research published in Stem Cell Research & therapy will also be deposited in several international bibliographic databases [ 5 ].

Stem Cell Research & Therapy will publish original research as well as regular commissioned articles. Our reviews will provide a comprehensive overview of specific topics, collating and discussing the ever-changing advances in the field. There will be a specific focus on the therapeutic elements of stem cell research. Commentaries and viewpoint articles will be speculative and allow authors to be more opinionated in their views. Readers are firmly encouraged to participate and can do so by submitting letters to the editor on articles published in Stem Cell Research & therapy and on any issue in a related area. Brief comments can also be posted online on any article by using the tools displayed on the article's webpage. These tools will also allow articles to be shared via 'social media' services such as Facebook and Twitter, reflecting the commitment of the journal to disseminating our articles widely via the most popular and modern means.

We welcome your contributions

Stem Cell Research & Therapy will provide a platform for translational research into stem cell therapy. We are delighted to introduce this much-needed journal to the stem cell research community, and we welcome your responses and submissions. The Editors-in-Chief, supported by a global Editorial Board [ 6 ], are committed to making this journal a success, and we look forward to receiving your contributions.

National Institutes of Health Guidelines on Human Stem Cell Research. [ http://stemcells.nih.gov/policy/2009guidelines.htm ]

Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006, 126: 663-676. 10.1016/j.cell.2006.07.024.

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Stem Cell Research and Therapy Editorial Board. [ http://www.stemcellres.com/edboard ]

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AD and SJ are employees of BioMed Central and receive fixed salaries. TO and RT are the Editors-in-Chief of Stem Cell Research & Therapy and receive an annual honorarium.

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v.39(12); 2014 Dec

Stem Cell Therapy: a Look at Current Research, Regulations, and Remaining Hurdles

Stem cell therapies offer great promise for a wide range of diseases and conditions. However, stem cell research—particularly human embryonic stem cell research—has also been a source of ongoing ethical, religious, and political controversy.

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In September 2014, the Sanford Stem Cell Clinical Center at the University of California, San Diego (UCSD) Health System announced the launch of a groundbreaking clinical trial to assess the safety of neural stem cell–based therapy in patients with chronic spinal cord injury. Researchers hope that the transplanted stem cells will develop into new neurons that replace severed or lost nerve connections and restore at least some motor and sensory function. 1

Two additional clinical trials at UCSD are testing stem cell–derived therapy for type-1 diabetes and chronic lymphocytic leukemia, the most common form of blood cancer. 1

These three studies are significant in that they are among the first efforts in stem cell research to make the leap from laboratory to human clinical trials. While the number of patients involved in each study is small, researchers are optimistic that as these trials progress and additional trials are launched, a greater number of patients will be enrolled. UCSD reports that trials for heart failure, amyotrophic lateral sclerosis, and blindness are in planning stages. 1

The study of stem cells offers great promise for better understanding basic mechanisms of human development, as well as the hope of harnessing these cells to treat a wide range of diseases and conditions. 2 However, stem cell research— particularly human embryonic stem cell (hESC) research, which involves the destruction of days-old embryos—has also been a source of ongoing ethical, religious, and political controversy. 2

The Politics of Progress

In 1973, the Department of Health, Education, and Welfare (now the Department of Health and Human Services) placed a moratorium on federally funded research using live human embryos. 3 , 4 In 1974, Congress adopted a similar moratorium, explicitly including in the ban embryos created through in vitro fertilization (IVF). In 1992, President George H.W. Bush vetoed legislation to lift the ban, and in 2001, President George W. Bush issued an executive order banning federal funding on stem cells created after that time. 3 , 4 Some states, however, have permitted their limited use. New Jersey, for example, allows the harvesting of stem cells from cloned human embryos, whereas several other states prohibit the creation or destruction of any human embryos for medical research. 3 , 4

In 2009, shortly after taking office, President Barack Obama lifted the eight-year-old ban on federally funded stem cell research, allowing scientists to begin using existing stem cell lines produced from embryos left over after IVF procedures. 5 (A stem cell line is a group of identical stem cells that can be grown and multiplied indefinitely.)

The National Institutes of Health (NIH) Human Embryonic Stem Cell Registry 6 lists the hESCs eligible for use in NIH-funded research. At this writing, 283 eligible lines met the NIH’s strict ethical guidelines for human stem cell research pertaining to the embryo donation process. 7 For instance, to get a human embryonic stem cell line approved, grant applicants must show that the embryos were “donated by individuals who sought reproductive treatment and who gave voluntary written consent for the human embryos to be used for research purposes.” 8 The ESCs used in research are not derived from eggs fertilized in a woman’s body. 9

Because of the separate legislative ban, it is still not possible for researchers to create new hESC lines from viable embryos using federal funds. Federal money may, however, be used to research lines that were derived using private or state sources of funding. 5

While funding restrictions and political debates may have slowed the course of stem cell research in the United States, 10 the field continues to evolve. This is evidenced by the large number of studies published each year in scientific journals on a wide range of potential uses across a variety of therapeutic areas. 11 – 13

The Food and Drug Administration (FDA) has approved numerous stem cell–based treatments for clinical trials. A 2013 report from the Pharmaceutical Research and Manufacturers of America lists 69 cell therapies as having clinical trials under review with the FDA, including 15 in phase 3 trials. The therapeutic categories represented in these trials include cardiovascular disease, skin diseases, cancer and related conditions, digestive disorders, transplantation, genetic disorders, musculoskeletal disorders, and eye conditions, among others. 14

Still, the earliest stem cell therapies are likely years away. To date, the only stem cell–based treatment approved by the FDA for use in this country is for bone marrow transplantation. 15 As of 2010 (the latest year for which data are available), more than 17,000 blood cancer patients had had successful stem cell transplants. 16

A Brief Stem Cell Timeline

Research on stem cells began in the late 19th century in Europe. German biologist Ernst Haeckel coined the term stem cell to describe the fertilized egg that becomes an organism. 17

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In the U.S., the study of adult stem cells took off in the 1950s when Leroy C. Stevens, a cancer researcher based in Bar Harbor, Maine, found large tumors in the scrotums of mice that contained mixtures of differentiated and undifferentiated cells, including hair, bone, intestinal, and blood tissue. Stevens and his team concluded that the cells were pluripotent, meaning they could differentiate into any cell found in a fully grown animal. Stem cell scientists are using that carefully documented research today. 17

In 1968, Robert A. Good, MD, PhD, at the University of Minnesota, performed the first successful bone marrow transplant on a child suffering from an immune deficiency. Scientists subsequently discovered how to derive ESCs from mouse embryos and in 1998 developed a method to take stem cells from a human embryo and grow them in a laboratory. 17

Why Stem Cells?

Many degenerative and currently untreatable diseases in humans arise from the loss or malfunction of specific cell types in the body. 9 While donated organs and tissues are often used to replace damaged or dysfunctional ones, the supply of donors does not meet the clinical demand. 18 Stem cells seemingly provide a renewable source of replacement cells and tissues for transplantation and the potential to treat a myriad of conditions.

Stem cells have two important and unique characteristics: First, they are unspecialized and capable of renewing themselves through cell division. When a stem cell divides, each new cell has the potential either to remain a stem cell or to differentiate into other kinds of cells that form the body’s tissues and organs. Stem cells can theoretically divide without limit to replenish other cells that have been damaged. 9

Second, under certain controlled conditions, stem cells can be induced to become tissue- or organ-specific cells with special functions. They can then be used to treat diseases affecting those specific organs and tissues. While bone marrow and gut stem cells divide continuously throughout life, stem cells in the pancreas and heart divide only under appropriate conditions. 9

Embryonic Versus Adult Stem Cells

There are two main types of stem cells: 1) embryonic stem cells (ESCs), found in the embryo at very early stages of development; and 2) somatic or adult stem cells (ASCs), found in specific tissues throughout the body after development. 9

The advantage of embryonic stem cells is that they are pluripotent—they can develop into any of the more than 200 cell types found in the body, providing the potential for a broad range of therapeutic applications. Adult stem cells, on the other hand, are thought to be limited to differentiating into different cell types of their tissue of origin. 9 Blood cells, for instance, which come from adult stem cells in the bone marrow, can specialize into red blood cells, but they will not become other cells, such as neurons or liver cells.

A significant advantage of adult stem cells is that they offer the potential for autologous stem cell donation. In autologous transplants, recipients receive their own stem cells, reducing the risk of immune rejection and complications. Additionally, ASCs are relatively free of the ethical issues associated with embryonic stem cells and have become widely used in research.

Induced Pluripotent Stem Cells

Representing a relatively new area of research, induced pluripotent stem cells (iPSCs) are adult stem cells that have been genetically reprogrammed back to an embryonic stem cell–like state. The reprogrammed cells function similarly to ESCs, with the ability to differentiate into any cell of the body and to create an unlimited source of cells. So iPSCs have significant implications for disease research and drug development.

Pioneered by Japanese researchers in 2006, iPSC technology involves forcing an adult cell, such as a skin, liver, or stomach cell, to express proteins that are essential to the embryonic stem cell identity. The iPSC technology not only bypasses the need for human embryos, avoiding ethical objections, but also allows for the generation of pluripotent cells that are genetically identical to the patient’s. Like adult cells, these unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection. 9

In 2013, researchers at the Spanish National Cancer Research Centre in Madrid successfully reprogrammed adult cells in mice, creating stem cells that can grow into any tissue in the body. Prior to this study, iPSCs had never been grown outside Petri dishes in laboratories. 19 And, in July 2013, Japan’s health minister approved the first use of iPSCs in human trials. The Riken Center for Developmental Biology will use the cells to attempt to treat age-related macular degeneration, a common cause of blindness in older people. The small-scale pilot study would test the safety of iPSCs transplanted into patients’ eyes. 20

The Promise of iPSCs

According to David Owens, PhD, Program Director of the Neuroscience Center at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), one of the fundamental hurdles to using stem cells to treat disease is that scientists do not yet fully understand the diseases themselves, that is, the genetic and molecular signals that direct the abnormal cell division and differentiation that cause a particular condition. “You want that before you propose a therapeutic,” he says, “because you want a firm, rational basis for what you’re trying to do, what you’re trying to change.”

Although most of the media attention around stem cells has focused on regenerative medicine and cell therapy, researchers are finding that iPSCs, in particular, hold significant promise as tools for disease modeling. 21 , 22 A major barrier to research is often inaccessibility of diseased tissue for study. 23 Because iPSCs can be derived directly from patients with a given disease, they display all of the molecular characteristics associated with the disease, thereby serving as useful models for the study of pathological mechanisms.

“The biggest payoff early on will be using these cells as a tool to understand the disease better,” says Dr. Owens. For instance, he explains that creating dopamine neurons from iPSC lines could help scientists more closely study the mechanisms behind Parkinson’s disease. “If we get a better handle on the disorders themselves, then that will also help us generate new therapeutic targets.” Recent studies show the use of these patient-specific cells to model other neurodegenerative disorders, including Alzheimer’s and Huntington’s diseases. 24 – 26

In addition to using iPSC technology, it is also possible to derive patient-specific stem cell lines using an approach called somatic cell nuclear transfer (SCNT). This process involves adding the nuclei of adult skin cells to unfertilized donor oocytes. As reported in spring 2014, a team of scientists from the New York Stem Cell Foundation Research Institute and Columbia University Medical Center used SCNT to create the first disease-specific embryonic stem cell line from a patient with type-1 diabetes. The insulin-producing cells have two sets of chromosomes (the normal number in humans) and could potentially be used to develop personalized cell therapies. 27

Many Hurdles Ahead

The development of iPSCs and related technologies may help address the ethical concerns and open up new possibilities for studying and treating disease, but there are still barriers to overcome. One major obstacle is the tendency of iPSCs to form tumors in vivo . Using viruses to genomically alter the cells can trigger the expression of cancer-causing genes, or oncogenes. 28

Much more research is needed to understand the full nature and potential of stem cells as future medical therapies. It is not known, for example, how many kinds of adult stem cells exist or how they evolve and are maintained. 9

Some of the challenges are technical, Dr. Owens explains. For instance, generating large enough numbers of a cell type to provide the amounts needed for treatment is difficult. Some adult stem cells have a very limited ability to divide, making it difficult to multiply them in large numbers. Embryonic stem cells grow more quickly and easily in the laboratory. This is an important distinction because stem cell replacement therapies require large numbers of cells. 29

Also, says Dr. Owens, stem cell transplants present immunological hurdles: “If you do introduce cells into a tissue, will they be rejected if they’re not autologous cells? Or, you might have immunosuppression with the individual who received the cells, and then there are additional complications involved with that. That’s still not entirely clear.”

Such safety issues need to be addressed before any new stem cell–based therapy can advance to clinical trials with real patients. According to Dr. Owens, the preclinical testing stage typically takes about five years. This would include assessment of toxicity, tumorigenicity, and immunogenicity of the cells in treating animal models for disease. 30

“Those are things we have to continually learn about and try to address. It will take time to understand them better,” Dr. Owens says. Asked about the importance of collaboration in overcoming the scientific, regulatory, and financial challenges that lie ahead, he says, “It’s unlikely that one entity could do it all alone. Collaboration is essential.”

Research and Clinical Trials

Ultimately, stem cells have huge therapeutic potential, and numerous studies are in progress at academic institutions and biotechnology companies around the country. Studies at the NIH span multiple disciplines, notes Dr. Owens, who oversees funding for stem cell research at NINDS. ( Figure 1 shows the recent history of NIH funding for stem cell research.) He describes one area of considerable interest as the promotion of regeneration in the brain based on endogenous stem cells. Until recently, it was believed that adult brain cells could not be replaced. However, the discovery of neurogenesis in bird brains in the 1980s led to startling evidence of neural stem cells in the human brain, raising new possibilities for treating neurodegenerative disorders and spinal cord injuries. 31

“It’s a fascinating idea,” says Dr. Owens. “It’s unclear still what the functions of those cells are. They could probably play different roles in different species, but just the fundamental properties themselves are very interesting.” He cites a number of NINDS-funded studies looking at those basic properties.

In another NIH-funded study, Advanced Cell Technology (ACT), a Massachusetts-based biotechnology company, is testing the safety of hESC-derived retinal cells to treat patients with an eye disease called Stargardt’s macular dystrophy. A second ACT trial is testing the safety of hESC-derived retinal cells to treat age-related macular degeneration patients. 32 , 33

In April 2014, scientists at the University of Washington reported that they had successfully regenerated damaged heart muscles in monkeys using heart cells created from hESCs. The research, published in the journal Nature , was the first to show that hESCs can fully integrate into normal heart tissue. 34

The study did not answer every question and had its complications—it failed to show whether the transplanted cells improved the function of the monkeys’ hearts, and some of the monkeys developed arrhythmias. 34 , 35 Still, the researchers are optimistic that it will pave the way for a human trial before the end of the decade and lead to significant advances in treating heart disease. 29

In May 2014, Asterias Biotherapeutics, a California-based biotechnology company focused on regenerative medicine, announced the results of a phase 1 clinical trial assessing the safety of its product AST-OPC1 in patients with spinal cord injuries. 36 The study represents the first-in-human trial of a cell therapy derived from hESCs. Results show that all five subjects have had no serious adverse events associated with the administration of the cells, with the AST-OPC1 itself, or with the immunosuppressive regimen. A phase 1/2a dose-escalation study of AST-OPC1 in patients with spinal cord injuries is awaiting approval from the FDA. 37

The FDA itself has a team of scientists studying the potential of mesenchymal stem cells (MSCs), adult stem cells traditionally found in the bone marrow. Multipotent stem cells, MSCs differentiate to form cartilage, bone, and fat and could be used to repair, replace, restore, or regenerate cells, including those needed for heart and bone repair. 38

Publicly available information about federally and privately funded clinical research studies involving stem cells can be found at http://clinicaltrials.gov . However, the FDA cautions that the information provided on that site is supplied by the product sponsors and is not reviewed or confirmed by the agency.

“The biggest payoff early on will be using these cells as a tool to understand the disease better. If we get a better handle on the disorders themselves, then that will also help us generate new therapeutic targets.” —David Owens, PhD, Program Director, Neuroscience Center, National Institute of Neurological Disorders and Stroke

Global Research Efforts

Stem cell research policy varies significantly throughout the world as countries grapple with the scientific and social implications. In the European Union, for instance, stem cell research using the human embryo is permitted in Belgium, Britain, Denmark, Finland, Greece, the Netherlands, and Sweden; however, it is illegal in Austria, Germany, Ireland, Italy, and Portugal. 39

In those countries where cell lines are accessible, research continues to create an array of scientific advances and widen the scope of stem cell application in human diseases, disorders, and injuries. For example, in February 2014, Cellular Biomedicine Group, a China-based company, released the six-month follow-up data analysis of its phase 1/2a clinical trial for ReJoin, a human adipose-derived mesenchymal precursor cell (haMPC) therapy for knee osteoarthritis. The study, which tested the safety and efficacy of intra-articular injections of autologous haMPCs to reduce inflammation and repair damaged joint cartilage, showed knee pain was significantly reduced and knee mobility was improved. 40 And the journal Stem Cell Research & Therapy reported that researchers at the University of Adelaide in Australia recently completed a project showing stem cells taken from teeth could form “complex networks of brain-like cells.” Although the cells did not grow into full neurons, the researchers say that it will happen given time and the right conditions. 41

The Regulation of Stem Cells

In February 2014, the U.S. Court of Appeals for the District of Columbia Circuit upheld a 2012 ruling that a patient’s stem cells for therapeutic use fall under the aegis of the FDA. 42 The appeals case involved the company Regenerative Sciences, which was using patients’ MSCs in its Regenexx procedure to treat orthopedic problems. 43

The FDA’s Center for Biologics Evaluation and Research (CBER) regulates human cells, tissues, and cellular and tissue-based products (HCT/P) intended for implantation, transplantation, infusion, or transfer into a human recipient, including hematopoietic stem cells. Under the authority of Section 361 of the Public Health Service Act, the FDA has established regulations for all HCT/Ps to prevent the transmission of communicable diseases. 44

The Regenexx case highlights an ongoing debate about whether autologous MSCs are biological drugs subject to FDA approval or simply human cellular and tissue products. Some medical centers collect, concentrate, and reinject MSCs into a patient to treat osteoarthritis but do not add other agents to the injection. The FDA contends that any process that includes culturing, expansion, and added growth factors or antibiotics requires regulation because the process constitutes significant manipulation. Regenerexx has countered that the process does not involve the development of a new drug, which could be given to a number of patients, but rather a patient’s own MSCs, which affects just that one patient.

Ensuring the safety and efficacy of stem cell–based products is a major challenge, says the FDA. Cells manufactured in large quantities outside their natural environment in the human body can potentially become ineffective or dangerous and produce significant adverse effects such as tumors, severe immune reactions, or growth of unwanted tissue. Even stem cells isolated from a person’s own tissue can potentially present these risks when put into an area of the body where they could not perform the same biological function that they were originally performing. Stem cells are immensely complex, the FDA cautions—far more so than many other FDA-regulated products—and they bring with them unique considerations for meeting regulatory standards.

To date, no U.S. companies have received FDA approval for any autologous MSC therapy, although a study is ongoing to assess the feasibility and safety of autologous MSCs for osteoarthritis. 45 One of the major risks with MSCs is that they could potentially lead to cancer or differentiation into bone or cartilage. 46

What’s Next

The numerous stem cell studies in progress across the globe are only a first step on the long road toward eventual therapies for degenerative and life-ending diseases. Because of their unlimited ability to self-renew and to differentiate, embryonic stem cells remain, theoretically, a potential source for regenerative medicine and tissue replacement after injury or disease. However, the difficulty of producing large quantities of stem cells and their tendency to form tumors when transplanted are just a few of the formidable hurdles that researchers still face. In the meantime, the shorter-term payoff of using these cells as a tool to better understand diseases has significant implications.

Social and ethical issues around the use of embryonic stem cells must also be addressed. Many nations, including the U.S., have government-imposed restrictions on either embryonic stem cell research or the production of new embryonic stem cell lines. Induced pluripotent stem cells offer new opportunities for development of cell-based therapies while also providing a way around the ethical dilemma of using embryos, but just how good an alternative they are to embryonic cells remains to be seen.

It is clear that many challenges must be overcome before stem cells can be safely, effectively, and routinely used in the clinical setting. However, their potential benefits are numerous and hold tremendous promise for an array of new therapies and treatments.

Acknowledgments

The authors wish to thank the FDA staff for their support in writing this article and Rachael Conklin, Consumer Safety Officer, Consumer Affairs Branch, Division of Communication and Consumer Affairs, Center for Biologics Evaluation and Research, for her help in organizing the comments provided by FDA staff.

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FDA approves first CAR T-cell therapy for adults with leukemia or lymphoma

by Lori Solomon

The U.S. Food and Drug Administration has approved Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel [liso-cel]) as the first CD19-directed chimeric antigen receptor (CAR) T-cell therapy for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The expanded approval for the one-time personalized infusion is for adults who have received at least two prior lines of therapy, including a Bruton tyrosine kinase inhibitor (BTKi) and a B-cell lymphoma 2 inhibitor (BCL2i). Boxed warnings for Breyanzi include risks for cytokine release syndrome, neurologic toxicities, and secondary hematological malignancies.

The accelerated approval was based on response rate and duration of response in the TRANSCEND CLL 004 study, the first pivotal multicenter trial to evaluate a CAR T-cell therapy in patients with relapsed or refractory CLL or SLL.

The results of the phase 1/2 trial of 89 patients indicated a complete response rate of 20 percent with Breyanzi treatment. For those achieving a complete response, the median duration of response was not yet reached.

The overall response rate was 45 percent, with a median duration of response of 35.3 months. Across patients treated with Breyanzi who achieved a complete response, the minimal residual disease negativity rate was 100 percent in the blood and 92.3 percent in the bone marrow.

"The FDA approval of liso-cel in relapsed or refractory CLL and SLL after treatment with prior BTKi and BCL2i is a remarkable breakthrough, shifting the treatment paradigm from continuous therapy with sequential regimens to overcome drug resistance , to a one-time personalized T-cell based approach that has the potential to offer patients complete and lasting remission," lead investigator Tanya Siddiqi, M.D., from the City of Hope National Medical Center in Duarte, California, said in a statement.

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IMAGES

How Stem Cell Therapy Works
What is Stem Cell Therapy & How to Become a Stem Cell Therapist
What Is Stem Cell Therapy And How Does It Work?
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Different Types of Stem Cells Used in Biomedical Research

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Stem Cell Research & Therapy is the major forum for translational research into stem cell therapies. An international peer-reviewed journal, it publishes high-quality open access research articles with a special emphasis on basic, translational and clinical research into stem cell therapeutics and regenerative therapies, including animal models and clinical trials.
Stem cells: What they are and what they do
Stem cells: The body's master cells. Stem cells are the body's raw materials — cells from which all other cells with specialized functions are generated. Under the right conditions in the body or a laboratory, stem cells divide to form more cells called daughter cells. These daughter cells become either new stem cells or specialized cells ...
Current state of stem cell-based therapies: an overview
Stem cell-based therapies. Stem cell-based therapies are defined as any treatment for a disease or a medical condition that fundamentally involves the use of any type of viable human stem cells including embryonic stem cells (ESCs), iPSCs and adult stem cells for autologous and allogeneic therapies ().Stem cells offer the perfect solution when there is a need for tissue and organ ...
Stem cell-based therapy for human diseases
The discovery of hPSCs, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), has revolutionized stem cell research and cell-based therapy. 98 hESCs were ...
Stem Cells in the Treatment of Disease
Address reprint requests to Dr. Blau at Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Clinical Sciences Research ...
Stem cells: a comprehensive review of origins and emerging clinical
Within these diseases a genetic defect or defects prevents the proper function of cells derived from the hematopoietic stem cell lineage. Treatment includes implantation of genetically normal cells from a healthy donor to serve as a lifelong self-renewing source of normally functioning blood cells. ... Stem Cell Research and Therapy. 2018;9(1 ...
Advances in stem cell research and therapeutic development
Stem Cell Research & Therapy (2023) Despite many reports of putative stem-cell-based treatments in genetic and degenerative disorders or severe injuries, the number of proven stem cell therapies ...
Putting Stem Cell-Based Therapies in Context
When communicating to the public about stem cell-based therapies, it is important to put any treatment claims in context. Stem cell-based therapies include any treatment that uses human stem cells. These cells have the potential to develop into many different types of cells in the body. They offer a theoretically unlimited source of repair ...
Stem-cell research
Stem-cell research is the area of research that studies the properties of stem cells and their potential use in medicine. ... The impact understanding of exosome therapy in COVID-19 and ...
Stem cells: Therapy, controversy, and research
Scientists are researching how to use stem cells to regenerate or treat the human body. The list of conditions that stem cell therapy could help treat may be endless. Among other things, it could ...
Stem Cells: Types, What They Are & What They Do
Stem Cells. Stem cells are the only cells in your body that make different cell types, like blood, bone and muscle cells. They also repair damaged tissue. Now, stem cells are essential blood cancer and blood disorder treatments. Medical researchers believe stem cells also have the potential to treat many other diseases.
Introduction and Basic Concepts in Stem Cell Research and Therapy: The
Despite the enormous number of research articles published each day regarding the potential of stem cells and stem cell therapy, the absence of clear, verifiable information can lead to tragedy. For example, various incidences were reported in macular degeneration patients who developed blindness, retinal detachment and intraocular bleeding ...
Current Stem Cell Research & Therapy
Research article Open access FBLN5 was Regulated by PRDM9, and Promoted Senescence and Osteogenic Differentiation of Human Periodontal Ligament Stem Cells Mengyao Zhao, ...
Stem cell-based therapy for human diseases
Stem cell therapy is a novel therapeutic approach that utilizes the unique ... has revolutionized stem cell research and cell-based therapy. 98 hESCs were first isolated from blastocyst-stage embryos in 1998, 99 followed by breakthrough reprogramming research that converted somatic cells into hiPSCs using just four genetic factors. 100,101 ...
Recent progress in mesenchymal stem cell-based therapy for ...
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases in critically ill patients. Although pathophysiology of ALI/ARDS has been investigated in many studies, effective therapeutic strategies are still limited. Mesenchymal stem cell (MSC)-based therapy is emerging as a promising therapeutic intervention for patients with ALI. During the last two ...
Progress and challenges in stem cell biology
Since stem cells were first discovered, researchers have identified distinct stem cell populations in different organs and with various functions, converging on the unique abilities of self ...
Multiple myeloma: Its evolution, treatment and the quest to catch it
Stem cell transplants can pose risks, and some people can have serious complications. If eligible, people with multiple myeloma typically have a stem cell transplant after about four to six months of induction chemotherapy. Before the transplant, they receive a high dose of a different type of chemotherapy called conditioning chemotherapy. Dr ...
Stem Cell Therapies: A Way to Promising Cures
The stem-cell-based treatment induced significant remission of the disease as measured by American College of Rheumatology's improvement criteria, ... The National Academies and the International Society for Stem Cell Research (ISSCR) encourage all researchers working with pluripotent stem cells to have their research approved by the Stem ...
Discovery could revolutionize stem cell-based brain repair therapy for
The Michael J. Fox Foundation awarded $300,000 to continue the development of the hydrogel. The new research aims to understand how the immune system in the brain reacts when cells are ...
Advancing Clinical Research for a CAR T-Cell Therapy for Systemic Lupus
Symptoms of lupus may include pain or swelling in the joints, extreme fatigue, a butterfly rash on the cheeks and nose, and more. The California Institute for Regenerative Medicine (CIRM) has awarded $7.9 million to Barbara Hickingbottom, MD, of Fate Therapeutics to advance clinical research for FT819, an induced pluripotent stem cell (iPSC)-derived CD19 CAR…
Scientists Create Elephant Stem Cells in the Lab
The changes happening in the cell may resemble the first steps toward cancer, causing the cells to self-destruct. Image A micrograph of elephant stem cells produced from an elephant umbilical cord.
Abstract 5557: Stem-like T cells maintain latent anticancer activity
Abstract. Pre-cancerous cells are normally recognized and eliminated by immune cells. Cancer progresses only when this immunosurveillance system fails. Although immunotherapy has driven the most significant and exciting advances in cancer treatment in modern times, current approaches are running into barriers. An emerging area of interest includes evidence for rare but highly potent stem cell ...
FDA Approves Lenmeldy for Metachromatic Leukodystrophy
Today the FDA approved Lenmeldy (atidarsagene autotemcel), a hematopoietic stem cell gene therapy for the treatment of children with metachromatic leukodystrophy (MLD), making it the first and only treatment in the U.S. for early-onset forms of the disease.. MLD is a rare disorder caused by a mutation in the gene responsible for encoding the enzyme arylsulfatase A (ARSA).
Efficacy and safety of CD19 CAR-T cell therapy for acute ...
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for B-cell acute lymphoblastic leukemia (B-ALL). Although allo-HSCT can be curative for some B-ALL patients, relapse still occurs in some patients following allo-HSCT. Conventional chemotherapies show poor efficacy in B-ALL patients who have relapsed following allo-HSCT. In the past decade, chimeric antigen ...
Welcome to Stem Cell Research & Therapy
Stem Cell Research & Therapy aims to be the major forum for translational research into stem cell therapies. The journal has a special emphasis on basic, translational, and clinical research into stem cell therapeutics, including animal models, and clinical trials. Stem cell research for therapeutic purposes has largely used adult stem cell ...
Stem Cell Therapy: a Look at Current Research, Regulations, and
Two additional clinical trials at UCSD are testing stem cell-derived therapy for type-1 diabetes and chronic lymphocytic leukemia, the most common form of blood cancer. 1. These three studies are significant in that they are among the first efforts in stem cell research to make the leap from laboratory to human clinical trials.
FDA approves first CAR T-cell therapy for adults with leukemia or lymphoma
The U.S. Food and Drug Administration has approved Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel [liso-cel]) as the first CD19-directed chimeric antigen receptor (CAR) T-cell therapy ...

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Progress and challenges in stem cell biology

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