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In this issue, acknowledgements, disclosures, plant stem cells: the source of plant vitality and persistent growth.

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Makoto Hayashi, Ari Pekka Mähönen, Hitoshi Sakakibara, Keiko U Torii, Masaaki Umeda, Plant Stem Cells: The Source of Plant Vitality and Persistent Growth, Plant and Cell Physiology , Volume 64, Issue 3, March 2023, Pages 271–273, https://doi.org/10.1093/pcp/pcad009

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Plants have amazing vitality and persistence. Some tree species can live for thousands of years, and even when cut down, new sprouts emerge from the stump continuing their life. Similarly, if a horsetail is cut and fragmented, it is also capable of regenerating and flourishing from a remaining rhizome. Such features are based on the remarkable characteristics of plant stem cells. Plants are able to maintain pluripotency in stem cells generated during embryogenesis, and even after their differentiation, the cells can reprogram themselves and regenerate the whole plant body by acquiring pluripotency in response to stresses, such as wounding. Although humankind depends on the productive capacity of plants to meet various needs such as food, raw materials and maintenance of the global environment, we are yet to gain an understanding of the regulatory systems that generate their robust vitality. In other words, the elucidation of the molecular basis of plant vitality is one of the central issues not only in plant and agricultural sciences but also in life sciences.

The history of stem cell study in plants is relatively young compared to that in animals. In plants, the dividing cell population containing stem cells is called a meristem and the maintenance and regulatory mechanisms of its activity have been studied. Nonetheless, our understanding of the intrinsic properties of plant stem cells had been somewhat limited due to difficulties in accessing these deeply embedded tissues. However, thanks to recent advances in molecular genetics and single cell technologies, it is now possible to study stem cell characteristics more deeply.

This special issue explores the latest research into plant stem cells. The idea for this special issue was borne from a consortium research project ‘Principles of pluripotent stem cells underlying plant vitality’, which was conducted from 2017 to 2021 and supported by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The project aimed to understand the characteristics of plant stem cells through a multifaceted approach to study the temporal and spatial control of stem cell proliferation and generation and the mechanisms underpinning the maintenance of pluripotency and genome homeostasis. The ultimate goal was to understand persistence and vitality characteristics of plants to enable sustainable organogenesis and regeneration, as also reflected in the pages of this special issue.

This special issue includes four mini-reviews and four original articles focusing on different aspects of plant stem cells, briefly summarized later.

Shoot stem cells are the source of all post-embryonic aerial organs. An elaborate regulatory system is required to ensure that plant stem cells maintain their correct status during growth and development. Wang et al. (2023) summarize recent breakthroughs in studies of genetic circuits controlling the fate of shoot stem cells, namely, arrest, senescence and death. More specifically, they illustrate a working model for shoot apical meristem arrest (or end-of-flowering) under the FRUITFULL–APETALA2 pathway ( Balanzà et al. 2018 ) and propose a model for stem cell death controlled by dynamic changes in reactive oxygen species.

Plants continuously form branches to increase their photosynthetic capacity and expand their territories. Shoot branches are derived from axillary meristems initiated at the leaf axils, and the continuous formation of new axillary meristems allows for the plastic expansion of highly branched shoot systems. Axillary meristems arise from the division of boundary domain cells at the leaf base, but how axillary meristems are established de novo remains to be fully elucidated ( Nicolas and Laufs 2022 ). Yang et al. (2023) summarize recent progress in understanding the regulation of axillary meristem initiation, focusing on the key transcription factors, phytohormones and microRNAs involved. The illustration of a working model helps us to understand sequential processes leading to axillary meristem initiation, which constitutes an excellent system for determining stem cell fate and de novo meristem formation.

In both shoots and roots, persistent growth and organogenesis depend on the continued activity of meristems located in their apices. To establish persistency, a key system is the separation of cells into specific domains with different activities, called zonation. In roots, a dynamic equilibrium is reached in which cell division in the stem cell niche and meristem and cell differentiation in the elongation/differentiation region are balanced, which stabilizes the number of dividing cells and maintains the position of the transition zone ( Salvi et al. 2020 , Svolacchia et al. 2020 ). Shtin et al. (2023) show that the mutual inhibitory regulation between the PLETHORA (PLT) and the ARABIDOPSIS RESPONSE REGULATOR (ARR) transcription factors is sufficient for root zonation, separating cell division and cell differentiation during organogenesis. Specifically, they demonstrated that ARR1 suppresses PLT activities and that PLTs suppress ARR1 and ARR12 by targeting their proteins for degradation via the KISS ME DEADLY 2 F-box protein. These findings provide new insight into the complex process of root zonation.

Plant cells, including highly differentiated cells, have a remarkable capacity for reprogramming, resulting in the de novo generation of a whole plant. In the past two decades, extensive studies using the model plant Arabidopsis have uncovered the basic molecular scheme for plant regeneration ( Mathew and Prasad 2021 ). However, many important questions, such as how plant cells retain both differentiated status and developmental plasticity, still remain. Morinaka et al. (2023) provide an overview of the representative modes of plant regeneration and key factors revealed in studies of Arabidopsis and re-examine historical tissue culture systems that enable us to investigate the molecular details of cell reprogramming in highly differentiated cells.

The precise control of cell growth and proliferation is essential for the appropriate development of multicellular organisms, including plants. Critical regulatory factors controlling cell division and growth have been identified, but the mechanisms underlying cell type–specific cell growth and proliferation are still poorly understood. Ta et al. (2023) characterized a rice mutant with reduced mitotic activity, which is defective in the progression of embryogenesis. The causal gene encodes a member of the MO25A family of proteins that have pivotal functions in cell proliferation and polarity in animals, yeasts and filamentous fungi. Functional analysis of MO25A in the moss Physcomitrium patens showed that P. patens MO25A takes part in cell tip growth and the initiation of cell division in stem cells, suggesting that MO25A proteins have a conserved function that controls cell proliferation and growth across all kingdoms.

Some plant cell types are generated de novo through stem-cell-like precursors. During stomatal development of Arabidopsis , the sequential process of cell division and differentiation is governed by the key transcription factors, such as MUTE and FAMA, which switch the cell cycle mode from asymmetric division to symmetric division and terminate the cell cycle. This sequential process occurs within a single round of the cell cycle; however, it remains elusive whether the cell cycle restricts the expression of these transcription factors. Zuch et al. (2023) investigated the expression patterns of MUTE and FAMA during the cell cycle and found that MUTE expression is gated by the cell cycle. Moreover, they revealed that, in the absence of MUTE, the G1 phase is prolonged as the meristemoids reiterate asymmetric cell divisions. This study highlights a mechanism for the eventual G1 arrest of an uncommitted stem-cell-like precursor.

The vascular system transports water and nutrient ions and assimilates throughout the plant body. Key factors and the regulatory networks of primary and secondary vascular development have been identified ( Haas et al. 2022 ). However, the complexity of the vascular system, which is composed of a variety of cells including xylem and phloem cells, makes it difficult to analyze vascular development and distinguish between vascular stem cells and developing xylem and phloem cells. Shimadzu et al. (2023) summarize recent findings on the establishment and maintenance of vascular stem cells, focusing on recent technical advances that enable cell type–specific analysis during vascular development.

Grafting is a horticultural technique that physically connects two individual plants of different genetic backgrounds to create or enhance properties such as abiotic stress resistance. During this process, callus formation at the graft junction facilitates organ attachment and vascular reconnection. Ikeuchi’s group recently identified WUSCHEL-RELATED HOMEOBOX13 (WOX13) as an essential regulator of organ grafting ( Ikeuchi et al. 2022 ), but how callus formation is differentially regulated at each cut end remained unsolved. In this issue, Tanaka et al. (2023) report that differential auxin signaling between the top and bottom cut ends of grafted stems is responsible for the commonly observed asymmetric callus formation. Specifically, they found that this process is regulated by differential auxin accumulation and that expression of auxin-responsive genes, including WOX13 , preferentially occurs in the top part of the graft. Their findings provide insight into the role of auxin signaling in organ attachment during the grafting process.

Finally, we hope that the papers in this special issue help readers to update their current understanding of plant stem cells and provide new ideas for future conceptual breakthroughs in plant stem cell biology.

Ministry of Education, Culture, Sports, Science and Technology, Japan [Grants-in-Aid for Scientific Research on Innovative Areas (Principles of Pluripotent Stem Cells Underlying Plant Vitality, 17H06470 and 22H04904) to M.U.].

We thank Professor Wataru Sakamoto, Editor-in-Chief, Plant and Cell Physiology , for providing the opportunity for this special issue. We would like to acknowledge the authors and reviewers who have greatly contributed to this issue.

The authors have no conflicts of interest to declare.

Balanzà   V. , Martínez-Fernández   I. , Sato   S. , Yanofsky   M.F. , Kaufmann   K. , Angenent   G.C. , et al.  ( 2018 ) Genetic control of meristem arrest and life span in Arabidopsis by a FRUITFULL-APETALA2 pathway . Nat. Commun.   9 : 565.

Google Scholar

Haas   A.S. , Shi   D. and Greb   T. ( 2022 ) Cell fate decisions within the vascular cambium–initiating wood and bast formation . Front. Plant Sci.   13 : 1 – 8 .

Ikeuchi   M. , Iwase   A. , Ito   T. , Tanaka   H. , Favero   D.S. , Kawamura   A. , et al.  ( 2022 ) Wound-inducible WUSCHEL-RELATED HOMEOBOX 13 is required for callus growth and organ reconnection . Plant Physiol.   188 : 425 – 441 .

Mathew   M.M. and Prasad   K. ( 2021 ) Model systems for regeneration: Arabidopsis . Development   148 : dev195347.

Morinaka   H. , Coleman   D. , Sugimoto   K. and Iwase   A. ( 2023 ) Molecular mechanisms of plant regeneration from differentiated cells: approaches from historical tissue culture systems . Plant Cell Physiol.   64 : 308 – 315 .

Nicolas   A. and Laufs   P. ( 2022 ) Meristem initiation and de novo stem cell formation . Front. Plant Sci.   13 : 891228.

Salvi   E. , Rutten   J.P. , Di Mambro   R. , Polverari   L. , Licursi   V. , Negri   R. , et al.  ( 2020 ) A self-organized PLT/Auxin/ARR-B network controls the dynamics of root zonation development in Arabidopsis thaliana . Dev. Cell.   53 : 431 – 443 .

Shimadzu   S. , Furuya   T. and Kondo   Y. ( 2023 ) Molecular mechanisms underlying the establishment and maintenance of vascular stem cells in Arabidopsis thaliana . Plant Cell Physiol.   64 : 285 – 294 .

Shtin   M. , Polverari   L. , Svolacchia   N. , Bertolotti   G. , Unterholzner   S.J. , Di Mambro   R. , et al.  ( 2023 ) The mutual inhibition between PLETHORAs and ARABIDOPSIS RESPONSE REGULATORs controls root zonation . Plant Cell Physiol.   64 : 328 – 335 .

Svolacchia   N. , Salvi   E. and Sabatini   S. ( 2020 ) Arabidopsis primary root growth: let it grow, can’t hold it back anymore!   Curr. Opin. Plant Biol.   57 : 133 – 141 .

Ta   K.N. , Yoshida   M.W. , Tezuka   T. , Shimizu-Sato   S. , Nosaka-Takahashi   M. , Toyoda   A. , et al.  ( 2023 ) Control of plant cell growth and proliferation by MO25A, a conserved major component of the Mammalian Sterile20-like kinase pathway . Plant Cell Physiol.   64 : 347 – 362 .

Tanaka   H. , Hashimoto   N. , Kawai   S. , Yumoto   E. , Shibata   K. , Tameshige   T. , et al.  ( 2023 ) Auxin-induced WUSCHEL-RELATED HOMEOBOX13 mediates asymmetric activity of callus formation upon cutting . Plant Cell Physiol.   64 : 316 – 327 .

Wang   Y. , Shirakawa   M. and Ito   T. ( 2023 ) Arrest, senescence and death of shoot apical stem cells in Arabidopsis thaliana . Plant Cell Physiol.   64 : 295 – 301 .

Yang   T. , Jiao   Y. and Wang   Y. ( 2023 ) Stem cell basis of shoot branching . Plant Cell Physiol.   64 : 302 – 307 .

Zuch   D.T. , Herrmann   A. , Kim   E.-D. and Torii   K.U. ( 2023 ) Cell cycle dynamics during stomatal development: window of MUTE action and ramification of its loss-of-function on an uncommitted precursor . Plant Cell Physiol.   64 : 336 – 346 .

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Plant stem cells and their applications: special emphasis on their marketed products

Affiliations.

• 1 Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh 201313 India.
• 2 Department of Botany, Ege University, Izmir, Turkey.
• PMID: 32550110
• PMCID: PMC7275108
• DOI: 10.1007/s13205-020-02247-9

Stem cells are becoming increasingly popular in public lexicon owing to their prospective applications in the biomedical and therapeutic domains. Extensive research has found various independent stem cell systems fulfilling specific needs of plant development. Plant stem cells are innately undifferentiated cells present in the plant's meristematic tissues. Such cells have various commercial uses, wherein cosmetic manufacture involving stem cell derivatives is the most promising field at present. Scientific evidence suggests anti-oxidant and anti-inflammatory properties possessed by various plants such as grapes ( Vitis vinifera ), lilacs ( Syringa vulgaris ), Swiss apples ( Uttwiler spatlauber ) etc. are of great importance in terms of cosmetic applications of plant stem cells. There are widespread uses of plant stem cells and their extracts. The products so formulated have a varied range of applications which included skin whitening, de-tanning, moisturizing, cleansing etc. Despite all the promising developments, the domain of plant stem cells remains hugely unexplored. This article presents an overview of the current scenario of plant stem cells and their applications in humans.

Keywords: Anti-ageing; Cosmetics; Plant stem cells; Skincare; Stem cell extract.

© King Abdulaziz City for Science and Technology 2020.

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Apical stem cells sustaining prosperous evolution of land plants

• Apical Stem Cell(s): Evolutionary Basis for 3D Body Plans in Land Plants
• Published: 28 April 2020
• Volume 133 , pages 279–282, ( 2020 )

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• Ryuichi Nishihama 1 &
• Satoshi Naramoto 2   nAff3  

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Ever since plants colonized the terrestrial environment ca. 470 million years ago, they have evolved to maximize the efficiency for the use of above-ground and underground spaces by coping with harsh environmental stresses on land, including drought, high salinity, and UV. Innovation of the shooting and rooting systems contributed greatly. For instance, shoots form leaves radially around a stem to achieve efficient light absorption, thicken their stems to increase body mass, and branch out new shoots to produce more descendants. Roots are comprised of centrifugally layered tissues and branch by forming lateral roots. These developmental patterns are based on the three-dimensional (3D) growth axes, namely the apical-basal and radial axes. One major evolutionary basis that enabled these inventions is the emergence of stem cells capable of dividing with multiple planes in a regulated fashion and the increase of stem cell numbers in the apex, i.e. single apical cells in bryophytes, one or two apical cells in lycophytes and ferns, and multiple stem cells in seed plants (Harrison 2017 ). This apical stem cell-based growth mode allowed the drastic expansion of diversity in land plants.

In the green lineage, the stem cell system was acquired in charophyte green algae. Stem cells in charophytes divide only in one or two directions and thereby can only direct up to 2D body plans, such as filaments, branching filaments and mats. Bryophytes, consisting of liverworts, mosses, and hornworts, are basal land plant lineages that diverged from charophytes and have 3D body plans, as clearly manifested by rotational leaf formation patterns in liverwort and moss species. Thus, coinciding with land colonization, a third dimension in the division plane of stem cells was acquired and paved the way for drastic morphological innovations.

Recent studies identified moss genes involved in the 3D regulation of stem cell’s division. The moss Physcomitrella patens protonemata grow as filamentous tissues with a single apical stem cell, that is 1D growth. Occasionally, new stem cells branch (2D growth) and divide obliquely to initiate formation of gametophores, or 3D leafy shoots. This transition from 2 to 3D growth was shown to be regulated by the APETALA2-type transcription factors APBs (for AINTEGUMENTA, PLETHORA, and BABY BOOM; Aoyama et al. 2012 ). The oblique division is defective in mutants for Defective Kernel 1 ( DEK1 ; Perroud et al. 2014 ), NO GAMETOPHORES 1 ( NOG1 ; Moody et al. 2018 ), and genes in the CLAVATA (CLV) signaling pathway (Whitewoods et al. 2018 ). The CLV pathway in angiosperms is well known for the regulation of the maintenance of stem cell pools in concert with the homeobox transcription factor WUSCHEL (WUS), a key regulator of stem cell fate (see below for WUS). Whitewoods et al. ( 2018 ) demonstrated that the CLV pathway regulates cell division planes also in the angiosperm Arabidopsis thaliana . As not only moss but also liverwort and hornwort species lack an orthologous gene for WUS (Bowman et al. 2017 ; Li et al. 2020 ; Sakakibara et al. 2014 ; Zhang et al. 2020 ), it is reasonable to assume that the CLV cell-communication system was originally invented to control 3D growth and then co-opted to control stem cell population by recruiting WUS. This example readily shows that it is of great significance to argue the evolution of stem cells in land plants by comparing their characteristics and functions, or mechanisms of their establishment and maintenance, in divergent taxonomical groups. This JPR symposium titled “Apical stem cell(s): evolutionary basis for 3D body plans in land plants” presents review and original articles regarding stem cell biology along land plant evolution.

The first three papers are review articles. In the first review, Moody ( 2020 ) describes comprehensively the morphologies of early streptophytes, from charophyte green algae to bryophytes, with nice illustrations and summarizes the evolution of their morphological complexities to discuss how it relates to the dimensions of stem cell division planes. This serves as a good introductory article for the traits and taxonomies of these green lineage species, with which readers can follow the evolutionary transition from 1D through 2D to 3D growth. The author also points out convergent evolution of 3D apical growth between land plants and brown algae, which are independently evolved lineages and may share similar principles.

Roots are thought to have evolved multiple times independently in vascular plants (Friedman et al. 2004 ; Kenrick and Crane 1997 ; Raven and Edwards 2001 ), and how root apical meristems (RAMs) evolved is an open question. Seed plant roots generally contain the quiescent center (QC), an organizer to maintain the root stem cell niche. In the second review article, Fujinami et al. ( 2020 ) classify RAM organizations in lycophytes into four types based on cell division activity and anatomy. The authors previously reported the existence of a QC-like area with low division activity in the root of a lycophyte species, but the absence of such areas in other lycophyte species (Fujinami et al. 2017 ). Together with the fact that lycophyte roots branch dichotomously, the data support the previous hypothesis of convergent evolution of roots in the vascular plant lineage and opens new questions on its molecular basis.

The shoot apical meristem (SAM) of A. thaliana consists of clonally distinct cell layers, that is L1, L2, and L3 from the outside, in all of which stem cells are embedded at the center. The number of stem cells is tightly regulated by their interaction with the organizing center (OC) located in the L3 layer. This non-cell autonomous control of stem cells is mediated by a negative feedback loop involving the CLV signaling pathway and the homeobox transcription factor WUS (Gaillochet et al. 2017 ). WUS mRNAs accumulate exclusively in the OC, but the proteins are detected in the L1 and L2 stem cells (Daum et al. 2014 ; Yadav et al. 2011 ), indicating cell-to-cell movement of WUS proteins. In the third review article, Fuchs and Lohmann ( 2020 ) comprehensively review previous studies on the WUS-mediated non-cell autonomous control of stem cells. A special emphasis is put on the mechanisms of cell-to-cell protein motility with detailed structural considerations and the function of WUS transcription factor.

It is known that position-dependent cell-fate determination underlies organ formation and tissue differentiation in angiosperms (Scheres 2001 ). In contrast, mosses and leafy liverworts were reported to form each leaf within a merophyte, a clonal group of cells derived from a daughter cell of the single apical cell (Crandall-Stotler 1980 ; Harrison et al. 2009 ), indicating cell-lineage-based organ development in these taxa of bryophytes. In this issue, Suzuki et al. ( 2020 ) apply a clonal analysis technique to a thalloid liverwort, Marchantia polymorpha , and elucidate that organs formed on the dorsal surface of the thallus contain cells derived from multiple merophytes. Thus, the positional cue-directed organ formation is likely to be a common theme in land plants associated with the 3D mode of apical cell division.

Gametophytes in bryophytes and sporophytes in angiosperms develop analogous apical meristems whose activities are regulated by apical stem cells (Prigge and Bezanilla 2010 ). Arabidopsis LIGHT-DEPENDENT SHORT HYPOCOTYLS1 and the Oryza G1 (ALOG) protein family regulates apical meristem activities and lateral organ development in angiosperms (MacAlister et al. 2012 ; Takeda et al. 2011 ; Yoshida et al. 2009 , 2013 ). Recent findings identified that the ALOG protein family regulates meristem maintenance and lateral organ development in M. polymorpha (Naramoto et al. 2019 ). This suggests that common regulatory mechanisms mediated by ALOG control apical meristem activities, such as cell proliferation and lateral organ formation in land plants despite their independent origins (Naramoto et al. 2019 ). In this issue, Naramoto et al. ( 2020 ) perform phylogenetic analysis of ALOG family proteins and identify that the ALOG protein family emerged before the evolution of land plants and that their molecular functions have been conserved at least in some part during the evolution of land plants. These findings imply that the ALOG gene had acted as an ancient mechanism controlling apical meristem activities in common ancestors of land plants, which subsequently recruited different regulatory mechanisms between bryophytes and angiosperms.

Stem cell maintenance and position-dependent cell differentiation are regulated by various means, including phytohormone signaling, cell-to-cell movement of proteins, and peptide-ligand signaling. Together with the moss CLV pathway function in the regulation of stem cell division planes, a recent finding that CLE (CLAVATA3/EMBRYO SURROUNDING REGION-related) peptide signaling regulates meristem activity in the liverwort (Hirakawa et al. 2019 ) suggests the acquisition of cell–cell communication systems via peptide ligands contributed greatly to 3D growth of land plants. In this issue, Cammarata and Scanlon ( 2020 ) focus on such systems regulating stem cells and report phylogenetic relationships of LEUCINE-RICH REPEAT-RECEPTOR LIKE KINASEs (LRR-RLKs) and related proteins across diverse land plant models. Their analysis finds structural evolution of some protein families and shows that several stem cell-regulating protein clades share origins with immune signaling proteins, providing new insights into the broader aspect of stem cell regulations.

We still do not know much about how stem cells can be defined in terms of gene expression, epigenetic status, chromatin structure, and division plane control. State-of-art technologies, such as single-cell analysis (e.g., Denyer et al. 2019 ; Jean-Baptiste et al. 2019 ; Ryu et al. 2019 ; Zhang et al. 2019 ), as well as comparative studies with a wide range of plant species (e.g., Frank et al. 2015 ; Frank and Scanlon 2015 ), will resolve these questions.

Aoyama T, Hiwatashi Y, Shigyo M, Kofuji R, Kubo M, Ito M, Hasebe M (2012) AP2-type transcription factors determine stem cell identity in the moss Physcomitrella patens . Development 139:3120–3129

Article   CAS   Google Scholar  

Bowman JL, Kohchi T, Yamato KT, Jenkins J, Shu S, Ishizaki K, Yamaoka S, Nishihama R, Nakamura Y, Berger F, Adam C, Aki SS, Althoff F, Araki T, Arteaga-Vazquez MA, Balasubrmanian S, Barry K, Bauer D, Boehm CR, Briginshaw L, Caballero-Perez J, Catarino B, Chen F, Chiyoda S, Chovatia M, Davies KM, Delmans M, Demura T, Dierschke T, Dolan L, Dorantes-Acosta AE, Eklund DM, Florent SN, Flores-Sandoval E, Fujiyama A, Fukuzawa H, Galik B, Grimanelli D, Grimwood J, Grossniklaus U, Hamada T, Haseloff J, Hetherington AJ, Higo A, Hirakawa Y, Hundley HN, Ikeda Y, Inoue K, Inoue SI, Ishida S, Jia Q, Kakita M, Kanazawa T, Kawai Y, Kawashima T, Kennedy M, Kinose K, Kinoshita T, Kohara Y, Koide E, Komatsu K, Kopischke S, Kubo M, Kyozuka J, Lagercrantz U, Lin SS, Lindquist E, Lipzen AM, Lu CW, De Luna E, Martienssen RA, Minamino N, Mizutani M, Mizutani M, Mochizuki N, Monte I, Mosher R, Nagasaki H, Nakagami H, Naramoto S, Nishitani K, Ohtani M, Okamoto T, Okumura M, Phillips J, Pollak B, Reinders A, Rovekamp M, Sano R, Sawa S, Schmid MW, Shirakawa M, Solano R, Spunde A, Suetsugu N, Sugano S, Sugiyama A, Sun R, Suzuki Y, Takenaka M, Takezawa D, Tomogane H, Tsuzuki M, Ueda T, Umeda M, Ward JM, Watanabe Y, Yazaki K, Yokoyama R, Yoshitake Y, Yotsui I, Zachgo S, Schmutz J (2017) Insights into land plant evolution garnered from the Marchantia polymorpha genome. Cell 171:287–304

Cammarata J, Scanlon MJ (2020) A functionally informed evolutionary framework for the study of LRR-RLKs during stem cell maintenance. J Plant Res. https://doi.org/10.1007/s10265-020-01197-w

Article   PubMed   Google Scholar  

Crandall-Stotler B (1980) Morphogenetic designs and a theory of bryophyte origins and divergence. Bioscience 30:580–585

Article   Google Scholar  

Daum G, Medzihradszky A, Suzaki T, Lohmann JU (2014) A mechanistic framework for noncell autonomous stem cell induction in Arabidopsis . Proc Natl Acad Sci USA 111:14619–14624

Denyer T, Ma X, Klesen S, Scacchi E, Nieselt K, Timmermans MCP (2019) Spatiotemporal developmental trajectories in the Arabidopsis root revealed using high-throughput single-cell RNA sequencing. Dev Cell 48:840–852

Frank MH, Scanlon MJ (2015) Transcriptomic evidence for the evolution of shoot meristem function in sporophyte-dominant land plants through concerted selection of ancestral gametophytic and sporophytic genetic programs. Mol Biol Evol 32:355–367

Frank MH, Edwards MB, Schultz ER, McKain MR, Fei Z, Sorensen I, Rose JK, Scanlon MJ (2015) Dissecting the molecular signatures of apical cell-type shoot meristems from two ancient land plant lineages. New Phytol 207:893–904

Friedman WE, Moore RC, Purugganan MD (2004) The evolution of plant development. Am J Bot 91:1726–1741

Fuchs M, Lohmann JU (2020) Aiming for the top: non-cell autonomous control of shoot stem cells in Arabidopsis. J Plant Res. https://doi.org/10.1007/s10265-020-01174-3

Fujinami R, Yamada T, Nakajima A, Takagi S, Idogawa A, Kawakami E, Tsutsumi M, Imaichi R (2017) Root apical meristem diversity in extant lycophytes and implications for root organs. New Phytol 215:1210–1220

Fujinami R, Yamada T, Imaichi R (2020) Root apical meristem diversity and the origin of roots: insights from extant lycophytes. J Plant Res. https://doi.org/10.1007/s10265-020-01167-2

Gaillochet C, Stiehl T, Wenzl C, Ripoll JJ, Bailey-Steinitz LJ, Li L, Pfeiffer A, Miotk A, Hakenjos JP, Forner J, Yanofsky MF, Marciniak-Czochra A, Lohmann JU (2017) Control of plant cell fate transitions by transcriptional and hormonal signals. eLife 6:e30135

Harrison CJ (2017) Development and genetics in the evolution of land plant body plans. Philos Trans R Soc B 372:20150490

Harrison CJ, Roeder AH, Meyerowitz EM, Langdale JA (2009) Local cues and asymmetric cell divisions underpin body plan transitions in the moss Physcomitrella patens . Curr Biol 19:461–471

Hirakawa Y, Uchida N, Yamaguchi YL, Tabata R, Ishida S, Ishizaki K, Nishihama R, Kohchi T, Sawa S, Bowman JL (2019) Control of proliferation in the haploid meristem by CLE peptide signaling in Marchantia polymorpha . PLoS Genet 15:e1007997

Jean-Baptiste K, McFaline-Figueroa JL, Alexandre CM, Dorrity MW, Saunders L, Bubb KL, Trapnell C, Fields S, Queitsch C, Cuperus JT (2019) Dynamics of gene expression in single root cells of Arabidopsis thaliana . Plant Cell 31:993–1011

Kenrick P, Crane PR (1997) The origin and early diversification of land plants. Smithsonian Institution Press, Washington

Google Scholar  

Li FW, Nishiyama T, Waller M, Frangedakis E, Keller J, Li Z, Fernandez-Pozo N, Barker MS, Bennett T, Blazquez MA, Cheng S, Cuming AC, de Vries J, de Vries S, Delaux PM, Diop IS, Harrison CJ, Hauser D, Hernandez-Garcia J, Kirbis A, Meeks JC, Monte I, Mutte SK, Neubauer A, Quandt D, Robison T, Shimamura M, Rensing SA, Villarreal JC, Weijers D, Wicke S, Wong GK, Sakakibara K, Szovenyi P (2020) Anthoceros genomes illuminate the origin of land plants and the unique biology of hornworts. Nat Plants 6:259–272

MacAlister CA, Park SJ, Jiang K, Marcel F, Bendahmane A, Izkovich Y, Eshed Y, Lippman ZB (2012) Synchronization of the flowering transition by the tomato TERMINATING FLOWER gene. Nat Genet 44:1393–1398

Moody LA (2020) Three-dimensional growth: a developmental innovation that facilitated plant terrestrialization. J Plant Res. https://doi.org/10.1007/s10265-020-01173-4

Moody LA, Kelly S, Rabbinowitsch E, Langdale JA (2018) Genetic regulation of the 2D to 3D growth transition in the moss Physcomitrella patens . Curr Biol 28:473–478

Naramoto S, Jones VAS, Trozzi N, Sato M, Toyooka K, Shimamura M, Ishida S, Nishitani K, Ishizaki K, Nishihama R, Kohchi T, Dolan L, Kyozuka J (2019) A conserved regulatory mechanism mediates the convergent evolution of plant shoot lateral organs. PLoS Biol 17:e3000560

Naramoto S, Hata Y, Kyozuka J (2020) The origin and evolution of the ALOG proteins, members of a plant-specific transcription factor family, in land plants. J Plant Res. https://doi.org/10.1007/s10265-020-01171-6

Perroud PF, Demko V, Johansen W, Wilson RC, Olsen OA, Quatrano RS (2014) Defective Kernel 1 (DEK1) is required for three-dimensional growth in Physcomitrella patens . New Phytol 203:794–804

Prigge MJ, Bezanilla M (2010) Evolutionary crossroads in developmental biology: Physcomitrella patens . Development 137:3535–3543

Raven JA, Edwards D (2001) Roots: evolutionary origins and biogeochemical significance. J Exp Bot 52:381–401

Ryu KH, Huang L, Kang HM, Schiefelbein J (2019) Single-cell RNA sequencing resolves molecular relationships among individual plant cells. Plant Physiol 179:1444–1456

Sakakibara K, Reisewitz P, Aoyama T, Friedrich T, Ando S, Sato Y, Tamada Y, Nishiyama T, Hiwatashi Y, Kurata T, Ishikawa M, Deguchi H, Rensing SA, Werr W, Murata T, Hasebe M, Laux T (2014) WOX13-like genes are required for reprogramming of leaf and protoplast cells into stem cells in the moss Physcomitrella patens . Development 141:1660–1670

Scheres B (2001) Plant cell identity. The role of position and lineage. Plant Physiol 125:112–114

Suzuki H, Harrison CJ, Shimamura M, Kohchi T, Nishihama R (2020) Positional cues regulate dorsal organ formation in the liverwort Marchantia polymorpha . J Plant Res. https://doi.org/10.1007/s10265-020-01180-5

Whitewoods CD, Cammarata J, Nemec Venza Z, Sang S, Crook AD, Aoyama T, Wang XY, Waller M, Kamisugi Y, Cuming AC, Szövényi P, Nimchuk ZL, Roeder AHK, Scanlon MJ, Harrison CJ (2018) CLAVATA was a genetic novelty for the morphological innovation of 3D growth in land plants. Curr Biol 28:2365–2376

Takeda S, Hanano K, Kariya A, Shimizu S, Zhao L, Matsui M, Tasaka M, Aida M (2011) CUP-SHAPED COTYLEDON1 transcription factor activates the expression of LSH4 and LSH3, two members of the ALOG gene family, in shoot organ boundary cells. Plant J 66:1066–1077

Yadav RK, Perales M, Gruel J, Girke T, Jönsson H, Reddy GV (2011) WUSCHEL protein movement mediates stem cell homeostasis in the Arabidopsis shoot apex. Genes Dev 25:2025–2030

Yoshida A, Suzaki T, Tanaka W, Hirano H (2009) The homeotic gene long sterile lemma (G1) specifies sterile lemma identity in the rice spikelet. Proc Natl Acad Sci USA 106:20103–20108

Yoshida A, Sasao M, Yasuno N, Takagi K, Daimon Y, Chen R, Yamazaki R, Tokunaga H, Kitaguchi Y, Sato Y, Nagamura Y, Ushijima T, Kumamaru T, Iida S, Maekawa M, Kyozuka J (2013) TAWAWA1, a regulator of rice inflorescence architecture, functions through the suppression of meristem phase transition. Proc Natl Acad Sci USA 110:767–772

Zhang TQ, Xu ZG, Shang GD, Wang JW (2019) A single-cell RNA sequencing profiles the developmental landscape of Arabidopsis root. Mol Plant 12:648–660

Zhang J, Fu XX, Li RQ, Zhao X, Liu Y, Li MH, Zwaenepoel A, Ma H, Goffinet B, Guan YL, Xue JY, Liao YY, Wang QF, Wang QH, Wang JY, Zhang GQ, Wang ZW, Jia Y, Wang MZ, Dong SS, Yang JF, Jiao YN, Guo YL, Kong HZ, Lu AM, Yang HM, Zhang SZ, Van de Peer Y, Liu ZJ, Chen ZD (2020) The hornwort genome and early land plant evolution. Nat Plants 6:107–118

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Satoshi Naramoto

Present address: Department of Biological Sciences, Faculty of Science, Hokkaido University, Hokkaido, 060-0810, Japan

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Graduate School of Biostudies, Kyoto University, Kyoto, 606-8502, Japan

Ryuichi Nishihama

Graduate School of Life Sciences, Tohoku University, Sendai, 980-8577, Japan

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Nishihama, R., Naramoto, S. Apical stem cells sustaining prosperous evolution of land plants. J Plant Res 133 , 279–282 (2020). https://doi.org/10.1007/s10265-020-01198-9

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Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review

• Ria Margiana 1 , 2 , 3 ,
• Alexander Markov 4 , 5 ,
• Angelina O. Zekiy 6 ,
• Mohammed Ubaid Hamza 7 ,
• Khalid A. Al-Dabbagh 8 ,
• Sura Hasan Al-Zubaidi 9 ,
• Noora M. Hameed 10 ,
• Irshad Ahmad 11 ,
• R. Sivaraman 12 ,
• Hamzah H. Kzar 13 ,
• Moaed E. Al-Gazally 14 ,
• Yasser Fakri Mustafa 15 &
• Homayoon Siahmansouri 16  

Stem Cell Research & Therapy volume  13 , Article number:  366 ( 2022 ) Cite this article

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The multipotency property of mesenchymal stem cells (MSCs) has attained worldwide consideration because of their immense potential for immunomodulation and their therapeutic function in tissue regeneration. MSCs can migrate to tissue injury areas to contribute to immune modulation, secrete anti-inflammatory cytokines and hide themselves from the immune system. Certainly, various investigations have revealed anti-inflammatory, anti-aging, reconstruction, and wound healing potentials of MSCs in many in vitro and in vivo models. Moreover, current progresses in the field of MSCs biology have facilitated the progress of particular guidelines and quality control approaches, which eventually lead to clinical application of MSCs. In this literature, we provided a brief overview of immunoregulatory characteristics and immunosuppressive activities of MSCs. In addition, we discussed the enhancement, utilization, and therapeutic responses of MSCs in neural, liver, kidney, bone, heart diseases, and wound healing.

Introduction

In the last decade, stem cells are increasingly applied as a therapeutic method for numerous disorders. Stem cell therapy, traditionally applied for hematopoietic disorders, nonetheless, is now established for the treatment of non-hematologic disorders [ 1 , 2 ].

Accumulating evidence has shown that mesenchymal stem cells (MSCs) offer an encouraging option for cell treatment and reconstruction of human tissues because of their differentiation multipotency, self‐renewal capacity, long‐term ex vivo proliferation, paracrine potentials, and immunoregulatory effect [ 3 ]. Furthermore, MSCs have the capability to support the progression and differentiation of other stem cells. They can release bioactive molecules, which is a key benefit in tissue regeneration [ 4 , 5 ]. These properties result in progression of treatments for a wide range of diseases, such as diseases affecting the bone, neuron, lung, liver, heart, kidney, etc. [ 4 ]. Due to these features, it is obvious that MSCs will hold a major therapeutic role in clinical trials. Because of these properties, we provided a general overview of the latest trials that studied the effectiveness of MSCs in several diseases such as neural, liver, kidney, bone, heart diseases, and wound healing.

Stem cells in regenerative medicine

In the last years, numerous studies have demonstrated that cellular therapy has exhibited great development in both in vitro and in vivo researches. Stem cells have the capability to self-renew, and also to differentiate into all cell types and are involved in physiological regeneration [ 6 ]. There are multiple stem cell sources of adult and pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for tissue regeneration. PSCs have a high potential for pluripotency and self-renewal, which makes these cells an important option for treatment of diseases. However, there are ethical issues when using these cells, in which ESCs are separated from blastocyst-stage embryos, requiring destruction of the embryo [ 7 , 8 , 9 ]. The results of studies have revealed the regenerative ability of iPSCs in preclinical setting and conducted the first clinical study for treatment of age-associated with macular deterioration [ 10 , 11 ]. Nonetheless, the tumorigenicity risk remains unsolved. Because of these limitations, researchers began to investigate adult stem cells, the multipotent stem cells found in tissues and organs of adults. Various investigations have reported that stem cell therapy can regenerate and repair injured organs in vivo, including bone repair, cutaneous wound, pulpitis, and ischemic cardiac tissue through stem cell differentiation and production of new particular cells [ 12 , 13 , 14 , 15 ]. Moreover, some investigations have demonstrated that cultured adult stem cells release many molecular factors with anti-apoptotic, immunoregulatory, angiogenic, and chemoattractant features that stimulate regeneration [ 16 , 17 , 18 ]. Hematopoietic stem cells (HSCs) and MSCs are part of adult stem cells, which are the most widely used, generally because they can be isolated from individuals in diseased conditions.

Mesenchymal stem cell

In the late 1960s, Friedenstein and colleagues discovered MSCs as multipotent stem cells for the first time [ 19 ]. MSCs are non-hematopoietic cells and have the capability to differentiate into various lineage including mesodermal (adipocytes, osteocytes, and chondrocytes), ectodermal (neurocytes), and endodermal lineage (hepatocytes) [ 20 , 21 ]. At the beginning, it was thought that MSCs are “stromal” cells instead of stem cells [ 22 ]. Several investigators tried to alter the name of MSCs to medicinal signaling cells due to their function in secretion of some metabolites molecules in the sites of diseases, injuries, and inflammations [ 23 , 24 ]. After that, some studies have stated that MSCs can release prostaglandin E2 (PGE2), which plays a major role in the self-renewal ability, immunomodulation of MSCs, and generating a cascade of events, that demonstrates the stemness of MSCs [ 25 ]. Therefore, the term mesenchymal stem cells is justified.

MSCs chiefly found in the bone marrow (BM) possess the ability of self-renewal and also display multilineage differentiation [ 8 , 26 , 27 ]. They were obtained from various tissues and organs including BM, adipose tissue, Wharton’s jelly, peripheral blood, umbilical cord, placenta, amniotic fluid, and dental pulp [ 3 , 28 , 29 , 30 ]. MSCs can express a wide range of surface markers and cytokine profiles according to the origin of isolation [ 31 ]. Nevertheless, the common characterization markers of MSCs are CD73, CD105, CD90 and lacking expression of CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR [ 32 , 33 , 34 ]. During the last decades, MSCs have shown various biological roles such as multilineage differentiation, immunomodulation, angiogenesis, anti-apoptotic and anti-fibrotic activity, chemo-attraction, and tissue repair development [ 35 , 36 , 37 ]. The MSCs have broad properties that make them a suitable source for cell therapy, such as stemness potency, easily isolation from different sources, they can be rapidly expanded in a large scale for clinical use, have less ethical issues as compared to ESCs, unlike iPSCs, MSCs transport a lower risk of teratoma formation, and they are beneficial for a wide scale of therapeutic applications due to their capability to migrate to injured tissue through chemo-attraction [ 38 , 39 , 40 ]. In addition, MSCs can release a variety of bioactive components including proteins, growth factors chemokines, microRNAs (miRNAs), and cytokines which can suggest their acceptable application [ 41 ].

The biological roles of MSCs

MSCs have the ability to inhibit the immune response in inflammatory cytokine-rich situations, including infections, wounds, or immune-mediated disorders. These immunomodulatory properties were discovered in preclinical and clinical trials, where MSCs effectively suppressed T cell activation and proliferation along with stimulation of macrophages shift from M1 to M2 [ 42 , 43 , 44 ]. This specific performance of MSCs in the presence and absence of inflammatory mediators is termed MSC polarization. MSCs have the ability to migrate to damaged areas after systemic infusion and consequently exert a beneficial effect by various mechanisms, chiefly immunoregulation, and angiogenesis [ 45 , 46 ]. Although the related mechanism-mediated MSC immunosuppression has not been entirely clear, it appears that cellular interaction, accompanied by many factors, performs the principal function in this process. In the presence of high levels of inflammatory cytokines, e.g., TNF-α and IFN-γ, MSCs release several cytokines including TGF-β and hepatocyte growth factor (HGF) and produce soluble factors including indoleamine 2,3-dioxygenase (IDO), PGE2, and nitric oxide (NO). These mediators suppress T effector cells and enhance the expression of FOXP3, CTLA4, and GITR in regulatory T cells (Tregs) to increase their immunomodulation effects [ 47 , 48 , 49 ]. Moreover, cell-to-cell communication facilitates the stimulation of Tregs by cytokine-primed MSCs [ 50 ]. Overexpression of inducible co-stimulator ligands (ICOSL) induces the stimulation of efficient Tregs [ 51 ].

In addition, MSCs can enhance the generation of Treg cells indirectly. According to the literature, MSCs stimulate M2 macrophage and alter the phenotype through secretion of extracellular vesicles in an in vitro study [ 52 ]. Also, M2 cells that are activated by MSCs express CCL-18 and induce Treg cells [ 53 ]. Moreover, MSCs increase the expression of cyclooxygenase 2 (COX2) and IDO, resulting in expression of CD206 and CD163 in M2 cells, as well as enhance the expression of IL-6 and IL-10 in the microenvironment [ 54 ]. The overexpression of IL-10 that is produced by dendritic cells (DCs) and M2 cells upon MSCs co-culture leads to further immunomodulation via inhibition of effector T cells [ 55 , 56 ]. Furthermore, the secretion of IDO from MSCs can induce the proliferation, activation, and IgG releasing of B cells, thereby suppressing T effector cells [ 57 , 58 ].

One of the typical properties of MSCs is their multipotency capacity in which these stem cells are able to differentiate into a number of tissues in vitro [ 59 ]. Chondrogenic differentiation of MSCs in vitro occurs commonly via culturing them in the existence of TGF-β1 or TGF-β3, IGF-1, FGF-2, or BMP-2 [ 60 , 61 , 62 , 63 ]. MSC differentiation into chondroblasts is characterized by the increasing of various genes such as collagen type II, IX, aggrecan, and proliferation of chondroblast cell morphology. During the process of chondrogenesis, FGF-2 promotes the MSCs induced with TGF-β1 or TGF-β3 and/ or IGF-1 [ 64 ]. According to the literature works, several molecular pathways such as hedgehog, Wnt/β-catenin, TGF-βs, BMPs, and FGFs can regulate chondrogenesis [ 65 ]. In addition, MSCs can exert the osteogenesis function by inducing MSCs with ascorbic acid, β-glycerophosphate, vitamin D3, and/or BMP-2, BMP-4, BMP-6, and BMP-7 [ 66 ].

One of the major abilities of MSCs is anti-fibrotic activity. These cells can differentiate into various cell lineages such as hepatocytes, both in vivo and in vitro [ 67 ]. MSCs contain multiple trophic factors which induce cells and matrix remodeling to stimulate progenitor cells and the recovery of damaged cells. MSCs can decrease myofibroblasts and reverse the fibrotic activity of injured tissues [ 68 ]. Furthermore, these cells release pro-angiogenic factors including VEGF, IGF-1, and anti-inflammatory factors that participate in the recovery of tissue function. For instance, MSCs can increase neovascularization of ischemic myocardium through VEGF in a mice model of heart disease [ 69 ]; also, IGF-1 exerts an advantageous effect on the survival and proliferation of cardiomyocytes [ 70 ].

Bone marrow mesenchymal stem cell-based regenerative medicine

So far, increasing data have lately studied the effects of MSCs in the treatment or regeneration of various disorders (Table 1 ). In this section, we reviewed the latest clinical studies that investigate the potential contribution of MSCs in the regenerative medicine, as shown in Fig.  1 .

Effect of bone marrow mesenchymal stem cell-based regenerative medicine

Neural regeneration

The application of BMSCs has demonstrated promising therapeutic results in the treatment of neurological diseases. Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a neurodegenerative disorder that leads to degeneration of the motor neurons that causes paralysis and muscle weakness [ 138 , 139 ]. Syková et al. [ 71 ] carried out a study that intrathecally injected 15 ± 4.5 × 10 6 autologous BMSCs into 26 patients with ALS. After mesenchymal stem cells transplantation (MSCT), ALS functional rating scale (ALSFRS) significantly reduced, forced vital capacity (FVC) remained stable or above 70%, and weakness scales (WSs) were stable in 75% of patients. They have shown that the intrathecal BMSCs intervention in ALS patients is a safe method and it can slow down the development of the disease. There were no significant adverse events related to the trial during and after transplantation of BMSCs. Barczewska and colleagues indicated that three intrathecal injections of 30 × 10 6 Wharton’s jelly-MSCs (WJ-MSCs) improved ALSFRS [ 77 ]. They showed that WJ-MSCs are safe and effective in individuals that suffer from ALS. However, one other group found that intrathecal injection of autologous adipose MSCs does not improve clinical symptoms of ALS patients [ 76 ]. Their results indicated that the levels of CSF protein and nucleated cells were increased and ALSFRS-R showed development of disease in all treated patients. In the trial by OH et al., autologous BMSCs were injected to treat seven participants that suffer from ALS [ 75 ]. The participants were injected twice with autologous BMSCs (one million cells per kg) and followed up for 12 months. No serious adverse events were reported during the follow-up period. Furthermore, during the 12-month follow-up, there was no acceleration in the decrease in the ALSFRS-Revised (ALSFRS-R) score, Appel ALS score, and FVC. Moreover, CSF analysis showed that the levels of TGF-β and IL-10 were evaluated, while MCP-1, which is chemokine-related and exacerbates the motor neuron damage in ALS, was decreased. Their results exhibited that two repeated MSC infusions have safety and feasibility for at least 1 year in seven individuals; nevertheless, the study has some limitations such as low number of participants and short-time follow-up. In another study [ 73 ], 15 ALS patients were transplanted with autologous BMSCs. These 15 patients were divided into two groups (group 1: patients who had ALS with an inherently slow course, group 2: individuals who had ALS with an inherently rapid course) and received three intrathecal infusions of MSCs. There were no significant adverse events in the course of multiple intrathecal injections of MSCs. In group 1, there were no major changes in the rate of disease development and in group 2 ameliorating of the disease was indicated following MSCs therapy. According to their observation, the response of patients with ALS to treatment with MSCs was variable. Also, the authors indicated that due to the small number of patients, less subgroups were available for statistical analysis, limiting their ability to draw conclusions from the data.

Spinal cord injury (SCI) is usually related to devastating results. The damage to the spinal cord leads to injury to the motor, sensory, and autonomic roles of the spinal cord that affects patients’ well-being such as their physical and psychological state [ 140 , 141 ]. In a phase I, nonrandomized, uncontrolled study by Mendonça et al. [ 84 ], 15 SCI patients were administered 1 × 10 7 cells/ml MSCs. The results of the investigation revealed that SCI symptoms were meaningfully decreased by MSCT, all participants showed variable improvements in tactile sensitivity, and eight participants improved lower limb motor functional gains, chiefly in the hip flexors. Seven patients revealed sacral sparing and developed American Spinal Injury Association impairment scale (AIS) grades B or C – partial damage. Nine participants had developments in urologic function and one patient showed alterations in somatosensory evoked potentials (SSEP) 3 and 6 months after MSCT. These results stated that treatment with MSCs ameliorated the organ malfunction in people with SCI and has clinical safety, because no serious adverse effects were reported. The authors indicated that their results should be confirmed in larger and controlled clinical trials. Albu and colleagues have been demonstrated that intrathecal administration of WJ-MSCs considerably improved the pinprick sensation in the dermatomes below the level of damage [ 88 ]. Further results showed that bladder maximum capacity was elevated and bladder neurogenic hyperactivity and external sphincter dyssynergy were reduced. In another study [ 85 ], ten SCI subjects received four subarachnoid injections of 30 × 10 6 autologous BMSCs, maintained in autologous plasma, at weeks 1, 16, 28, and 40 of the trial and followed up for 12 months. There were no adverse events and all participants tolerated the therapy. Vaquero et al. [ 86 ] demonstrated that MSCT is safe and improves sensitivity, motor power, spasms, spasticity, neuropathic pain, sexual function, or sphincter dysfunction in the SCI patients. The results of their study have shown that 55.5% of patients improved in SSEP and 44.4% of patients ameliorated in voluntary muscle contraction together with intralesional active muscle reinnervation. Hur et al. carried out a study in which 14 patients with SCI were administered intrathecally 9 × 10 7 adipose MSCs [ 87 ]. Their observations showed mild progresses in neurological function. No serious adverse events were observed. In a phase 2 study, 13 patients with SCI were intravenously administered a single dose of autologous MSCs cultured in auto-serum [ 82 ]. The results of this trial revealed that SCI symptoms were considerably declined by MSC therapy, ASI, International Standards for Neurological and Functional Classification of Spinal Cord (ISCSCI-92), and Spinal Cord Independence Measure (SCIM-III) demonstrated functional improvements after MSC injection. No severe adverse effects were related to MSC administration.

Parkinson’s disease (PD) is a neurological disorder principally characterized by the deterioration of motor activities due to the impairment of the dopaminergic nigrostriatal system [ 142 , 143 ]. It has been indicated that MSCs improved the symptoms of PD. In a phase I controlled, randomized clinical study, patients that suffer from progressive supranuclear palsy were administered autologous BMSCs via intra-arterial injection [ 78 ]. The results of the study exhibited that autologous BMSCs are safe and reduce disease progression. Canesi et al. [ 79 ] have demonstrated that injection of MSCs into cerebral arteries of PD patients led to positive results in 17 PD participants: all treated participants were alive and motor function rating scales remained stable for at least 6 months during the 12-month follow-up period. One patient died 9 months after the injection for reasons not associated with cell infusion or to disease development.

In a study conducted by Jaillard and colleagues in 2019 [ 89 ], 31 individuals with subacute stroke were administered the intravenous injections of autologous BMSCs. The results of the trial exhibited significant improvements in motor-National Institute of the Health Stroke Scale (NIHSS) score, motor-Fugl-Meyer scores, and task-related functional MRI activity in motor cortex-4a. However, there was no remarkable progress in Barthel Index, NIHSS, and modified Rankin scores. In general, their results suggested that BMSCs improved motor recovery via sensorimotor neuroplasticity. In another study, 17 patients with subacute middle cerebral artery infarct received two million cells/kg autologous BMSCs [ 92 ]. During the follow-up process, NIHSS score, modified Rankin Scale or Barthel Index did not improve after the transplantation. Nonetheless, there was a significant improvement in absolute change in median infarct volume, but no treatment-related adverse effects were observed.

In sum, these outcomes suppose that BMSCs can safely and efficiently treat neural diseases, inhibit disease development, and considerably ameliorate the quality of life and clinical manifestations of patients. Consequently, BMSCs can become a new option for the clinical treatment of neural diseases.

Liver regeneration

The potential of BMSCs to differentiate into the endodermal lineage, such as hepatocyte‐like cells, makes them an attractive alternative for the treatment of liver diseases [ 144 ]. Some clinical studies have demonstrated the efficacy and feasibility of BMSC therapy in patients with liver diseases. The effect of BMSCs has been studied in individuals suffering from liver cirrhosis by Suk et al. [ 98 ]. Seventy-two patients were enrolled in this trial and randomly classified into three groups: one control group and two autologous BMSC groups that received one-time or two-time hepatic arterial administrations of fifty million autologous BMSCs 30 days after BM aspiration. Fibrosis quantification exhibited that in one-time and two-time BMSC groups there are a reduction of 25% and 37% in the proportion of collagen, respectively. In addition, the Child–Pugh (CP) scores of both test groups were meaningfully improved following BMSC administration in comparison with the control group. No serious adverse events were associated with MSC injection during the 12-month follow-up. Wang and coworkers have found that intravenous injection of UC-MSCs (0.5 × 10 6 cells/kg) is feasible and well tolerated in patients with primary biliary cirrhosis (PBC) [ 93 ]. They exhibited that MSCs significantly decreased the level of ALP and GGT; however, there were no considerable changes in serum AST, ALT, total bilirubin, albumin, prothrombin time activity, or immunoglobulin M levels. Similarly, Zhang et al. [ 94 ] have demonstrated that intravenous administration of 1.0 × 10 6 cells/kg UC-MSCs is safe and efficient for patients with ischemic-type biliary lesions after liver transplantation. According to their results, MSCs therapy reduced the serum ALP, GGT, and total bilirubin. In a randomized placebo-controlled phase I–II single-center study, nine patients that suffer from acute-on-chronic liver failure (ACLF) grades 2 and 3 were enrolled [ 95 ]. The experiment group (n = 4) received standard medical therapy along with five injections of 1 × 10 6 cells/kg of BMSC for 3 weeks. There were no transplant-related adverse events; however, one patient in the experiment group showed hypernatremia and a gastric ulcer, after the third and fifth administrations, respectively. Furthermore, MSCT revealed a considerable improvement in CP, model for end-stage liver disease (MELD), and ACLF (grade 3 to 0). Thus, MSCT is safe and viable in individuals with ACLF. In an open-label non-blinded randomized controlled study conducted by Lin et al. [ 96 ], 110 patients with hepatitis B virus (HBV)-related ACLF were enrolled in this trial. These patients were divided into two groups: control group (N = 54) was treated with standard medical therapy only and the intervention group (N = 56) was injected four times with 1.0–10 × 10 5 cells/kg allogeneic BMSCs, and then followed up for 6 months. There were no serious adverse events associated with transplantation. The results of that study demonstrated that MSCT significantly improved clinical laboratory measurements, such as serum total bilirubin, and MELD scores in comparison with control group. In addition, mortality from multiple organ failure and prevalence rate of serious infection in the intervention group was lower than that in the control group. Their results clearly established the safety and feasibility of the clinical use of peripheral administration of allogeneic BMSCs for subjects with HBV-associated ACLF, and markedly enhanced the survival rate through enhancing liver function and reducing the prevalence of severe infections.

In summary, MSCT can meaningfully ameliorate the clinical manifestations of these patients, reduce the liver fibrosis, and inhibit the development of disease.

Kidney regeneration

Hurt to renal cells can occur because of a wide range of ischemic and toxic insults and results in inflammation and cell death, which can lead to kidney damage. Inflammation has a significant role in the damage of renal cells, as well as following cellular regeneration processes [ 3 , 145 ]. Various investigations have consistently demonstrated a supportive effect of MSC on acute and chronic renal injury [ 146 ]. Makhlough et al. declared that intravenous administration of 1–2 × 10 6 cells/kg into seven patients with chronic kidney disease failed to induce remission [ 101 ]. They indicated that variations in estimated glomerular filtration rate (eGFR) and serum creatinine during the 18-month follow-up were not statistically significant. Nonetheless, no severe adverse events were reported, and they could not assess the efficacy because of their study design. Authors postulated that limited sample size and lack of a control group led to the lack of success. A study conducted by Swaminathan et al. in 2021, has displayed the effect of allogeneic BMSCs in acute kidney injury patients. They have shown that treatment of MSCs with SBI-101 stimulated an immunotherapeutic response that initiated an enhanced phenotypic alteration from tissue injury to tissue repair [ 102 ]. In a single-arm phase I clinical trial carried out by Makhlough et al. [ 100 ], six patients with autosomal dominant polycystic kidney disease (ADPKD) were intravenously injected 2 × 10 6 cells/kg autologous BMSCs. The results of the study showed that the mean eGFR value declined and the level of serum creatinine enhanced during the 1-year follow-up. Moreover, no remarkable modifications in renal function parameters and blood pressure were observed during the year after intervention. However, there were no severe adverse events after 1-year follow-up. In addition, the authors indicated that there are some reasons for the lack of success, including small number of patients, absence of a comparison group, limited follow-up period, single dose administration, and they did not utilize htTKV as a surrogate endpoint. Abumoawad and colleagues have established that adipose MSCs enhanced blood flow, GFR and reduced inflammatory injury in poststenotic kidneys of individuals that suffer from atherosclerotic renovascular disease (ARVD) [ 99 ]. Their results illustrated that mean renal blood flow was considerably enhanced, and hypoxia, renal vein inflammatory cytokines, and angiogenic factors were considerably attenuated.

Heart regeneration

Heart disease is the first and most frequently diagnosed disease and the leading cause of disease death [ 147 ]. When cardiomyocytes are damaged via ischemic and other factors, the remaining viable cardiomyocytes have a restricted ability to proliferate and dead cardiomyocytes are changed by non-contractile fibrous tissue, leading to functional impairment that elicits the progression of heart failure. According to the developing number of patients with heart disease, there is a vital need to expand an innovative remedy to rescue deteriorating hearts. Regenerative medicine and cell therapy are the upcoming therapeutic opportunities for heart diseases. According to the literature, the transplantation of BM-derived cells and cardiac stem cells into deteriorating hearts appeared to provide functional benefits [ 148 , 149 ].

In a study by Yagyu et al. [ 110 ], 8 individuals with symptomatic heart failure were infused with BMSCs. During the follow-up period, no serious adverse events were observed. There were no major differences in B-type natriuretic peptide, left ventricular ejection fraction (LVEF), and peak oxygen uptake at 2 months. The results of this study recommend further research regarding the feasibility and efficacy of MSCs. In a study by Gao et al. [ 107 ], 116 patients with acute myocardial infarction randomly received an intracoronary injection of WJ-MSCs. They indicated that MSCs therapy elevated the myocardial viability and perfusion within the infarcted territory. In addition, the LVEF was elevated and LV end-systolic volumes and end-diastolic volumes were decreased in the WJ-MSCs group.

Chan et al. demonstrated that intramyocardial infusion of autologous BMSCs in conjunction with transmyocardial revascularization or coronary artery bypass graft surgery was technically feasible and could be performed safely. The results showed that regional contractility in the cell-treated regions improved during the 1-year follow-up; also, the quality of life was improved along with a substantial decrease in angina scores at 12 month post-treatment [ 104 ]. In a study by Kaushal et al. [ 113 ], 12 participants with hypoplastic left heart syndrome were transplanted with allogeneic human MSCs (2.5 × 10 5 cells/kg). This study determined the safety, feasibility, and usefulness of MSC administration into the left ventricular myocardium. No serious adverse effects were reported during the trial. Mathiasen et al. observed that after BM-MSCT, left ventricular end-systolic volume was significantly reduced, also LVEF, stroke volume, and myocardial mass remarkably improved [ 103 ]. In addition, a major decrease in the amount of scar tissue and quality of life score was observed. No side effects were identified. In a randomized, double-blind, placebo-controlled, multicenter, phase II study, 100 patients with anterior ST elevation myocardial infarction received autologous BMSCs and atorvastatin (ATV) treatment. The results of that study represented the absolute change of LEVF within 12 months, improvement in cardiac function, induction of remodeling and regeneration, and improvement in quality of life [ 108 ]. Recently, Celis-Ruiz and coworkers conducted a study in which intravenous administration of adipose MSCs within the first 2 weeks of ischemic stroke onset is safe at 24 months of follow-up [ 106 ]. In a study conducted by Hare et al. [ 112 ], 37 non-ischemic dilated cardiomyopathy patients were divided into two groups and received 10 × 10 7 allogeneic and autologous BMSCs. Minnesota Living with Heart Failure Questionnaire score decreased in both groups. The major adverse cardiac event rate was lower in allo vs. auto. Also, TNF-α decreased, to a greater extent in allo vs. auto at 6 months. These results suggested the clinically meaningful efficacy of allogeneic vs. autologous BMSCs in non-ischemic dilated cardiomyopathy patients. Qayyum et al. have found that intra‑myocardial injections of autologous adipose MSCs ameliorated cardiac functions and unchanged exercise capacity, in contrast to deterioration in the placebo group [ 115 ].

Levy et al. indicated that after allogeneic BMSCs in patients with chronic stroke, Barthel Index scores increased. Moreover, electrocardiograms, laboratory tests, and computed tomography scans of chest/abdomen/pelvis suggest that BMSCs could alleviate the clinical symptoms in patients with stroke [ 90 ].

In sum, BMSC therapy can be an effective, achievable, and safe process that remarkably improves cardiac function and promotes patients’ quality of life.

Bone regeneration

Bone regeneration is a hot topic of research in clinical studies. Bone regeneration is a crucial problem in numerous cases, including bone fracture, defect, osteoarthritis, and osteoporosis, which should be resolved [ 150 , 151 , 152 ]. Autogenous bone grafts are considered the standard approach for bone formation by means of the participants’ own cells that stimulate osteoinductive, bone conductivity, and histocompatibility in bone diseases [ 153 ]. Nevertheless, there are some shortcomings of this procedure such as unpredictable absorption, extended recovery time, and patients commonly experience pain and nerve injury at the harvest area [ 154 , 155 , 156 ]. With the development of understanding bone tissue biology as well as recent approaches in the improvement in tissue regeneration, the application of MSC has become an attractive subject in augmenting bone tissue forming [ 157 , 158 ].

In a pilot study by Jayankura and coworkers, allogeneic BMSCs were applied to treat 22 participants with bone fractures [ 128 ]. All participants received percutaneous implantation of autologous BMSCs (5 to 10 × 10 7 cells) into the fracture area. After intervention, Tomographic Union Score (TUS) and Global Disease Evaluation (GDE) score were improved, and pain at palpation at the fracture site was reduced. In addition, the ratio of blood samples comprising donor-specific anti-HLA antibodies enhanced at 6 months post-intervention. Three serious cell-related adverse events were reported. In another study by Shim and coworkers [ 129 ], intramedullary (4 × 10 7 cells) and intravenous (2 × 10 8 cells) infusion of WJ-MSCs in combination with teriparatide showed beneficial results in individuals with osteoporotic vertebral compression fractures. Their observation displayed that the mean visual analog scale, Oswestry Disability Index, and Short Form-36 scores meaningfully improved. They stated that WJ-MSCs in combination with teriparatide are viable and have a clinical profit for fracture healing by stimulating bone architecture.

Several studies investigated the effect of BMSCs in osteoarthritis (OA) patients. Chahal et al. carried out a clinical phase I/IIa trial that involved 12 individuals with late-stage Kellgren–Lawrence knee OA. These 12 patients were injected with a single intra-articular of 1 × 10 6 , 10 × 10 6 , and 50 × 10 6 BMSCs. The results showed that patients had improved Knee Injury and Osteoarthritis Outcome Score (KOOS) pain, symptoms, quality of life, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness relative to baseline. Moreover, cartilage catabolic biomarkers and MRI synovitis were meaningfully lower at higher doses and the levels of pro-inflammatory monocytes/macrophages and IL-2 reduced in the synovial fluid after intervention. No serious events had occurred [ 116 ]. Dilogo et al. have reported that UC-MSCs (10 × 10 6 cells) significantly decreased the WOMAC and could be a potentially new regenerative treatment for patients with knee OA [ 127 ]. In a study conducted by Hernigou et al. [ 117 ], 140 patients with OA received a subchondral infusion of BMSCs on one side and received total knee arthroplasty (TKA) on the contralateral knee. They demonstrated that subchondral MSCs had a significant effect on pain to postpone or avoid the TKA in the contralateral joint of patients with OA. In a phase II multicenter randomized controlled clinical trial, 60 OA patients received 10 × 10 7 cells of autologous BMSCs along with platelet-rich plasma and followed up for 12 months [ 119 ]. No serious adverse effects were observed after MSCs injection or during follow‑up. According to the observations, treatment with BMSC related to platelet-rich plasma was demonstrated to be a feasible alternative treatment for individuals with OA, along with clinical development at the end of follow-up. Similarly, Bastos et al. have reported that MSCs alone or in combination with platelet-rich plasma are safe and have an advantageous effect on symptoms in OA individuals [ 121 ]. They found that MSCs group and MSCs + platelet-rich plasma group can improve the pain, function and daily living activities, and quality of life subscales. Ten adverse events were reported in three participants in the MSCs group and in two of the MSCs + platelet-rich plasma group. PERS and colleagues reported another clinical phase Ia study that involved 19 individuals suffering from knee OA [ 123 ]. These 18 individuals were classified into three groups and received a single intra-articular administration of 2 × 10 6 , 10 × 10 6 , and 50 × 10 6 adipose MSCs. According to their results, individuals had experienced significant improvement in pain levels and function. There were no severe adverse events; however, 4 individuals experienced transient knee joint pain and swelling after local administration. In a long-term follow-up of a multicenter randomized controlled clinical trial by Espinosa et al. [ 120 ], 30 OA patients were administered the intra-articular infusion of two diverse doses of autologous BMSCs cells (10 × 10 6 or 10 × 10 7 ) versus hyaluronic acid in the treatment of OA. No adverse effects occurred after MSCT or during the 4-year follow‑up. Their results showed that intra-articular infusion of BMSCs together with hyaluronic acid is a safe and viable process that leads to a clinical and functional improvement in knee OA.

Overall, these data display that BMSCs can be a promising, safe and effective alternative for bone regeneration, significantly improve the clinical manifestation of patients, and inhibit development of diseases.

Wound regeneration

The skin has several layers along with different compounds and roles that work together to support internal organs and serve various biological roles. It has three main layers, the epidermis, the dermis, and the subcutaneous layer [ 159 ]. Generally, skin wound healing, triggered by tissue injury, includes four stages: hemostasis, inflammation, proliferation, and maturation. MSCs can assist in all stages of the wound healing process. The use of MSCs for the treatment of skin can improve the regeneration of skin and reduce scarring. MSCs exert their functions through migration into the skin damage site, suppressing inflammation, and increasing the growth and differentiation ability of fibroblasts, epidermal cells, and endothelial cells [ 160 , 161 ]. As MSCs have exhibited wound healing in many preclinical studies, the application of MSCs for chronic wounds contributes to progress toward clinical trials. Falanga et al. have demonstrated that autologous BMSCs are an impressive and safe treatment method for wound healing [ 131 ]. The results of the study indicated a trend toward a reduction in ulcer size or complete wound closure by 4–5 months. No adverse events were noted. In a study by Zhou et al., 346 patients with skin wounds were administered adipose MSCs [ 132 ]. There were no adverse events during the trial. They reported that the granulation tissue coverage rate and thickness of granulation tissue were considerably ameliorated. In an open-label phase I/II study, sixteen participants with vocal fold scarring were administered a single dose of 0.5–2 × 10 6 cells autologous MSCs [ 137 ]. Video ratings of vocal fold vibrations and digitized analysis of high-speed laryngoscopy and phonation pressure threshold were considerably enhanced for 62–75% of the participants. Voice Handicap Index was meaningfully enhanced in eight participants, with the remaining experiencing no remarkable alteration. No serious adverse events or minor side effects were reported. Lonardi et al. observed that micro-fragmented adipose tissue improved skin tropism in patients with diabetic foot ulcer [ 135 ]. Furthermore, the results of studies have shown that adipose-derived stem cells had a beneficial effect on the full-thickness foot dorsal skin wound in diabetic mice with a considerably decreased ulcer area [ 162 ]. Recently, Huang et al. carried out a clinical study in which six subjects with intrauterine adhesion and four with cesarean scar diverticulum enrolled in this trial [ 136 ]. They found that intrauterine injection of UC-MSCs improved the endometrial thickness, cesarean scar diverticulum, and the volume of the uterus.

In the last decades, optimizations of isolation, culture, and differentiation procedures have permitted MSCs to improve closer to clinical uses for improving disorders and various tissue regeneration. MSCs have some important characteristics that make them preferred candidates to use for regenerative medicine: immunomodulatory capability valuable to improve immune system abnormalities, paracrine or autocrine roles that produce growth factors, and the vital potential to differentiate into various cells. Several clinical trials have reported that both autologous and allogeneic MSCs are valuable sources for tissue forming. Particularly, autologous MSCs signify the chief sources examined safe for administration and minimization of immunological threat, regardless of the lack of reported grievances concerning allogeneic MSC-based therapy. According to the studies described in this literature, administration of MSCs appear to be more effective and the usefulness of MSC therapy in bone and heart disorders has been broadly established. In terms of safety, no significant relationship was found between the MSC therapy and incidence of cancer and infection. Intravenous injection of MSCs is the most widely used form of administration and the dosage commonly fluctuates between 1 × 10 6 cells/kg and 2 × 10 8 cells/kg. According to the literature works mentioned in this review, the repeated administration of MSCs suggests being more beneficial than a single injection. In addition, the effectiveness of MSCs therapy in osteoarthritis disorder has been widely established. Long-term follow-up studies exhibited that serum tumor markers did not enhance before and 3 years after MSCs therapy. Nevertheless, there is still a lack of reliable scientific data on the mechanisms whereby the MSC therapy improves the numerous disorders that can develop the MSC modification and increase their prospective clinical application.

Availability of data and materials

Not applicable.

Abbreviations

Amyotrophic lateral sclerosis

Association impairment scale

ALS functional rating scale

ALSFRS-revised

Acute-on-chronic liver failure

Autosomal dominant polycystic kidney disease

Atorvastatin

Bone marrow

Bone marrow mesenchymal stem cells

Cyclooxygenase 2

Dendritic cells

Embryonic stem cells

Estimated glomerular filtration rate

Forced vital capacity

Global Disease Evaluation

Hematopoietic stem cells

Hepatitis B virus

Hepatocyte growth factor

Induced pluripotent stem cells

Indoleamine 2,3-dioxygenase

Inducible co-stimulator ligands

International Standards for Neurological and Functional Classification of Spinal Cord

Knee injury and osteoarthritis outcome score

Left ventricular ejection fraction

Mesenchymal stem cells

Mesenchymal stem cells transplantation

Model for end-stage liver disease

Nitric oxide

Osteoarthritis

Pluripotent stem cells

Prostaglandin E2

Spinal cord injury

Somatosensory evoked potentials

Spinal cord independence measure

Regulatory T cells

Tomographic Union Score

Total knee arthroplasty

Weakness scales

Western Ontario and McMaster Universities Osteoarthritis Index

Fugger L, Jensen LT, Rossjohn J. Challenges, progress, and prospects of developing therapies to treat autoimmune diseases. Cell. 2020;181(1):63–80.

Article   CAS   PubMed   Google Scholar  

Swart JF, et al. Haematopoietic stem cell transplantation for autoimmune diseases. Nat Rev Rheumatol. 2017;13(4):244–56.

Abbaszadeh H, et al. Regenerative potential of Wharton’s jelly-derived mesenchymal stem cells: a new horizon of stem cell therapy. J Cell Physiol. 2020;235(12):9230–40.

Saeedi P, Halabian R, Imani Fooladi AA. A revealing review of mesenchymal stem cells therapy, clinical perspectives and Modification strategies. Stem Cell Investig. 2019;6:34.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Patel DM, Shah J, Srivastava AS. Therapeutic potential of mesenchymal stem cells in regenerative medicine. Stem Cells Int. 2013;2013: 496218.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Rao M. Stem cells and regenerative medicine. Stem Cell Res Ther. 2012;3(4):27.

Article   PubMed   PubMed Central   Google Scholar  

Ilic D, Ogilvie C. Concise Review: Human Embryonic Stem Cells-What Have We Done? What Are We Doing? Where Are We Going? Stem Cells. 2017;35(1):17–25.

Zakrzewski W, et al. Stem cells: past, present, and future. Stem Cell Res Ther. 2019;10(1):68.

Chen Y, et al. Dental-derived mesenchymal stem cell sheets: a prospective tissue engineering for regenerative medicine. Stem Cell Res Ther. 2022;13(1):38.

Kanemura H, et al. Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. PLoS ONE. 2014;9(1):e85336–e85336.

Souied E, Pulido J, Staurenghi G. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med. 2017;377(8):792–3.

Article   PubMed   Google Scholar  

Rong X, et al. Antler stem cell-conditioned medium stimulates regenerative wound healing in rats. Stem Cell Res Ther. 2019;10(1):326.

Hong H, et al. Dental follicle stem cells rescue the regenerative capacity of inflamed rat dental pulp through a paracrine pathway. Stem Cell Res Ther. 2020;11(1):333.

Chimutengwende-Gordon M, Khan WS. Advances in the use of stem cells and tissue engineering applications in bone repair. Curr Stem Cell Res Ther. 2012;7(2):122–6.

Yu Y, et al. Human embryonic stem cell-derived cardiomyocyte therapy in mouse permanent ischemia and ischemia-reperfusion models. Stem Cell Res Ther. 2019;10(1):167.

Jin L, et al. Mesenchymal stem cells ameliorate myocardial fibrosis in diabetic cardiomyopathy via the secretion of prostaglandin E2. Stem Cell Res Ther. 2020;11(1):122.

Chugh RM, et al. Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10. Stem Cell Res Ther. 2021;12(1):388.

Saldaña L, et al. Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors. Stem Cell Res Ther. 2019;10(1):58.

Friedenstein AJ, Piatetzky S II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16(3):381–90.

CAS   PubMed   Google Scholar  

Abbaszadeh H, et al. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles: a novel therapeutic paradigm. J Cell Physiol. 2020;235(2):706–17.

Chang D, et al. Application of mesenchymal stem cell sheet to treatment of ischemic heart disease. Stem Cell Res Ther. 2021;12(1):384.

Horwitz EM, et al. Clarification of the nomenclature for MSC: the international society for cellular therapy position statement. Cytotherapy. 2005;7(5):393–5.

Caplan AI. What’s in a name? Tissue Eng Part A. 2010;16(8):2415–7.

Caplan AI. Mesenchymal stem cells: time to change the name! Stem Cells Transl Med. 2017;6(6):1445–51.

Lee BC, et al. PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact. Sci Rep. 2016;6:26298.

Jiang Y, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418(6893):41–9.

Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant. 2011;20(1):5–14.

Meirelles LDS, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119(11):2204–13.

Article   CAS   Google Scholar  

Ghorbani F, et al. Renoprotective effects of extracellular vesicles: a systematic review. Gene Reports. 2022;26: 101491.

Article   Google Scholar  

Tang Y, Zhou Y, Li H-J. Advances in mesenchymal stem cell exosomes: a review. Stem Cell Res Ther. 2021;12(1):71.

Wu Y, et al. Adipose tissue-derived mesenchymal stem cells have a heterogenic cytokine secretion profile. Stem Cells Int. 2017;2017:4960831.

Mushahary D, et al. Isolation, cultivation, and characterization of human mesenchymal stem cells. Cytometry A. 2018;93(1):19–31.

Barberini DJ, et al. Equine mesenchymal stem cells from bone marrow, adipose tissue and umbilical cord: immunophenotypic characterization and differentiation potential. Stem Cell Res Ther. 2014;5(1):25.

Abbaszadeh H, et al. Chronic obstructive pulmonary disease and asthma: mesenchymal stem cells and their extracellular vesicles as potential therapeutic tools. Stem Cell Res Ther. 2022;13(1):262.

Jiang XX, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005;105(10):4120–6.

Marinescu C-I, Preda MB, Burlacu A. A procedure for in vitro evaluation of the immunosuppressive effect of mouse mesenchymal stem cells on activated T cell proliferation. Stem Cell Res Ther. 2021;12(1):319.

Malekpour K, et al. The potential use of mesenchymal stem cells and their derived exosomes for orthopedic diseases treatment. Stem Cell Rev Reports. 2022;18(3):933–51.

Steens J, Klein D. Current strategies to generate human mesenchymal stem cells in vitro. Stem Cells Int. 2018;2018:6726185.

Beeravolu N, et al. Isolation and characterization of mesenchymal stromal cells from human umbilical cord and fetal placenta. J Vis Exp. 2017;122:e55224.

Google Scholar  

Hmadcha A, et al. Therapeutic potential of mesenchymal stem cells for cancer therapy. Front Bioeng Biotechnol. 2020;8:43.

Aravindhan S, et al. Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature. Cancer Cell Int. 2021;21(1):158.

Di Nicola M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–43.

Bartholomew A, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30(1):42–8.

Djouad F, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 2003;102(10):3837–44.

Swartzlander MD, et al. Immunomodulation by mesenchymal stem cells combats the foreign body response to cell-laden synthetic hydrogels. Biomaterials. 2015;41:79–88.

Rigotti G, et al. Expanded stem cells, stromal-vascular fraction, and platelet-rich plasma enriched fat: comparing results of different facial rejuvenation approaches in a clinical trial. Aesthet Surg J. 2016;36(3):261–70.

Djouad F, et al. Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor α in collagen-induced arthritis. Arthritis Rheum. 2005;52(5):1595–603.

Ge W, et al. Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. Am J Transplant. 2009;9(8):1760–72.

Waterman RS, et al. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS ONE. 2010;5(4): e10088.

Miyagawa I, et al. Induction of regulatory T cells and its regulation with insulin-like growth factor/insulin-like growth factor binding protein-4 by human mesenchymal stem cells. J Immunol. 2017;199(5):1616–25.

Lee H-J, et al. ICOSL expression in human bone marrow-derived mesenchymal stem cells promotes induction of regulatory T cells. Sci Rep. 2017;7(1):1–15.

CAS   Google Scholar  

Heo JS, Choi Y, Kim HO. Adipose-derived mesenchymal stem cells promote M2 macrophage phenotype through exosomes. Stem Cells Int. 2019;2019:7921760.

Morrison TJ, et al. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am J Respir Crit Care Med. 2017;196(10):1275–86.

Melief SM, et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells. 2013;31(9):1980–91.

Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22.

Beyth S, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105(5):2214–9.

Corcione A, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367–72.

Glennie S, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood. 2005;105(7):2821–7.

Naji A, et al. Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci. 2019;76(17):3323–48.

Pittenger MF, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.

Pelttari K, Steck E, Richter W. The use of mesenchymal stem cells for chondrogenesis. Injury. 2008;39(Suppl 1):S58-65.

Pourakbari R, et al. Identification of genes and miRNAs associated with angiogenesis, metastasis, and apoptosis in colorectal cancer. Gene Reports. 2020;18: 100552.

Tuli R, et al. Transforming growth factor-beta-mediated chondrogenesis of human mesenchymal progenitor cells involves N-cadherin and mitogen-activated protein kinase and Wnt signaling cross-talk. J Biol Chem. 2003;278(42):41227–36.

Longobardi L, et al. Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling. J Bone Miner Res. 2006;21(4):626–36.

Chen Q, et al. Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ. 2016;23(7):1128–39.

Friedman MS, Long MW, Hankenson KD. Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein-6. J Cell Biochem. 2006;98(3):538–54.

Eom YW, Shim KY, Baik SK. Mesenchymal stem cell therapy for liver fibrosis. Korean J Intern Med. 2015;30(5):580–9.

Quintanilha LF, et al. Canine mesenchymal stem cells show antioxidant properties against thioacetamide-induced liver injury in vitro and in vivo. Hepatol Res. 2014;44(10):E206–17.

Tang JM, et al. VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovasc Res. 2011;91(3):402–11.

Troncoso R, et al. New insights into IGF-1 signaling in the heart. Trends Endocrinol Metab. 2014;25(3):128–37.

Syková E, et al. Transplantation of Mesenchymal stromal cells in patients with amyotrophic lateral sclerosis: results of phase I/IIa clinical trial. Cell Transplant. 2017;26(4):647–58.

Mazzini L, et al. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A phase I clinical trial. Exp Neurol. 2010;223(1):229–37.

Siwek T, et al. Repeat Administration of bone marrow-derived mesenchymal stem cells for treatment of amyotrophic lateral sclerosis. Med Sci Monit. 2020;26: e927484.

Petrou P, et al. Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis: results of phase 1/2 and 2a clinical trials. JAMA Neurol. 2016;73(3):337–44.

Oh KW, et al. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med. 2015;4(6):590–7.

Staff NP, et al. Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS. Neurology. 2016;87(21):2230–4.

Barczewska M, et al. Umbilical cord mesenchymal stem cells in amyotrophic lateral sclerosis: an original study. Stem Cell Rev Rep. 2020;16(5):922–32.

Giordano R, et al. Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study. J Transl Med. 2014;12:14.

Canesi M, et al. Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy. J Transl Med. 2016;14(1):127.

Venkataramana NK, et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl Res. 2010;155(2):62–70.

Zamani H, et al. Safety and feasibility of autologous olfactory ensheathing cell and bone marrow mesenchymal stem cell co-transplantation in chronic human spinal cord injury: a clinical trial. Spinal Cord. 2022;60(1):63–70.

Honmou O, et al. Intravenous infusion of auto serum-expanded autologous mesenchymal stem cells in spinal cord injury patients: 13 case series. Clin Neurol Neurosurg. 2021;203: 106565.

Satti HS, et al. Autologous mesenchymal stromal cell transplantation for spinal cord injury: a phase I pilot study. Cytotherapy. 2016;18(4):518–22.

Mendonça MV, et al. Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury. Stem Cell Res Ther. 2014;5(6):126.

Vaquero J, et al. Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury. Cytotherapy. 2017;19(3):349–59.

Vaquero J, et al. Intrathecal administration of autologous mesenchymal stromal cells for spinal cord injury: safety and efficacy of the 100/3 guideline. Cytotherapy. 2018;20(6):806–19.

Hur JW, et al. Intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury: a human trial. J Spinal Cord Med. 2016;39(6):655–64.

Albu S, et al. Clinical effects of intrathecal administration of expanded Wharton jelly mesenchymal stromal cells in patients with chronic complete spinal cord injury: a randomized controlled study. Cytotherapy. 2021;23(2):146–56.

Jaillard A, et al. Autologous mesenchymal stem cells improve motor recovery in subacute ischemic stroke: a randomized clinical trial. Transl Stroke Res. 2020;11(5):910–23.

Levy ML, et al. Phase I/II study of safety and preliminary efficacy of intravenous allogeneic mesenchymal stem cells in chronic stroke. Stroke. 2019;50(10):2835–41.

Shichinohe H, et al. Research on advanced intervention using novel bone marrOW stem cell (RAINBOW): a study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke. BMC Neurol. 2017;17(1):179.

Law ZK, et al. The effects of intravenous infusion of autologous mesenchymal stromal cells in patients with subacute middle cerebral artery infarct: a phase 2 randomized controlled trial on safety, tolerability and efficacy. Cytotherapy. 2021;23(9):833–40.

Wang L, et al. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 2013;28(Suppl 1):85–92.

Zhang YC, et al. Therapeutic potentials of umbilical cord-derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation. Cytotherapy. 2017;19(2):194–9.

Schacher FC, et al. Bone marrow mesenchymal stem cells in acute-on-chronic liver failure grades 2 and 3: a phase I-II randomized clinical trial. Can J Gastroenterol Hepatol. 2021;2021:3662776.

Lin BL, et al. Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: A randomized controlled trial. Hepatology. 2017;66(1):209–19.

Lanthier N, et al. Autologous bone marrow-derived cell transplantation in decompensated alcoholic liver disease: what is the impact on liver histology and gene expression patterns? Stem Cell Res Ther. 2017;8(1):88.

Suk KT, et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial. Hepatology. 2016;64(6):2185–97.

Abumoawad A, et al. In a Phase 1a escalating clinical trial, autologous mesenchymal stem cell infusion for renovascular disease increases blood flow and the glomerular filtration rate while reducing inflammatory biomarkers and blood pressure. Kidney Int. 2020;97(4):793–804.

Makhlough A, et al. Safety and tolerability of autologous bone marrow mesenchymal stromal cells in ADPKD patients. Stem Cell Res Ther. 2017;8(1):116.

Makhlough A, et al. Bone marrow-mesenchymal stromal cell infusion in patients with chronic kidney disease: A safety study with 18 months of follow-up. Cytotherapy. 2018;20(5):660–9.

Swaminathan M, et al. Pharmacological effects of ex vivo mesenchymal stem cell immunotherapy in patients with acute kidney injury and underlying systemic inflammation. Stem Cells Transl Med. 2021;10(12):1588–601.

Mathiasen AB, et al. Bone marrow-derived mesenchymal stromal cell treatment in patients with ischaemic heart failure: final 4-year follow-up of the MSC-HF trial. Eur J Heart Fail. 2020;22(5):884–92.

Chan JL, et al. Intramyocardial bone marrow stem cells in patients undergoing cardiac surgical revascularization. Ann Thorac Surg. 2020;109(4):1142–9.

Bolli R, et al. A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial. Eur J Heart Fail. 2021;23(4):661–74.

de Celis-Ruiz E, et al. Final results of allogeneic adipose tissue-derived mesenchymal stem cells in acute ischemic stroke (AMASCIS): a phase II, randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. Cell Transplant. 2022;31:9636897221083864.

PubMed   Google Scholar  

Gao LR, et al. Intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial. BMC Med. 2015;13:162.

Xu JY, et al. Transplantation efficacy of autologous bone marrow mesenchymal stem cells combined with atorvastatin for acute myocardial infarction (TEAM-AMI): rationale and design of a randomized, double-blind, placebo-controlled, multi-center, Phase II TEAM-AMI trial. Regen Med. 2019;14(12):1077–87.

Bartolucci J, et al. Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]). Circ Res. 2017;121(10):1192–204.

Yagyu T, et al. Long-term results of intracardiac mesenchymal stem cell transplantation in patients with cardiomyopathy. Circ J. 2019;83(7):1590–9.

Florea V, et al. The impact of patient sex on the response to intramyocardial mesenchymal stem cell administration in patients with non-ischaemic dilated cardiomyopathy. Cardiovasc Res. 2020;116(13):2131–41.

Hare JM, et al. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM trial. J Am Coll Cardiol. 2017;69(5):526–37.

Kaushal S, et al. Study design and rationale for ELPIS: A phase I/IIb randomized pilot study of allogeneic human mesenchymal stem cell injection in patients with hypoplastic left heart syndrome. Am Heart J. 2017;192:48–56.

Xiao W, et al. A randomized comparative study on the efficacy of intracoronary infusion of autologous bone marrow mononuclear cells and mesenchymal stem cells in patients with dilated cardiomyopathy. Int Heart J. 2017;58(2):238–44.

Qayyum AA, et al. Autologous adipose-derived stromal cell treatment for patients with refractory angina (MyStromalCell Trial): 3-years follow-up results. J Transl Med. 2019;17(1):360.

Chahal J, et al. Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation. Stem Cells Transl Med. 2019;8(8):746–57.

Hernigou P, et al. Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up. Int Orthop. 2021;45(2):365–73.

Hernigou P, et al. Subchondral bone or intra-articular injection of bone marrow concentrate mesenchymal stem cells in bilateral knee osteoarthritis: what better postpone knee arthroplasty at fifteen years? A randomized study. Int Orthop. 2021;45(2):391–9.

Lamo-Espinosa JM, et al. Phase II multicenter randomized controlled clinical trial on the efficacy of intra-articular injection of autologous bone marrow mesenchymal stem cells with platelet rich plasma for the treatment of knee osteoarthritis. J Transl Med. 2020;18(1):356.

Lamo-Espinosa JM, et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2018;16(1):213.

Bastos R, et al. Intra-articular injections of expanded mesenchymal stem cells with and without addition of platelet-rich plasma are safe and effective for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2018;26(11):3342–50.

Al-Najar M, et al. Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study. J Orthop Surg Res. 2017;12(1):190.

Pers YM, et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016;5(7):847–56.

Freitag J, et al. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial. Regen Med. 2019;14(3):213–30.

Lee WS, et al. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial. Stem Cells Transl Med. 2019;8(6):504–11.

Matas J, et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial. Stem Cells Transl Med. 2019;8(3):215–24.

Dilogo IH, et al. Umbilical cord-derived mesenchymal stem cells for treating osteoarthritis of the knee: a single-arm, open-label study. Eur J Orthop Surg Traumatol. 2020;30(5):799–807.

Jayankura M, et al. Percutaneous administration of allogeneic bone-forming cells for the treatment of delayed unions of fractures: a pilot study. Stem Cell Res Ther. 2021;12(1):363.

Shim J, et al. Safety and efficacy of Wharton’s jelly-derived mesenchymal stem cells with teriparatide for osteoporotic vertebral fractures: a phase I/IIa study. Stem Cells Transl Med. 2021;10(4):554–67.

Talaat WM, et al. Autologous bone marrow concentrates and concentrated growth factors accelerate bone regeneration after enucleation of mandibular pathologic lesions. J Craniofac Surg. 2018;29(4):992–7.

Falanga V, et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007;13(6):1299–312.

Zhou L, et al. Efficacy of human adipose derived mesenchymal stem cells in promoting skin wound healing. J Healthc Eng. 2022;2022:6590025.

Moon KC, et al. Potential of allogeneic adipose-derived stem cell-hydrogel complex for treating diabetic foot ulcers. Diabetes. 2019;68(4):837–46.

Qin HL, et al. Clinical evaluation of human umbilical cord mesenchymal stem cell transplantation after angioplasty for diabetic foot. Exp Clin Endocrinol Diabetes. 2016;124(8):497–503.

Lonardi R, et al. Autologous micro-fragmented adipose tissue for the treatment of diabetic foot minor amputations: a randomized controlled single-center clinical trial (MiFrAADiF). Stem Cell Res Ther. 2019;10(1):223.

Huang J, et al. Intrauterine infusion of clinically graded human umbilical cord-derived mesenchymal stem cells for the treatment of poor healing after uterine injury: a phase I clinical trial. Stem Cell Res Ther. 2022;13(1):85.

Hertegård S, et al. Treatment of vocal fold scarring with autologous bone marrow-derived human mesenchymal stromal cells-first phase I/II human clinical study. Stem Cell Res Ther. 2020;11(1):128.

Hardiman O, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071.

van Es MA, et al. Amyotrophic lateral sclerosis. Lancet. 2017;390(10107):2084–98.

Eli I, Lerner DP, Ghogawala Z. Acute traumatic spinal cord injury. Neurol Clin. 2021;39(2):471–88.

McDonald JW, Sadowsky C. Spinal-cord injury. Lancet. 2002;359(9304):417–25.

Pajares M, et al. Inflammation in Parkinson’s disease: mechanisms and therapeutic implications. Cells. 2020;9(7):1687.

Article   CAS   PubMed Central   Google Scholar  

Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896–912.

Hu C, et al. Mesenchymal stem cell-based cell-free strategies: safe and effective treatments for liver injury. Stem Cell Res Ther. 2020;11(1):377.

Baer PC, Koch B, Geiger H. Kidney Inflammation, Injury and Regeneration. Int J Mol Sci. 2020;21(3):1164.

Article   PubMed Central   Google Scholar  

Fleig SV, Humphreys BD. Rationale of mesenchymal stem cell therapy in kidney injury. Nephron Clin Pract. 2014;127(1–4):75–80.

Virani SS, et al. Heart disease and stroke statistics—2021 update. Circulation. 2021;143(8):e254–743.

Chien KR, et al. Regenerating the field of cardiovascular cell therapy. Nat Biotechnol. 2019;37(3):232–7.

Murry CE, MacLellan WR. Stem cells and the heart-the road ahead. Science. 2020;367(6480):854–5.

Oryan A, Alidadi S. Reconstruction of radial bone defect in rat by calcium silicate biomaterials. Life Sci. 2018;201:45–53.

Qaseem A, et al. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(11):818–39.

Čamernik K, et al. Comprehensive analysis of skeletal muscle- and bone-derived mesenchymal stem/stromal cells in patients with osteoarthritis and femoral neck fracture. Stem Cell Res Ther. 2020;11(1):146.

Raghoebar GM, et al. Resorbable screws for fixation of autologous bone grafts. Clin Oral Implants Res. 2006;17(3):288–93.

Felice P, et al. Inlay versus onlay iliac bone grafting in atrophic posterior mandible: a prospective controlled clinical trial for the comparison of two techniques. Clin Implant Dent Relat Res. 2009;11(Suppl 1):e69-82.

Swan MC, Goodacre TE. Morbidity at the iliac crest donor site following bone grafting of the cleft alveolus. Br J Oral Maxillofac Surg. 2006;44(2):129–33.

Amini AR, Laurencin CT, Nukavarapu SP. Bone tissue engineering: recent advances and challenges. Crit Rev Biomed Eng. 2012;40(5):363–408.

Fu J, et al. Systemic therapy of MSCs in bone regeneration: a systematic review and meta-analysis. Stem Cell Res Ther. 2021;12(1):377.

Gjerde C, et al. Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial. Stem Cell Res Ther. 2018;9(1):213.

Hsu YC, Li L, Fuchs E. Emerging interactions between skin stem cells and their niches. Nat Med. 2014;20(8):847–56.

Hu MS, et al. Mesenchymal Stromal Cells and Cutaneous Wound Healing: A Comprehensive Review of the Background, Role, and Therapeutic Potential. Stem Cells Int. 2018;2018:6901983.

Marfia G, et al. Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds. Organogenesis. 2015;11(4):183–206.

Shi R, et al. Localization of human adipose-derived stem cells and their effect in repair of diabetic foot ulcers in rats. Stem Cell Res Ther. 2016;7(1):155.

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Acknowledgements

The authors express their gratitude to the Deanship of Scientific Research at King Khalid University for funding this work through the Research Group Program under grant number RGP. 2/122/43.

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Alexander Markov

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Margiana, R., Markov, A., Zekiy, A.O. et al. Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review. Stem Cell Res Ther 13 , 366 (2022). https://doi.org/10.1186/s13287-022-03054-0

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Advancing plant biology with breakthroughs in single-cell RNA sequencing

by NanJing Agricultural University

Recent breakthroughs in single-cell RNA sequencing (scRNA), such as the recently developed "RevGel-seq" method, have revolutionized plant cell analysis. This technique, independent of special instruments, streamlines processes and resolves protoplast isolation challenges.

Now, a multinational team of researchers review this and other recent advances in plant scRNA sequencing with the intention of providing guidance for facilitating the appropriate selection of scRNA methods for different plant samples. Their review article is published in the journal BioDesign Research .

In the world of plant biology, understanding the intricacies of individual plant cells has been a complex challenge, particularly due to the unique structure of these cells encapsulated by rigid cell walls. This challenge has, in turn, hindered the isolation of intact nuclei or protoplasts, which are essential for in-depth analysis.

Now, although traditional RNA sequencing has played an instrumental role in helping researchers understand the intricacies of plant cells, the development of single-cell RNA (scRNA) sequencing has enabled groundbreaking advancements in our understanding and analysis of plant biosystems.

In addition, other technical advancements in scRNA sequencing, such as the development of protocols for cell isolation, library preparation, and sequencing technologies have furthered researchers' ability to overcome plant-specific challenges in analysis. Although past studies have reviewed the utility and practical applicability of scRNA sequencing, not many have attempted to look at the technological developments with regard to scRNA sequencing.

In the recent review article, researchers have comprehensively looked at the recent advances and paradigm shifts in plant systems biology. Plant systems, with their complex cellular architecture, demand innovative approaches to unravel the secrets hidden within plant cells. The review captures these recent developments in scRNA technology, and also discusses the challenges and future potential opportunities in this field.

The review first discusses the methods popularly used in single-cell transcriptomics, which include experimental and computational components, and also elaborates on the general workflow for scRNA sequencing. Given the challenges and limitations of protoplast preparation and nuclei isolation methods, the use of microfluidics platform offers a primary workflow for single-cell isolation, separation, and analysis.

And while the choice between the protoplast and nuclei for plant scRNA sequencing depends on the research objective, the review urges researchers to carefully consider the choice of multiple factors, such as research goal, plant species, and other trade-offs, when determining the most suitable method.

The review then touches upon the advancements in scRNA sequencing library construction and sequencing, highlighting the significant achievements, such as the Nextera XT DNA Library Preparation Kit, the BD Rhapsody system, and Illumina sequencing technologies. Next, the researchers discuss the multiple steps involved in scRNA sequencing, before moving on to discuss the recent developments in scRNA databases.

PlantscRNAdb, for instance, was developed for analyzing scRNA-seq data in plants, and contains 26,326 marker genes. Plant Cell Marker DataBase, on the other hand, contains 81,117 cell marker genes of 263 cell types in 22 tissues across six plant species.

The authors then discuss the improvements made by researchers to address the limitations with plant scRNA databases, such as "scPlantDB," a comprehensive database created by He et al., covering about 2.5 million cells across 17 plant species.

The researchers continue with a discussion of the applications of scRNA sequencing in plant systems biology and elaborate on how scRNA sequencing has been used to study plant biology at the cellular level, shedding light on molecular mechanisms of plant development, plant responses to biotic and abiotic stresses, epigenetic regulation in plants, cell fate determination and organogenesis, among others.

While discussing the challenges and potential for further development of scRNA sequencing, the researchers highlight a recent breakthrough development aimed at optimizing protoplast isolation methods and establishing standardized single-cell RNA sequencing (scRNA-seq) processes across diverse laboratories.

Employing a multifaceted approach, the development sought to combined innovative scRNA-seq technologies with traditional methods to tackle the intricate world of plant cells. Sample preparation became a meticulous process, focusing on variables like enzyme treatment duration, temperature, and osmotic potential.

Notably, the study explored novel scRNA-seq technologies, including RevGel-seq, originally developed for animal systems but now introduced to the realm of plant research.

Dr. Xiaohan Yang, the lead researcher of this review affiliated with the Oak Ridge National Laboratory, explains, "RevGel-seq, a recently developed breakthrough in scRNA-seq methods, is truly a game-changer. Unlike traditional methods that rely on specific single-cell RNA instruments during sample preparation, RevGel-seq operates on cell-barcoded bead complexes.

"This innovation sample preparation for scRNA-seq in human and mouse cell not only convenient but also highly efficient."

RevGel-seq also eliminates the need for specific instruments, providing flexibility in sample collection and processing at different times or locations. Needless to say, the results surpassed expectations, showcasing RevGel-seq's potential to reshape how single-cell RNA sequencing is conducted in plant research.

The recent advancements listed in this review have significant implications for the future of plant biology. While scRNA sequencing has indeed emerged as a groundbreaking technology in the field of plant systems biology and synthetic biology, the review sheds light on the possible path for addressing existing challenges and offers direction for future researchers.

It also highlights the need to integrate scRNA sequencing technologies with other omics technologies and with other computational tools for enhancing the understanding of complex cellular interactions in plants.

In conclusion, the review suggests a positive way forward in the field of plant biology, with single-cell RNA sequencing for plant cells shedding light on their inner workings and opening doors for deeper insights. In addition to addressing current hurdles, it can serve as a guide for researchers working toward a more sustainable future.

Provided by NanJing Agricultural University

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Editorial: Directing Stem Cell Fate Using Plant Extracts and Their Bioactive Compounds

Farhana ferdousi.

1 AIST-University of Tsukuba Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), AIST, University of Tsukuba, Tsukuba, Japan

2 Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan

Kazunori Sasaki

3 Cardiovascular Division, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

Yun-Wen Zheng

4 Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

Francis G Szele

5 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

Hiroko Isoda

6 Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan

The rapidly evolving field of stem cell therapy has great potential for treating a broad array of diseases, including currently incurable diseases. However, the use of stem cell-based products as therapeutics is often limited by high rejection rate, insufficient availability, and expensive in vitro expansion methods ( McNeish, 2004 ; Laustriat et al., 2010 ; Rubin and Haston, 2011 ). The external control of stem cells using plant-derived bioactive compounds, such as polyphenols, flavonoids, tannins, terpenoids, and fatty acids, may provide potential solutions to overcome many of these current limitations. Many naturally occurring bioactive compounds have been shown to promote stem cell proliferation and lineage-specific differentiation ( Udalamaththa et al., 2016 ). This Research Topic aimed to cover promising and novel research findings on the effects of plant extracts and their bioactive compounds on regulating cell division and differentiation of pluripotent and adult stem cells and stem cells obtained from alternative sources. This article Research Topic includes ten original research articles, one brief research report, and one review article covering the potentials of bioactive compounds for neurodegenerative, cardiovascular, metabolic, cancer, musculoskeletal, and hair loss diseases through regulating stem cell proliferation and differentiation. Below we present the focus and key findings of each article.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can be differentiated into skin cells, such as fibroblasts and keratinocytes. Apart from their differentiation capacity, MSCs exert unique paracrine actions to accelerate wound healing and maintain tissue homeostasis and, therefore, have been regarded as a potentially promising therapeutic option for tissue injury and diseases ( Guillamat-Prats, 2021 ). Plant-derived components that can promote biological events, such as migration and homing of MSCs, may offer novel therapeutic options for regenerative medicine. The review by Maeda addresses the role of plant-derived components in promoting the migration and homing of MSCs to damaged sites, where they contribute to the healing process ( Maeda ).

The following group of five original research articles was dedicated to exploring the potential of plant components on neurodegenerative and neuropsychiatric conditions through regulating neural stem cells (NSCs) proliferation and differentiation in vitro and in vivo ( Houghton et al. ; Iwata et al. ; Achour et al. ; He Y. et al. ; Sasaki et al. ).

An interesting paper by Houghton et al. reported that exposure to supraphysiological caffeine condition could significantly reduce progenitor integrity and proliferation of human hippocampal progenitor cells, HPC0A07/03, compared to control conditions. This finding indicates that regular dietary components, such as caffeine, can affect cognitive outcomes by influencing NSC integrity and proliferation and highlights the potential of leveraging dietary interventions to promote cognitive health.

Iwata et al. evaluated the benefits of sugarcane (Saccharum officinarum L.) top as a putative dietary supplement to improve aging consequences using in vitro and in vivo strategies. They showed that the ethanolic extract of sugarcane top (STEE), rich in caffeoylquinic acid derivatives, could rescue age-associated decline in spatial learning and memory, increase the number of newborn neurons in the subgranular zone of hippocampus, and restore the levels of neurotransmitters in the cerebral cortex of senescence-accelerated mouse SAMP8. They also demonstrated that STEE enhanced cellular energy metabolism through upregulation of glycolytic reaction in human neuroblastoma cells, SH-SY5Y, and positively affected proliferation, induced neuronal differentiation and astrocyte morphogenesis in human NSCs (hNSCs).

He Y. et al. analyzed the effect of Alpinia oxyphylla Miq. extract (AOM) and its bioactive compound p -coumaric acid ( p -CA) on post-stroke recovery in rats. They reported that both AOM and p -CA improved cognitive functions, reduced anxiety, and increased hippocampal neurogenesis in the post-middle cerebral artery occlusion ischemic rats in vivo through activating BDNF/TrkB/AKT signaling pathway.

The study by Sasaki et al. investigated the neurodevelopmental and neuroprotective effects of the microalgae Aurantiochytrium sp. in a number of experimental models. They reported that Aurantiochytrium inhibited amyloid-β-induced cell death and increased ATP production in SH-SY5Y human neuroblastoma cells, increased proliferation of murine neurospheres, improved spatial learning and memory in the senescence-accelerated SAMP8 mice and enhanced neurogenesis in the mice hippocampal dentate gyrus.

The final article in this Research Topic by Achour et al. reported that natural flavone luteolin inhibited notch signaling and therefore inhibited the self-renewal of hNSCs, and directed the differentiation of hNSCs towards astrocytes likely via mediating WNT-β-catenin-BMP2-STAT3 pathways. In vivo , luteolin improved neuroinflammation by decreasing proinflammatory cytokine levels in mice astrocytes and sera and increased neurotransmitter and neurotrophic factor levels in the hypothalamus in lipopolysaccharide (LPS)-induced neuroinflammatory model of depression in mice. They have also presented a comprehensive whole-genome transcriptome analysis, which provided a detailed view of the changes in biological functions in mice hippocampus and brain-derived NSCs by luteolin administration and highlighted the possible therapeutic benefits of luteolin in neuroinflammatory and neurodegenerative diseases.

All these five papers had a common parameter-neurogenesis in hippocampus. Discovering adult hippocampal neurogenesis (AHN) led to a paradigm shift in neuroscience. Adult-born hippocampal neurons are one of the key mediators of hippocampus-dependent functions, such as learning, memory encoding, mood regulation, and stress response. Recent scientific evidence suggests that impairment of AHN underlies the pathophysiology of neurodegenerative and affective disorders ( Mu and Gage, 2011 ; Baptista and Andrade, 2018 ; Toda et al., 2019 ; Gomes-Leal, 2021 ). Therefore, hippocampal neurogenesis-inspired therapies using plant-derived bioactive compounds offer a promising approach to reducing symptoms of neurodegenerative and mood disorders in humans ( Zhang et al., 2014 ; Sasikumar et al., 2022 ).

In this article Research Topic, there are two interesting studies on perinatal stem cell human amniotic epithelial cells (hAECs/hAESCs) ( Aonuma et al. ; Uchida et al. ). The hAECs are obtained from discarded term placenta and therefore are readily available. hAECs possess both ESC-like pluripotent potential and adult stem cell-like immunomodulatory properties. In recent years, stem-cell-based approaches using ESCs and iPSC have received great attention as effective drug screening tools. However, invasive extraction and expensive cell reprogramming and maintenance procedures as well as ethical constraints, limit the use of these types of stem cells for drug screening ( Chen et al., 2014 ). In this context, hAECs offer a suitable alternative to ESCs and iPSCs ( Miki et al., 2005 ; Murphy et al., 2010 ; Miki, 2018 ). In their study, Aonuma et al. considered hAECs as a drug screening tool and investigated the cardiac antifibrotic potential of a plant flavonol isorhamnetin in hAECs through whole-genome transcriptome analysis and then validated the findings in angiotensin II (AgII)-induced mice model of cardiac fibrosis and hypertrophy. On the other hand, Uchida et al. reported that isorhamnetin regulated early biological events to induce hepatic-lineage-specific differentiation in hAECs in the absence of any growth factor or cytokine. The differentiated hAECs expressed a subset of hepatic differentiation-related genes, induced cytochromes P450 (CYPs) mRNA levels, and showed some key functional properties of hepatic cells, including indocyanine green (ICG) uptake and release, glycogen storage, and urea secretion. There are few other studies that explored directed differentiation potential of different natural bioactive compounds in hAECs ( Ferdousi et al., 2019 ; Bejaoui et al., 2021 ), while other studies explored improved therapeutic potential of hAECs in combinations with natural compounds ( Ferdousi et al., 2020 ; Xu et al., 2021 ). These study findings would encourage multidirectional research approaches through integrating natural bioactive compounds with the existing hAECs research platforms ( Ferdousi and Isoda, 2022 ).

The study by Kubo et al. has drawn much attention due to its promising findings on the hair growth potential of several polyphenols. Hair thinning and alopecia is more than just cosmetic concern and has a significant negative impact on the quality of life. To date, only two compounds, finasteride and minoxidil, are commonly used to improve hair loss conditions, but they are not without side effects. Therefore, there has been growing interest in natural bioactive compounds with properties that promote hair growth or limit hair loss as a safe alternative to drug-based therapy ( Park and Lee, 2021 ). However, although many medicinal plants have been used anecdotally from ancient times to prevent hair loss, the scientific evidence is lacking about whether and how these plant-derived products are effective for the treatment of hair thinning and alopecia. In their study, Kubo et al. used an in vitro screening system in the human keratinocyte cell line, HaCaT, to identify polyphenols that can augment the expression of telomerase reverse transcriptase (TERT), a catalytic subunit of the enzyme telomerase, that activates the hair follicle bulge stem cells and triggers the initiation of new hair follicle growth phase and thereby promotes hair growth. They have identified the polyphenols-fisetin and resveratrol as potent hTERT-augmenting compounds that also enhanced β-catenin and hair growth cycle-related growth factors in vitro and in vivo .

Moqbel et al. investigated the anti-inflammatory effects of tectorigenin, an extracted component of Belamcanda chinensis , on TNFα-stimulated tendon-derived stem cells (TDSCs) and an animal model of tendinopathy. TDSCs are pluripotent stem cells that control tendon homeostasis and play a central role in tendon regeneration and healing and, therefore, are considered a potential cell-based therapy for tendon injuries ( Wei and Lu, 2021 ). Moqbel et al. showed that tectorigenin inhibited TNFα-induced matrix-degradation, inflammation, apoptosis, senescence, and osteogenic differentiation of TDSCs in NF-κB/MAPK-dependent manner in vitro . Furthermore, tectorigenin ameliorated tendinopathy in a tendon transection rat model. This study highlights the potential of plant-derived compounds with strong anti-inflammatory effects in tendinopathy and other musculoskeletal disorders.

The study by Ganbold et al. explored the effect of a new amphiphilic squalene derivative (HH-Sq) in comparison to squalene (Sq) on the adipocyte differentiation of adipose-derived stem cells (ASCs) obtained from type 2 diabetic subject. ASCs are adult stem cells that can be differentiated into mesodermal cell lineages, including adipocytes, osteocytes, myocytes, and chondrocytes and have the potential to be used for cell therapy in the treatment of insulin resistance, obesity, and type 2 diabetes ( Mazini et al., 2020 ). On the other hand, Sq is a polyunsaturated hydrocarbon found in deep-sea shark liver oil, numerous plant oils and algae ( Spanova and Daum, 2011 ). Ganbold et al. demonstrated that the amphiphilic HH-Sq, synthesized by adding mono ethylene glycol moiety to Sq, showed improved metabolism of adipocytes, enhanced energy homeostasis and insulin sensitivity, and importantly, in contrast to Sq, HH-Sq prevented excessive lipogenesis in the presence of adipocyte differentiation. This finding emphasizes the enhanced therapeutic potentials of synthesized derivatives from a natural compound in cell-based therapies.

He B. et al. reported that fraxinellone (FRA), the bioactive component isolated from the D. dasycarpus plant, inhibited the proliferation and migration of human osteosarcoma cells HOS and MG63 in a dose-dependent manner. FRA simultaneously induced osteosarcoma cell apoptosis and increased autophagy flux in vitro . The authors further demonstrated the anticancer effects of FRA in the xenograft orthotopic mice model. They have proposed that the anticancer effects of FRA were achieved through autophagy flux. Targeting autophagy is recognized as a promising therapeutic strategy to overcome drug resistance and reduce metastasis in osteosarcoma ( Liao et al., 2019 ). The study findings of He B. et al. would strengthen the idea of exploiting more plant natural compounds as potential novel antitumor therapeutics for osteosarcoma by targeting autophagy pathways.

Taken together, the current Research Topic provides multidirectional insights on plant-derived natural compounds-based research in stem cells.

Acknowledgments

We would like to thank all the contributing authors for their outstanding work and all the reviewers for their valuable time, careful thoughts, and constructive suggestions to enrich these manuscripts. We also would like to sincerely thank the members of the editorial office of Frontiers in Cell and Developmental Biology for their support.

Author Contributions

FF contributed to drafting the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

HI was supported by the Japan Science and Technology Agency (JST); Science and Technology Research Partnership for Sustainable Development (SATREPS, Grant No. JPMJSA1506).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

• Baptista P., Andrade J. P. (2018). Adult Hippocampal Neurogenesis: Regulation and Possible Functional and Clinical Correlates . Front. Neuroanat. 12 , 44. 10.3389/fnana.2018.00044 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Bejaoui M., Ferdousi F., Zheng Y.-W., Oda T., Isoda H. (2021). Regulating Cell Fate of Human Amnion Epithelial Cells Using Natural Compounds: an Example of Enhanced Neural and Pigment Differentiation by 3,4,5-Tri-O-Caffeoylquinic Acid . Cell Commun. Signal 19 ( 1 ), 26. 10.1186/s12964-020-00697-5 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Chen K. G., Mallon B. S., McKay R. D. G., Robey P. G. (2014). Human Pluripotent Stem Cell Culture: Considerations for Maintenance, Expansion, and Therapeutics . Cell stem Cell 14 ( 1 ), 13–26. 10.1016/j.stem.2013.12.005 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Ferdousi F., Isoda H. (2022). Regulating Early Biological Events in Human Amniotic Epithelial Stem Cells Using Natural Bioactive Compounds: Extendable Multidirectional Research Avenues . Front. Cell Dev. Biol. 10 , 865810. 10.3389/fcell.2022.865810 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Ferdousi F., Kondo S., Sasaki K., Uchida Y., Ohkohchi N., Zheng Y.-W., et al. (2020). Microarray Analysis of Verbenalin-Treated Human Amniotic Epithelial Cells Reveals Therapeutic Potential for Alzheimer's Disease . Aging 12 ( 6 ), 5516–5538. 10.18632/aging.102985 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Ferdousi F., Sasaki K., Uchida Y., Ohkohchi N., Zheng Y.-W., Isoda H. (2019). Exploring the Potential Role of Rosmarinic Acid in Neuronal Differentiation of Human Amnion Epithelial Cells by Microarray Gene Expression Profiling . Front. Neurosci. 13 , 779. 10.3389/fnins.2019.00779 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Gomes-Leal W. (2021). Adult Hippocampal Neurogenesis and Affective Disorders: New Neurons for Psychic Well-Being . Front. Neurosci. 15 , 712. 10.3389/fnins.2021.594448 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Guillamat-Prats R. (2021). The Role of MSC in Wound Healing, Scarring and Regeneration . Cells 10 ( 7 ), 1729. 10.3390/cells10071729 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Kubo C., Ogawa M., Uehara N., Katakura Y. (2020). Fisetin Promotes Hair Growth by Augmenting TERT Expression . Front. Cell Dev. Biol. 8 , 566617. 10.3389/fcell.2020.566617 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Laustriat D., Gide J., Peschanski M. (2010). Human Pluripotent Stem Cells in Drug Discovery and Predictive Toxicology . Biochem. Soc. Trans. 38 ( 4 ), 1051–1057. 10.1042/BST0381051 [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Liao Y. X., Yu H. Y., Lv J. Y., Cai Y. R., Liu F., He Z. M., et al. (2019). Targeting Autophagy Is a Promising Therapeutic Strategy to Overcome Chemoresistance and Reduce Metastasis in Osteosarcoma . Int. J. Oncol. 55 ( 6 ), 1213–1222. 10.3892/ijo.2019.4902 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Mazini L., Rochette L., Admou B., Amal S., Malka G. (2020). Hopes and Limits of Adipose-Derived Stem Cells (ADSCs) and Mesenchymal Stem Cells (MSCs) in Wound Healing . Ijms 21 ( 4 ), 1306. 10.3390/ijms21041306 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• McNeish J. (2004). Embryonic Stem Cells in Drug Discovery . Nat. Rev. Drug Discov. 3 ( 1 ), 70–80. 10.1038/nrd1281 [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Miki T., Lehmann T., Cai H., Stolz D. B., Strom S. C. (2005). Stem Cell Characteristics of Amniotic Epithelial Cells . Stem cells 23 ( 10 ), 1549–1559. 10.1634/stemcells.2004-0357 [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Miki T. (2018). Stem Cell Characteristics and the Therapeutic Potential of Amniotic Epithelial Cells . Am. J. Reprod. Immunol. 80 ( 4 ), e13003. 10.1111/aji.13003 [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Mu Y., Gage F. H. (2011). Adult Hippocampal Neurogenesis and its Role in Alzheimer's Disease . Mol. Neurodegener. 6 ( 1 ), 85–89. 10.1186/1750-1326-6-85 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Murphy S., Rosli S., Acharya R., Mathias L., Lim R., Wallace E., et al. (2010). Amnion Epithelial Cell Isolation and Characterization for Clinical Use . Curr. Protoc. Stem Cell Biol. 13 ( 1 ), 1E 6 1–1E 6 25. 10.1002/9780470151808.sc01e06s13 [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Park S., Lee J. (2021). Modulation of Hair Growth Promoting Effect by Natural Products . Pharmaceutics 13 ( 12 ), 2163. 10.3390/pharmaceutics13122163 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Rubin L. L., Haston K. M. (2011). Stem Cell Biology and Drug Discovery . BMC Biol. 9 ( 1 ), 42–11. 10.1186/1741-7007-9-42 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Sasikumar P., Aswathy M., Prem P. T., Radhakrishnan K. V., Chakrapani P. S. B. (2022). Plant Derived Bioactive Compounds and Their Potential to Enhance Adult Neurogenesis . Phytomedicine Plus 2 ( 1 ), 100191. [ Google Scholar ]
• Spanova M., Daum G. (2011). Squalene - Biochemistry, Molecular Biology, Process Biotechnology, and Applications . Eur. J. Lipid Sci. Technol. 113 ( 11 ), 1299–1320. 10.1002/ejlt.201100203 [ CrossRef ] [ Google Scholar ]
• Toda T., Parylak S. L., Linker S. B., Gage F. H. (2019). The Role of Adult Hippocampal Neurogenesis in Brain Health and Disease . Mol. Psychiatry 24 ( 1 ), 67–87. 10.1038/s41380-018-0036-2 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Udalamaththa V. L., Jayasinghe C. D., Udagama P. V. (2016). Potential Role of Herbal Remedies in Stem Cell Therapy: Proliferation and Differentiation of Human Mesenchymal Stromal Cells . Stem Cell Res. Ther. 7 ( 1 ), 110. 10.1186/s13287-016-0366-4 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Wei B., Lu J. (2021). Characterization of Tendon-Derived Stem Cells and Rescue Tendon Injury . Stem Cell Rev Rep 17 ( 5 ), 1534–1551. 10.1007/s12015-021-10143-9 [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Xu Z., Liu C., Wang R., Gao X., Hao C., Liu C. (2021). A Combination of Lycopene and Human Amniotic Epithelial Cells Can Ameliorate Cognitive Deficits and Suppress Neuroinflammatory Signaling by Choroid Plexus in Alzheimer's Disease Rat . J. Nutr. Biochem. 88 , 108558. 10.1016/j.jnutbio.2020.108558 [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Zhang E., Shen J., So K. F. (2014). Chinese Traditional Medicine and Adult Neurogenesis in the hippocampus . J. traditional complementary Med. 4 ( 2 ), 77–81. 10.4103/2225-4110.130372 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

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Scientists take a step closer to resurrecting the woolly mammoth.

Could woolly mammoths walk again among humans? Scientists are working to resurrect the extinct species. Mark Garlick/Getty Images/Science Photo Library hide caption

Could woolly mammoths walk again among humans? Scientists are working to resurrect the extinct species.

A biotech company that hopes to resurrect extinct species said Wednesday that it has reached an important milestone: the creation of a long-sought kind of stem cell for the closest living relative of the woolly mammoth.

"This is probably the most significant step in the early stages of this project," said George Church , a geneticist at Harvard University and the Massachusetts Institute of Technology who co-founded Colossal Biosciences in Dallas.

The woolly mammoth was a big, shaggy species of elephant that roamed the tundra before going extinct thousands of years ago. Colossal has been working to bring the mammoth, the dodo bird and other extinct species back to life using the latest cloning and genetic engineering techniques.

And now the company says scientists have for the first time created induced pluripotent stem cells for the mammoth's closest living relative: Asian elephants. The company described the work in a scientific paper posted on the bioRxiv preprint server. It hasn't been peer-reviewed, but the company says that's in progress.

A steppingstone from modern elephant to mammoth

The achievement is still far from the ultimate goal of creating herds of giant hairy beasts roaming in the wild again, but Church said it's a major step. "This is kind of like asking Neil Armstrong if he plans to go to Mars — kind of misses the point he just landed on the moon on Apollo 11," Church said.

Scientists can now try to use cloning techniques and gene editing to manipulate the cells in the hopes of someday creating elephants with key traits of mammoths, such as their heavy coats and the layers of fat that enabled them to survive in cold climates.

"We don't necessarily need to bring back a perfect genome of a mammoth, because we want one that has certain things that mammoths didn't have. Like we want them to be resistant to the herpesvirus that is causing a huge fraction of infant elephants to die," Church said.

Technical possibility raises ethical concerns

But some scientists object to the whole idea of trying to revive extinct animals.

"What are you going to get out of this?" asked Karl Flessa , a professor of geosciences at the University of Arizona. "First of all, I think you're going to get a bit of a freak show in a zoo somewhere. And then if you're going to release a herd into the Arctic tundra, is that herd going to go marching off to its second extinction in the face of global warming?"

"I think it's irresponsible," Flessa added.

But Church and his colleagues defended the project.

Scientists Say They Could Bring Back Woolly Mammoths. But Maybe They Shouldn't

"Some people think it's a bad idea because there will be only one lonely cold-adapted elephant. That's not our intention," Church said. "It's to have them fully socialized in large herds. Some people think it's a bad idea because it takes money away from conservation efforts, when in fact we're injecting money into conservation efforts."

Church said the woolly mammoth program could lead to new ways to protect endangered species like Asian elephants by expanding their habitat and helping scientists study the animals.

Researchers say the work will advance conservation

"We're very, very excited that we have derived the first elephant induced pluripotent stem cells," said Eriona Hysolli , who heads Colossal's mammoth project. "These cells will benefit the elephant conservation community just as much as being engineered to bring back the woolly mammoth."

Reintroducing elephants with woolly mammoth traits could also help fight global warming by restoring ecosystems in ways that would help reduce the amount of carbon being released into the atmosphere, Church said.

Some scientists say the creation of the specialized elephant stem cells is a noteworthy scientific achievement.

"Producing induced pluripotent stems has proved to be very difficult for some species — notoriously the elephant," said Oliver Ryder , director of conservation genetics at the San Diego Zoo Wildlife Alliance. "It's a great advancement to have been able to accomplish this for elephants."

The cells can be used to study the biology, reproduction and health of elephants, he said.

"It opens up new possibilities for conserving species' genetic diversity, preventing extinction and contributing to the sustainability of species," Ryder said. "There's an enormous potential."

While that may be true, others argue that using the cells to try to bring back mammoths is misguided.

"What I find troubling is bringing back some sort of a surrogate that is part- mammoth, part-elephant," said Joseph Bennett , an associate professor of biology at Carleton University in Ottawa, Canada. "Bringing that back as something that would somehow be portrayed as conservation would be a difficult sell on my part."

Others agree.

"There are so many species going extinct today. We're actually not going to be able to help any of them if we're thinking about the woolly mammoth. We need to focus on the species here today. Living animals versus fossils is really where our focus should be," said Gabriela Mastromonaco , senior director of wildlife science at the Toronto Zoo. "It's just a distraction."

• asian elephants
• animal conservation
• woolly mammoth

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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 .

Research sheds light on new strategy to treat infertility

Ohsu research advances technique to turn a skin cell into an egg; could help same-sex couples, others have children genetically related to both parents.

New research from Oregon Health & Science University describes the science behind a promising technique to treat infertility by turning a skin cell into an egg that is capable of producing viable embryos.

Researchers at OHSU documented in vitro gametogenesis, or IVG, in a mouse model through the preliminary steps of a technique that relies upon transferring the nucleus of a skin cell into a donated egg whose nucleus has been removed. Experimenting in mice, researchers coaxed the skin cell's nucleus into reducing its chromosomes by half, so that it could then be fertilized by a sperm cell to create a viable embryo.

The study published today in the journal Science Advances .

"The goal is to produce eggs for patients who don't have their own eggs," said senior author Shoukhrat Mitalipov, Ph.D., director of the OHSU Center for Embryonic Cell and Gene Therapy.

The technique could be used by women of advanced maternal age or for those who are unable to produce viable eggs due to previous treatment for cancer or other causes. It also raises the possibility of men in same-sex relationships having children who are genetically related to both parents.

Rather than attempting to differentiate induced pluripotent stem cells, or iPSCs, into sperm or egg cells, OHSU researchers are focused on a technique based on somatic cell nuclear transfer, in which a skin cell nucleus is transplanted into a donor egg stripped of its nucleus. In 1996, researchers famously used this technique to clone a sheep in Scotland named Dolly.

In that case, researchers created a clone of one parent.

In contrast, the OHSU study described the result of a technique that resulted in embryos with chromosomes contributed from both parents. The process involves three steps:

• Researchers transplant the nucleus of a mouse skin cell into a mouse egg that is stripped of its own nucleus.
• Prompted by cytoplasm -- liquid that fills cells -- within the donor egg, the implanted skin cell nucleus discards half of its chromosomes. The process is similar to meiosis, when cells divide to produce mature sperm or egg cells. This is the key step, resulting in a haploid egg with a single set of chromosomes.
• Researchers then fertilize the new egg with sperm, a process called in vitro fertilization. This creates a diploid embryo with two sets of chromosomes -- which would ultimately result in healthy offspring with equal genetic contributions from both parents.

OHSU researchers previously demonstrated the proof of concept in a study published in January 2022, but the new study goes further by meticulously sequencing the chromosomes.

The researchers found that the skin cell's nucleus segregated its chromosomes each time it was implanted in the donor egg. In rare cases, this happened perfectly, with one from each pair of matching egg and sperm chromosomes.

"This publication basically shows how we achieved haploidy," Mitalipov said. "In the next phase of this research, we will determine how we enhance that pairing so each chromosome-pair separates correctly."

Laboratories around the world are involved in a different technique of IVG that involves a time-intensive process of reprogramming skin cells to become iPSCs, and then differentiating them to become egg or sperm cells.

"We're skipping that whole step of cell reprogramming," said co-author Paula Amato, M.D., professor of obstetrics and gynecology in the OHSU School of Medicine. "The advantage of our technique is that it avoids the long culture time it takes to reprogram the cell. Over several months, a lot of deleterious genetic and epigenetic changes can happen."

Although researchers are also studying the technique in human eggs and early embryos, Amato said it will be years before the technique would be ready for clinical use.

"This gives us a lot of insight," she said. "But there is still a lot of work that needs to be done to understand how these chromosomes pair and how they faithfully divide to actually reproduce what happens in nature."

All research involving animal subjects at OHSU must be reviewed and approved by the university's Institutional Animal Care and Use Committee . The IACUC's priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. No live animal work may be conducted at OHSU without IACUC approval.

• Diseases and Conditions
• Pregnancy and Childbirth
• Developmental Biology
• Cell Biology
• Molecular Biology
• Somatic cell nuclear transfer
• Breast cancer
• Egg (biology)
• Malignant melanoma
• Cervical cancer
• Sex education
• Adult stem cell

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Materials provided by Oregon Health & Science University . Note: Content may be edited for style and length.

Journal Reference :

• Aleksei Mikhalchenko, Nuria Marti Gutierrez, Daniel Frana, Zahra Safaei, Crystal Van Dyken, Ying Li, Hong Ma, Amy Koski, Dan Liang, Sang-Goo Lee, Paula Amato, Shoukhrat Mitalipov. Induction of somatic cell haploidy by premature cell division . Science Advances , 2024; 10 (10) DOI: 10.1126/sciadv.adk9001

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ORIGINAL RESEARCH article

Metabolite and transcriptome analyses reveal the effects of salinity stress on the biosynthesis of proanthocyanidins and anthocyanins in grape suspension cells.

• 1 Center for Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China, Beijing, China
• 2 Key Laboratory of Viticulture and Enology, Ministry of Agriculture and Rural Affairs, Beijing, China
• 3 College of Biological Sciences and Technology, Beijing Forestry University, Beijing Forestry University, Beijing, Beijing, China

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Proanthocyanidins (PAs) and anthocyanins are flavonoids that contribute to the quality and health benefits of grapes and wine. Salinity affects their biosynthesis, but the underlying mechanism is still unclear. We studied the effects of NaCl stress on PA and anthocyanin biosynthesis in grape suspension cells derived from berry skins of Vitis vinifera L. Cabernet Sauvignon using metabolite profiling and transcriptome analysis. We treated the cells with low (75 mM NaCl) and high (150 mM NaCl) salinity for 4 and 7 days. High salinity inhibited cell growth and enhanced PA and anthocyanin accumulation more than low salinity. The salinity-induced PAs and anthocyanins lacked C5'-hydroxylation modification, suggesting the biological significance of delphinidin-and epigallocatechin-derivatives in coping with stress.The genes up-regulated by salinity stress indicated that the anthocyanin pathway was more sensitive to salt concentration than the PA pathway, and WGCNA analysis revealed the coordination between flavonoid biosynthesis and cell wall metabolism under salinity stress. We identified transcription factors potentially involved in regulating NaCl dose-and time-dependent PA and anthocyanin accumulation, showing the dynamic remodeling of flavonoid regulation network under different 2 salinity levels and durations. Our study provides new insights into regulator candidates for tailoring flavonoid composition and molecular indicators of salt stress in grape cells.

Keywords: Proanthocyanidins, Anthocyanins, Salinity, Suspension cells, Flavonoid biosynthesis, Transcription Factors, WGCNA

Received: 06 Dec 2023; Accepted: 07 Mar 2024.

Copyright: © 2024 Zhao, Lan, Shi, Duan and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Keji Yu, Center for Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China, Beijing, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Scientists move step closer to making IVF eggs from skin cells

Procedure could overcome common forms of infertility and help people have children who share their DNA

Scientists are a step closer to making IVF eggs from patients’ skin cells after adapting the procedure that created Dolly the sheep, the first cloned mammal, more than two decades ago.

The work raises the prospect of older women being able to have children who share their DNA, and to overcome common forms of infertility caused by a woman’s eggs becoming damaged by disease or cancer treatment.

The radical procedure, which may take a decade to perfect and approve in humans, would also enable male couples to have genetically related children, since the men’s DNA could be combined in the fertilised egg and carried to term by a surrogate mother.

“Should this technology become clinically viable in the future, it holds the potential to revolutionise IVF and offer hope to many infertile patients who have lost gametes due to disease, ageing or cancer treatments,” said Aleksei Mikhalchenko, the first author on the study, at Oregon Health and Science University in Portland, US. Gametes are sperm and egg cells.

Shoukhrat Mitalipov, a senior author on the study, said his lab had spent the past 20 years developing fertility treatments for patients who lack healthy sperm or eggs. Existing options, he said, forced people to use donated sperm or eggs and have genetically unrelated children. “Our technology would enable infertile patients to have genetically related children, providing a path to parenthood that is currently unavailable even with IVF,” he said.

Scientists around the world are working on several approaches to create eggs and sperm in the lab. Last year, Japanese researchers created eggs from the skin cells of male mice, leading to the birth of mouse pups with two fathers . Other teams hope to create sperm and eggs from embryonic stem cells , which are versatile enough to form any tissue in the body.

While many countries, including the UK, outlaw the use of artificial sperm and eggs to treat infertile couples, advances in the coming years may drive calls to permit the procedures if they are deemed safe and effective.

The latest experiments, published in Science Advances , were performed in mice and took a different, much swifter approach to creating IVF eggs. The researchers start with a donor egg and remove its nucleus. They then transfer in the nucleus from a mouse skin cell. The egg is then cultured in such a way that it naturally discards half of its chromosomes. This crucial step ensures the egg contains the correct number of chromosomes – half from each parent – once it is fertilised with a sperm. “Eggs can be made by our approach in a matter of two to three hours,” said Mikhalchenko.

Dolly the sheep was created in 1996 through a similar process, known as somatic cell nuclear transfer, or SCNT. Prof Ian Wilmut and his team at the Roslin Institute in Edinburgh extracted the nucleus from a mammary gland cell of a Finn Dorset ewe and fused it with an egg, producing an embryo that carried all of the ewe’s DNA.

Mitalipov’s team announced in 2022 the birth of three live mice from their experiments, but the success rate was less than 1%. Their latest study focuses on how the eggs discard half of their chromosomes, which is necessary for them to develop into a healthy embryo. “Our current objective is to enhance the success rate at each stage of the process,” Mitalipov said.

Paula Amato, a professor of obstetrics and gynaecology, and a co-author on the study, said the advantage of the team’s technique was that it avoided the long culture times used by other approaches that reprogram cells. “Over several months, a lot of harmful genetic and epigenetic changes can happen,” she said.

“While the clinical applications of this technology may still be a decade away and will require thorough evaluation of safety, efficacy and ethical aspects, its potential to address fertility-related issues offers promising prospects for future reproductive medicine,” Mikhalchenko added.

• Medical research
• Fertility problems

More on this story

There’s a crisis in male fertility. But you wouldn’t know it from the way many men behave

Woman who had child after womb transplant calls for wider availability

Friends assumed I would keep going, but after three rounds of IVF I knew I’d had enough

Black women are more likely to experience infertility than white women. They’re less likely to get help, too

Egg and sperm donors in UK to lose right to anonymity at birth under new plans

Woman ‘over the moon’ after sister donates womb in UK first

Home insemination kits to be trialled on NHS to explore non-IVF methods

The NHS helps same-sex couples like us access IVF. But why must we first pay the ‘queer tax’?

Secondary infertility forced us to re-evaluate life as a ‘triangle family’

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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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Authors and affiliations.

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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Scientists have used cells from fluid drawn during pregnancy to grow mini lungs and other organs

This microscope image provided by researchers in March 2024 shows a lung organoid created from cells collected from amniotic fluid. In a study published Monday, March 4, 2024, in the journal Nature Medicine, scientists in the United Kingdom described how they have made mini-organs from cells floating in amniotic fluid – an advance they believe could open up new areas of prenatal medicine. (Giuseppe Calà, Paolo De Coppi, Mattia Gerli via AP)

This microscope image provided by researchers in March 2024 shows an intestinal organoid with its distinctive ‘bud’ structure, created from cells collected from amniotic fluid. In a study published Monday, March 4, 2024, in the journal Nature Medicine, scientists in the United Kingdom described how they have made mini-organs from cells floating in amniotic fluid – an advance they believe could open up new areas of prenatal medicine. (Giuseppe Calà, Paolo De Coppi, Mattia Gerli via AP)

This microscope image provided by researchers in March 2024 shows a kidney organoid resembling renal tubules, created from cells collected from amniotic fluid. In a study published Monday, March 4, 2024, in the journal Nature Medicine, scientists in the United Kingdom described how they have made mini-organs from cells floating in amniotic fluid – an advance they believe could open up new areas of prenatal medicine. (Giuseppe Calà, Paolo De Coppi, Mattia Gerli via AP)

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Scientists have created miniorgans from cells floating in the fluid that surrounds a fetus in the womb – an advance they believe could open up new areas of prenatal medicine.

Miniorgans, or “ organoids ,” are tiny simplified structures that can be used to test new medical treatments or study how the real organs they mimic work, whether they are healthy or diseased.

Researchers from University College London and Great Ormond Street Hospital in the United Kingdom collected cells from amniotic fluid samples taken during 12 pregnancies as part of routine prenatal testing. Then, for the first time, they grew mini-organs from cells taken during active pregnancies. They envision their approach could eventually help doctors monitor and treat congenital conditions before birth and develop personalized therapies for a baby in the womb.

“We’re really excited” about that possibility, said Mattia Gerli of University College London, an author of the study published Monday in the journal Nature Medicine.

The tissue-specific stem cells Gerli and his colleagues collected were shed by the fetus, as normally happens during pregnancy. The scientists identified which tissues the stem cells came from, and found cells from the lungs, kidneys and intestines.

Previously, mini-organs have been derived from adult stem cells, which more closely resemble adult tissue , or fetal tissue after an abortion.

Collecting cells from amniotic fluid gets around regulations about taking stem cells directly from fetal tissue, allowing these scientists to get cells from fetuses into the latter part of pregnancy. In the U.K., the legal limit for terminating a pregnancy is generally 22 weeks after conception. Scientists can’t get fetal samples after that, limiting their ability to study normal human development or congenital diseases past that point.

In the U.S., abortion restrictions vary by state. It’s legal in most to use fetal tissue for research, said Alta Charo, an emeritus professor of law and bioethics at the University of Wisconsin at Madison. Fetal tissue is defined by the National Institutes of Health as coming from a dead human embryo or fetus after a miscarriage, abortion or stillbirth – and the use of tissue from an abortion has long been controversial.

Charo, who wasn’t involved in the study, said the new approach doesn’t raise the same ethical issues. “Obtaining cells from amniotic fluid that is already being sampled for standard clinical purposes does not appear to add any physical risks to either fetus or pregnant woman,” she said in an email.

Dr. Arnold Kriegstein, who directs the Developmental and Stem Cell Biology Program at the University of California, San Francisco, and also wasn’t involved in the research, said getting cells this way has “the potential of giving you some information about that individual fetus as it’s growing.”

And since growing mini-organs from cells in amniotic fluid takes about 4 to 6 weeks, Gerli said, there’s enough time for prenatal therapy to fix problems doctors might find.

To examine one practical use of their approach, the U.K. team worked with colleagues in Belgium to study the development of babies with a condition called a congenital diaphragmatic hernia, in which organs such as the liver and intestines get displaced into the chest because of a hole in the diaphragm. The lungs don’t develop the way they should, and about 30% of fetuses with the condition die. If doctors detect the hernia, they can operate on the fetus while it’s still in the womb.

Researchers grew lung organoids from the cells of fetuses with the condition before and after treatment and compared them to organoids from healthy fetuses. Dr. Paolo de Coppi, an author of the study from University College London and Great Ormond Street Hospital, said they were able to assess the affected child’s condition before birth using this method. Doctors are now unable to tell families much about the outcome of a prenatal diagnosis because each case is different, he said. The ability to study functioning prenatal miniorgans, he added, is the first step toward a more detailed prognosis and more effective treatments.

Kriegstein said more research is needed. “It’s in the very early stages,” he added, “and we’ll have to wait and see how useful it’ll be in the long run.”

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.