Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases
Toru Yamashita, Yoshihiro Kushida, Koji Abe, Mari Dezawa, Toru Yamashita, Yoshihiro Kushida, Koji Abe, Mari Dezawa
Abstract
Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.
Keywords: ALS; MSCs; SSEA-3; encephalitis; ischemia; pluripotent; sphingosine-1-phosphate; stroke.
Conflict of interest statement
Y.K. and M.D. are parties to a co-development and co-research agreement with Life Science Institute, Inc. (LSII: Tokyo, Japan). M.D. has a patent for Muse cells, and the Muse cell isolation method is licensed to LSII. T.Y., Y.K., K.A., and M.D. received a joint research grant from LSII.
Figures
References
- Kuroda Y., Kitada M., Wakao S., Nishikawa K., Tanimura Y., Makinoshima H., Goda M., Akashi H., Inutsuka A., Niwa A., et al. Unique multipotent cells in adult human mesenchymal cell populations. Proc. Natl. Acad. Sci. USA. 2010;107:8639–8643. doi: 10.1073/pnas.0911647107.
- Kushida Y., Wakao S., Dezawa M. Muse Cells Are Endogenous Reparative Stem Cells. Adv. Exp. Med. Biol. 2018;1103:43–68. doi: 10.1007/978-4-431-56847-6_3.
- Tanaka T., Nishigaki K., Minatoguchi S., Nawa T., Yamada Y., Kanamori H., Mikami A., Ushikoshi H., Kawasaki M., Dezawa M., et al. Mobilized Muse Cells After Acute Myocardial Infarction Predict Cardiac Function and Remodeling in the Chronic Phase. Circ. J. 2018;82:561–571. doi: 10.1253/circj.CJ-17-0552.
- Sato T., Wakao S., Kushida Y., Tatsumi K., Kitada M., Abe T., Niizuma K., Tominaga T., Kushimoto S., Dezawa M. A Novel Type of Stem Cells Double-Positive for SSEA-3 and CD45 in Human Peripheral Blood. Cell Transplant. 2020;29:963689720923574. doi: 10.1177/0963689720923574.
- Weigert A., Olesch C., Brüne B. Sphingosine-1-Phosphate and Macrophage Biology—How the Sphinx Tames the Big Eater. Front. Immunol. 2019;10:1706. doi: 10.3389/fimmu.2019.01706.
- Yamada Y., Wakao S., Kushida Y., Minatoguchi S., Mikami A., Higashi K., Baba S., Shigemoto T., Kuroda Y., Kanamori H., et al. S1P–S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction. Circ. Res. 2018;122:1069–1083. doi: 10.1161/CIRCRESAHA.117.311648.
- Hori E., Hayakawa Y., Hayashi T., Hori S., Okamoto S., Shibata T., Kubo M., Horie Y., Sasahara M., Kuroda S. Mobilization of Pluripotent Multilineage-Differentiating Stress-Enduring Cells in Ischemic Stroke. J. Stroke Cerebrovasc. Dis. 2016;25:1473–1481. doi: 10.1016/j.jstrokecerebrovasdis.2015.12.033.
- Dezawa M. Muse Cells Provide the Pluripotency of Mesenchymal Stem Cells: Direct Contribution of Muse Cells to Tissue Regeneration. Cell Transplant. 2016;25:849–861. doi: 10.3727/096368916X690881.
- Minatoguchi S., Mikami A., Tanaka T., Minatoguchi S., Yamada Y. Acute Myocardial Infarction, Cardioprotection, and Muse Cells. Adv. Exp. Med. Biol. 2018;1103:153–166. doi: 10.1007/978-4-431-56847-6_8.
- Noda T., Nishigaki K., Minatoguchi S. Safety and Efficacy of Human Muse Cell-Based Product for Acute Myocardial Infarction in a First-in-Human Trial. Circ. J. 2020;84:1189–1192. doi: 10.1253/circj.CJ-20-0307.
- Fujita Y., Nohara T., Takashima S., Natsuga K., Adachi M., Yoshida K., Shinkuma S., Takeichi T., Nakamura H., Wada O., et al. Intravenous allogeneic multilineage-differentiating stress-enduring cells in adults with dystrophic epidermolysis bullosa: A phase 1/2 open-label study. J. Eur. Acad. Dermatol. Venereol. 2021 doi: 10.1111/jdv.17201.
- Shevinsky L.H., Knowles B.B., Damjanov I., Solter D. Monoclonal antibody to murine embryos defines a stage-specific embryonic antigen expressed on mouse embryos and human teratocarcinoma cells. Cell. 1982;30:697–705. doi: 10.1016/0092-8674(82)90274-4.
- Kannagi R., Cochran N.A., Ishigami F., Hakomori S., Andrews P.W., Knowles B.B., Solter D. Stage-specific em-bryonic antigens (SSEA-3 and -4) are epitopes of a unique globo-series ganglioside isolated from human teratocarcino-ma cells. EMBO J. 1983;2:2355–2361. doi: 10.1002/j.1460-2075.1983.tb01746.x.
- Yang Z., Liu J., Liu H., Qiu M., Liu Q., Zheng L., Pang M., Quan F., Zhang Y. Isolation and Characterization of SSEA3+ Stem Cells Derived from Goat Skin Fibroblasts. Cell. Reprogr. 2013;15:195–205. doi: 10.1089/cell.2012.0080.
- Nitobe Y., Nagaoki T., Kumagai G., Sasaki A., Liu X., Fujita T., Fukutoku T., Wada K., Tanaka T., Kudo H., et al. Neurotrophic Factor Secretion and Neural Differentiation Potential of Multilineage-differentiating Stress-enduring (Muse) Cells Derived from Mouse Adipose Tissue. Cell Transplant. 2019;28:1132–1139. doi: 10.1177/0963689719863809.
- Iseki M., Mizuma M., Wakao S., Kushida Y., Kudo K., Fukase M., Ishida M., Ono T., Shimura M., Ise I., et al. The evaluation of the safety and efficacy of intravenously administered allogeneic multilineage-differentiating stress-enduring cells in a swine hepatectomy model. Surg. Today. 2021;51:634–650. doi: 10.1007/s00595-020-02117-0.
- Sun D., Yang L., Cao H., Shen Z., Song H. Study of the protective effect on damaged intestinal epithelial cells of rat multilineage-differentiating stress-enduring (Muse) cells. Cell Biol. Int. 2020;44:549–559. doi: 10.1002/cbin.11255.
- Wakao S., Kushida Y., Dezawa M. Muse Cells. Springer; Tokyo, Japan: 2019. Correction to: Basic Characteristics of Muse Cells; p. C1.
- Leng Z., Sun D., Huang Z., Tadmori I., Chiang N., Kethidi N., Sabra A., Kushida Y., Fu Y.-S., Dezawa M., et al. Quantitative Analysis of SSEA3+ Cells from Human Umbilical Cord after Magnetic Sorting. Cell Transplant. 2019;28:907–923. doi: 10.1177/0963689719844260.
- Rompolas P., Greco V. Stem cell dynamics in the hair follicle niche. Semin. Cell Dev. Biol. 2014;25–26:34–42. doi: 10.1016/j.semcdb.2013.12.005.
- Boulais P.E., Frenette P.S. Making sense of hematopoietic stem cell niches. Blood. 2015;125:2621–2629. doi: 10.1182/blood-2014-09-570192.
- Wakao S., Kitada M., Kuroda Y., Shigemoto T., Matsuse D., Akashi H., Tanimura Y., Tsuchiyama K., Kikuchi T., Goda M., et al. Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts. Proc. Natl. Acad. Sci. USA. 2011;108:9875–9880. doi: 10.1073/pnas.1100816108.
- Tsuchiyama K., Wakao S., Kuroda Y., Ogura F., Nojima M., Sawaya N., Yamasaki K., Aiba S., Dezawa M. Functional Melanocytes Are Readily Reprogrammable from Multilineage-Differentiating Stress-Enduring (Muse) Cells, Distinct Stem Cells in Human Fibroblasts. J. Investig. Dermatol. 2013;133:2425–2435. doi: 10.1038/jid.2013.172.
- Amin M., Kushida Y., Wakao S., Kitada M., Tatsumi K., Dezawa M. Cardiotrophic Growth Factor–Driven Induction of Human Muse Cells into Cardiomyocyte-Like Phenotype. Cell Transplant. 2018;27:285–298. doi: 10.1177/0963689717721514.
- Kuroda Y., Wakao S., Kitada M., Murakami T., Nojima M., Dezawa M. Isolation, culture and evaluation of multilineage-differentiating stress-enduring (Muse) cells. Nat. Protoc. 2013;8:1391–1415. doi: 10.1038/nprot.2013.076.
- Ogura F., Wakao S., Kuroda Y., Tsuchiyama K., Bagheri M., Heneidi S., Chazenbalk G., Aiba S., Dezawa M. Human Adipose Tissue Possesses a Unique Population of Pluripotent Stem Cells with Nontumorigenic and Low Telomerase Activities: Potential Implications in Regenerative Medicine. Stem Cells Dev. 2014;23:717–728. doi: 10.1089/scd.2013.0473.
- Iseki M., Kushida Y., Wakao S., Akimoto T., Mizuma M., Motoi F., Asada R., Shimizu S., Unno M., Chazenbalk G., et al. Human Muse Cells, Nontumorigenic Phiripotent-Like Stem Cells, Have Liver Regeneration Capacity through Specific Homing and Cell Replacement in a Mouse Model of Liver Fibrosis. Cell Transplant. 2017;26:821–840. doi: 10.3727/096368916X693662.
- Alessio N., Özcan S., Tatsumi K., Murat A., Peluso G., Dezawa M., Galderisi U. The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation. Cell Cycle. 2017;16:33–44. doi: 10.1080/15384101.2016.1211215.
- Alessio N., Squillaro T., Özcan S., Di Bernardo G., Venditti M., Melone M., Peluso G., Galderisi U. Stress and stem cells: Adult Muse cells tolerate extensive genotoxic stimuli better than mesenchymal stromal cells. Oncotarget. 2018;9:19328–19341. doi: 10.18632/oncotarget.25039.
- Gimeno M.L., Fuertes F., Tabarrozzi A.E.B., Attorressi A.I., Cucchiani R., Corrales L., Oliveira T.C., Sogayar M.C., Labriola L., Dewey R.A., et al. Pluripotent Nontumorigenic Adipose Tissue-Derived Muse Cells have Immunomodulatory Capacity Mediated by Transforming Growth Factor-β1. Stem Cells Transl. Med. 2016;6:161–173. doi: 10.5966/sctm.2016-0014.
- Milstien S., Spiegel S. Generation and metabolism of bioactive sphingosine-1-phosphate. J. Cell. Biochem. 2004;92:882–899. doi: 10.1002/jcb.20097.
- De Becker A., Van Riet I. Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy? World J. Stem Cells. 2016;8:73–87. doi: 10.4252/wjsc.v8.i3.73.
- Fujita Y., Komatsu M., Lee S.E., Kushida Y., Nakayama-Nishimura C., Matsumura W., Takashima S., Shinkuma S., Nomura T., Masutomi N., et al. Intravenous Injection of Muse Cells as a Potential Therapeutic Approach for Epidermolysis Bullosa. J. Investig. Dermatol. 2021;141:198–202.e6. doi: 10.1016/j.jid.2020.05.092.
- Uchida H., Niizuma K., Kushida Y., Wakao S., Tominaga T., Borlongan C.V., Dezawa M. Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model. Stroke. 2017;48:428–435. doi: 10.1161/STROKEAHA.116.014950.
- Uchida N., Kushida Y., Kitada M., Wakao S., Kumagai N., Kuroda Y., Kondo Y., Hirohara Y., Kure S., Chazenbalk G., et al. Beneficial Effects of Systemically Administered Human Muse Cells in Adriamycin Nephropathy. J. Am. Soc. Nephrol. 2017;28:2946–2960. doi: 10.1681/ASN.2016070775.
- Yamashita T., Kushida Y., Wakao S., Tadokoro K., Nomura E., Omote Y., Takemoto M., Hishikawa N., Ohta Y., Dezawa M., et al. Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis. Sci. Rep. 2020;10:1–11. doi: 10.1038/s41598-020-74216-4.
- Ozuru R., Wakao S., Tsuji T., Ohara N., Matsuba T., Amuran M.Y., Isobe J., Iino M., Nishida N., Matsumoto S., et al. Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice. Mol. Ther. 2020;28:100–118. doi: 10.1016/j.ymthe.2019.09.023.
- Uchida H., Morita T., Niizuma K., Kushida Y., Kuroda Y., Wakao S., Sakata H., Matsuzaka Y., Mushiake H., Tominaga T., et al. Transplantation of Unique Subpopulation of Fibroblasts, Muse Cells, Ameliorates Experimental Stroke Possibly via Robust Neuronal Differentiation. Stem Cells. 2016;34:160–173. doi: 10.1002/stem.2206.
- Suzuki T., Sato Y., Kushida Y., Tsuji M., Wakao S., Ueda K., Imai K., Iitani Y., Shimizu S., Hida H., et al. Intra-venously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and mi-croglial activation in experimental perinatal hypoxic ischemic encephalopathy. J. Cereb. Blood Flow. 2020:0271678X20972656. doi: 10.1177/0271678X20972656.
- Shimamura N., Kakuta K., Wang L., Naraoka M., Uchida H., Wakao S., Dezawa M., Ohkuma H. Neuro-regeneration therapy using human Muse cells is highly effective in a mouse intracerebral hemorrhage model. Exp. Brain Res. 2017;235:565–572. doi: 10.1007/s00221-016-4818-y.
- Katagiri H., Kushida Y., Nojima M., Kuroda Y., Wakao S., Ishida K., Endo F., Kume K., Takahara T., Nitta H., et al. A Distinct Subpopulation of Bone Marrow Mesenchymal Stem Cells, Muse Cells, Directly Commit to the Replacement of Liver Components. Arab. Archaeol. Epigr. 2016;16:468–483. doi: 10.1111/ajt.13537.
- Hosoyama K., Wakao S., Kushida Y., Ogura F., Maeda K., Adachi O., Kawamoto S., Dezawa M., Saiki Y. Intravenously injected human multilineage-differentiating stress-enduring cells selectively engraft into mouse aortic aneurysms and attenuate dilatation by differentiating into multiple cell types. J. Thorac. Cardiovasc. Surg. 2018;155:2301–2313.e4. doi: 10.1016/j.jtcvs.2018.01.098.
- Ankrum J.A., Ong J.F., Karp J.M. Mesenchymal stem cells: Immune evasive, not immune privileged. Nat. Biotechnol. 2014;32:252–260. doi: 10.1038/nbt.2816.
- Zhao L., Chen S., Yang P., Cao H., Li L. The role of mesenchymal stem cells in hematopoietic stem cell transplantation: Prevention and treatment of graft-versus-host disease. Stem Cell Res. Ther. 2019;10:1–13. doi: 10.1186/s13287-019-1287-9.
- Najima Y., Ohashi K. Mesenchymal Stem Cells: The First Approved Stem Cell Drug in Japan. J. Hematop. Cell Transplant. 2017;6:125–132. doi: 10.7889/hct-16-031.
- Loustau M., Anna F., Dréan R., LeComte M., Langlade-Demoyen P., Caumartin J. HLA-G Neo-Expression on Tumors. Front. Immunol. 2020;11:1685. doi: 10.3389/fimmu.2020.01685.
- Yabuki H., Wakao S., Kushida Y., Dezawa M., Okada Y. Human Multilineage-differentiating Stress-Enduring Cells Exert Pleiotropic Effects to Ameliorate Acute Lung Ischemia–Reperfusion Injury in a Rat Model. Cell Transplant. 2018;27:979–993. doi: 10.1177/0963689718761657.
- Shono Y., Kushida Y., Wakao S., Kuroda Y., Unno M., Kamei T., Miyagi S., Dezawa M. Protection of liver sinusoids by intravenous administration of human Muse cells in a rat extra-small partial liver transplantation model. Arab. Archaeol. Epigr. 2020 doi: 10.1111/ajt.16461.
- Surgucheva I., Chidambaram K., Willoughby D.A., Surguchov A. Matrix metalloproteinase 9 expression: New regulatory elements. J. Ocul. Biol. Dis. Inform. 2010;3:41–52. doi: 10.1007/s12177-010-9054-2.
- Ratajczak M.Z., Shin D.-M., Liu R., Mierzejewska K., Ratajczak J., Kucia M., Zuba-Surma E.K. Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation—An update and comparison to other primitive small stem cells isolated from adult tissues. Aging. 2012;4:235–246. doi: 10.18632/aging.100449.
- Jiang Y., Vaessen B., Lenvik T., Blackstad M., Reyes M., Verfaillie C.M. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp. Hematol. 2002;30:896–904. doi: 10.1016/S0301-472X(02)00869-X.
- Nichols J., Smith A. Naive and Primed Pluripotent States. Cell Stem Cell. 2009;4:487–492. doi: 10.1016/j.stem.2009.05.015.
- Ying Q.-L., Nichols J., Chambers I., Smith A. BMP Induction of Id Proteins Suppresses Differentiation and Sustains Embryonic Stem Cell Self-Renewal in Collaboration with STAT3. Cell. 2003;115:281–292. doi: 10.1016/S0092-8674(03)00847-X.
- Tesar P.J., Chenoweth J.G., Brook F.A., Davies T.J., Evans E.P., Mack D.L., Gardner R.L., McKay R.D.G. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nat. Cell Biol. 2007;448:196–199. doi: 10.1038/nature05972.
- Masrori P., Van Damme P. Amyotrophic lateral sclerosis: A clinical review. Eur. J. Neurol. 2020;27:1918–1929. doi: 10.1111/ene.14393.
- Ogasawara M., Matsubara Y., Narisawa K., Aoki M., Nakamura S., Itoyama Y., Abe K. Mild ALS in Japan associated with novel SOD mutation. Nat. Genet. 1993;5:323–324. doi: 10.1038/ng1293-323.
- Gurney M.E., Pu H., Chiu A.Y., Dal Canto M.C., Polchow C.Y., Alexander D.D., Caliendo J., Hentati A., Kwon Y.W., Deng H.X., et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264:1772–1775. doi: 10.1126/science.8209258.
- Arai T., Hasegawa M., Akiyama H., Ikeda K., Nonaka T., Mori H., Mann D., Tsuchiya K., Yoshida M., Hashizume Y., et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 2006;351:602–611. doi: 10.1016/j.bbrc.2006.10.093.
- DeJesus-Hernandez M., Mackenzie I.R., Boeve B.F., Boxer A.L., Baker M., Rutherford N.J., Nicholson A.M., Finch N.A., Flynn H., Adamson J., et al. Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron. 2011;72:245–256. doi: 10.1016/j.neuron.2011.09.011.
- Paré B., Lehmann M., Beaudin M., Nordström U., Saikali S., Julien J.-P., Gilthorpe J.D., Marklund S.L., Cashman N.R., Andersen P.M., et al. Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis. Sci. Rep. 2018;8:1–13. doi: 10.1038/s41598-018-31773-z.
- Ferrante R.J., Browne S.E., Shinobu L.A., Bowling A.C., Baik M.J., MacGarvey U., Kowall N.W., Brown R.H., Jr., Beal M.F. Evidence of Increased Oxidative Damage in Both Sporadic and Familial Amyotrophic Lateral Sclerosis. J. Neurochem. 2002;69:2064–2074. doi: 10.1046/j.1471-4159.1997.69052064.x.
- Warita H., Hayashi T., Murakami T., Manabe Y., Abe K. Oxidative damage to mitochondrial DNA in spinal motoneurons of transgenic ALS mice. Mol. Brain Res. 2001;89:147–152. doi: 10.1016/S0169-328X(01)00029-8.
- Miyazaki K., Ohta Y., Nagai M., Morimoto N., Kurata T., Takehisa Y., Ikeda Y., Matsuura T., Abe K. Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J. Neurosci. Res. 2011;89:718–728. doi: 10.1002/jnr.22594.
- Abe K., Itoyama Y., Sobue G., Tsuji S., Aoki M., Doyu M., Hamada C., Kondo K., Yoneoka T., Akimoto M., et al. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph. Lateral Scler. Front. Degener. 2014;15:610–617. doi: 10.3109/21678421.2014.959024.
- Abe K., Aoki M., Tsuji S., Itoyama Y., Sobue G., Togo M., Hamada C., Tanaka M., Akimoto M., Nakamura K., et al. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: A randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16:505–512. doi: 10.1016/S1474-4422(17)30115-1.
- Abe T., Aburakawa D., Niizuma K., Iwabuchi N., Kajitani T., Wakao S., Kushida Y., Dezawa M., Borlongan C.V., Tominaga T. Intravenously Transplanted Human Multilineage-Differentiating Stress-Enduring Cells Afford Brain Repair in a Mouse Lacunar Stroke Model. Stroke. 2020;51:601–611. doi: 10.1161/STROKEAHA.119.026589.
- Pittenger M.F., Mackay A.M., Beck S.C., Jaiswal R.K., Douglas R., Mosca J.D., Moorman M.A., Simonetti D.W., Craig S., Marshak D.R. Multilineage Potential of Adult Human Mesenchymal Stem Cells. Science. 1999;284:143–147. doi: 10.1126/science.284.5411.143.
- Fu Y., Karbaat L., Wu L., Leijten J., Both S.K., Karperien M. Trophic Effects of Mesenchymal Stem Cells in Tissue Regeneration. Tissue Eng. Part B Rev. 2017;23:515–528. doi: 10.1089/ten.teb.2016.0365.
Source: PubMed