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Advances in stem cell research and therapeutic development

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

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Abstract

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

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Fig. 1: Ongoing stem cell therapies.
Fig. 2: Stem cells from the bone marrow.
Fig. 3: Schematic representation of corneal regeneration and combined cell and gene therapy of Epidermolysis Bullosa.
Fig. 4: Ongoing therapies using ESC-derivatives.

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References

  1. Sipp, D. et al. Marketing of unproven stem cell-based interventions: a call to action. Sci. Transl. Med. 9, eaag0426 (2017).

    PubMed  Google Scholar 

  2. Thomas, E. D., Lochte, H. L. Jr., Lu, W. C. & Ferrebee, J. W. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 257, 491–496 (1957).

    CAS  PubMed  Google Scholar 

  3. Thomas, E. D. et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49, 511–533 (1977).

    CAS  PubMed  Google Scholar 

  4. Gatti, R. A., Meuwissen, H. J., Allen, H. D., Hong, R. & Good, R. A. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet 2, 1366–1369 (1968).

    CAS  PubMed  Google Scholar 

  5. Chabannon, C. et al. Hematopoietic stem cell transplantation in its 60s: a platform for cellular therapies. Sci. Transl. Med. 10, eaap9630 (2018).

    PubMed  Google Scholar 

  6. Dunbar, C. E. et al. Gene therapy comes of age. Science 359, eaan4672 (2018).

    PubMed  Google Scholar 

  7. Aiuti, A. et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N. Engl. J. Med. 360, 447–458 (2009).

    CAS  PubMed  Google Scholar 

  8. Naldini, L. Gene therapy returns to centre stage. Nature 526, 351–360 (2015).

    CAS  PubMed  Google Scholar 

  9. Bernardo, M. E. & Aiuti, A. The role of conditioning in hematopoietic stem-cell gene therapy. Hum. Gene Ther. 27, 741–748 (2016).

    CAS  PubMed  Google Scholar 

  10. Aiuti, A. et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410–2413 (2002).

    CAS  PubMed  Google Scholar 

  11. Cicalese, M. P. et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood 128, 45–54 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kohn, D. B. et al. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J. Allergy Clin. Immunol. 143, 852–863 (2018).

    PubMed  Google Scholar 

  13. Tucci, F. et al. Successful treatment with ledipasvir/sofosbuvir in an infant with severe combined immunodeficiency caused by adenosine deaminase deficiency with HCV allowed gene therapy with strimvelis. Hepatology 68, 2434–2437 (2018).

    PubMed  Google Scholar 

  14. Hacein-Bey-Abina, S. et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348, 255–256 (2003).

    PubMed  Google Scholar 

  15. Braun, C. J. et al. Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity. Sci. Transl. Med. 6, 227ra33 (2014).

    PubMed  Google Scholar 

  16. Cavazzana, M., Bushman, F.D., Miccio, A., André-Schmutz, I. & Six, E. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat. Rev. Drug Discov. https://doi.org/10.1038/s41573-019-0020-9 (2019).

    CAS  PubMed  Google Scholar 

  17. Cartier, N. et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818–823 (2009).

    CAS  PubMed  Google Scholar 

  18. Sessa, M. et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 388, 476–487 (2016).

    CAS  PubMed  Google Scholar 

  19. Biffi, A. et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341, 1233158 (2013).

    PubMed  Google Scholar 

  20. De Ravin, S. S. et al. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci. Transl. Med. 8, 335ra57 (2016).

    PubMed  PubMed Central  Google Scholar 

  21. Aiuti, A. et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341, 1233151 (2013).

    PubMed  PubMed Central  Google Scholar 

  22. Ferrua, F. et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 6, e239–e253 (2019).

    PubMed  PubMed Central  Google Scholar 

  23. Hacein-Bey Abina, S. et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. J. Am. Med. Assoc. 313, 1550–1563 (2015).

    Google Scholar 

  24. Thompson, A. A. et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 378, 1479–1493 (2018).

    CAS  PubMed  Google Scholar 

  25. Marktel, S. et al. Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia. Nat. Med. 25, 234–241 (2019).

    CAS  PubMed  Google Scholar 

  26. Scala, S. et al. Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nat. Med. 24, 1683–1690 (2018).

    CAS  PubMed  Google Scholar 

  27. Vakulskas, C. A. et al. A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells. Nat. Med. 24, 1216–1224 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu, Y. et al. Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat. Med. 25, 776–783 (2019).

    CAS  PubMed  Google Scholar 

  29. Biasco, L. et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell 19, 107–119 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Rheinwald, J. G. & Green, H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6, 331–343 (1975).

    CAS  PubMed  Google Scholar 

  31. Green, H., Kehinde, O. & Thomas, J. Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. Proc. Natl Acad. Sci. USA 76, 5665–5668 (1979).

    CAS  PubMed  Google Scholar 

  32. Gallico, G. G. III, O’Connor, N. E., Compton, C. C., Kehinde, O. & Green, H. Permanent coverage of large burn wounds with autologous cultured human epithelium. N. Engl. J. Med. 311, 448–451 (1984).

    PubMed  Google Scholar 

  33. De Luca, M., Pellegrini, G. & Green, H. Regeneration of squamous epithelia from stem cells of cultured grafts. Regen. Med. 1, 45–57 (2006).

    PubMed  Google Scholar 

  34. Barrandon, Y. & Green, H. Three clonal types of keratinocyte with different capacities for multiplication. Proc. Natl Acad. Sci. USA 84, 2302–2306 (1987).

    CAS  PubMed  Google Scholar 

  35. Pellegrini, G. et al. The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin. Transplantation 68, 868–879 (1999).

    CAS  PubMed  Google Scholar 

  36. Ronfard, V., Rives, J. M., Neveux, Y., Carsin, H. & Barrandon, Y. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation 70, 1588–1598 (2000).

    CAS  PubMed  Google Scholar 

  37. Rama, P. et al. Limbal stem-cell therapy and long-term corneal regeneration. N. Engl. J. Med. 363, 147–155 (2010).

    CAS  PubMed  Google Scholar 

  38. Hirsch, T. et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature 551, 327–332 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Pellegrini, G. et al. Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface. J. Cell Biol. 145, 769–782 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Schermer, A., Galvin, S. & Sun, T. T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. J. Cell Biol. 103, 49–62 (1986).

    CAS  PubMed  Google Scholar 

  41. Cotsarelis, G., Cheng, S. Z., Dong, G., Sun, T. T. & Lavker, R. M. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 57, 201–209 (1989).

    CAS  PubMed  Google Scholar 

  42. Lehrer, M. S., Sun, T. T. & Lavker, R. M. Strategies of epithelial repair: modulation of stem cell and transit amplifying cell proliferation. J. Cell Sci. 111, 2867–2875 (1998).

    CAS  PubMed  Google Scholar 

  43. Majo, F., Rochat, A., Nicolas, M., Jaoudé, G. A. & Barrandon, Y. Oligopotent stem cells are distributed throughout the mammalian ocular surface. Nature 456, 250–254 (2008).

    CAS  PubMed  Google Scholar 

  44. Pellegrini, G., Rama, P., Mavilio, F. & De Luca, M. Epithelial stem cells in corneal regeneration and epidermal gene therapy. J. Pathol. 217, 217–228 (2009).

    CAS  PubMed  Google Scholar 

  45. Kenyon, K. R. & Tseng, S. C. Limbal autograft transplantation for ocular surface disorders. Ophthalmology 96, 709–723 (1989).

    CAS  PubMed  Google Scholar 

  46. Lindberg, K., Brown, M. E., Chaves, H. V., Kenyon, K. R. & Rheinwald, J. G. In vitro propagation of human ocular surface epithelial cells for transplantation. Invest. Ophthalmol. Vis. Sci. 34, 2672–2679 (1993).

    CAS  PubMed  Google Scholar 

  47. Pellegrini, G. et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 349, 990–993 (1997).

    CAS  PubMed  Google Scholar 

  48. Rama, P. et al. Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation 72, 1478–1485 (2001).

    CAS  PubMed  Google Scholar 

  49. Pellegrini, G. et al. Biological parameters determining the clinical outcome of autologous cultures of limbal stem cells. Regen. Med. 8, 553–567 (2013).

    CAS  PubMed  Google Scholar 

  50. Hsu, Y. C., Li, L. & Fuchs, E. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157, 935–949 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yang, A. et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell 2, 305–316 (1998).

    CAS  PubMed  Google Scholar 

  52. Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999).

    CAS  PubMed  Google Scholar 

  53. Mills, A. A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–713 (1999).

    CAS  PubMed  Google Scholar 

  54. Senoo, M., Pinto, F., Crum, C. P. & McKeon, F. p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129, 523–536 (2007).

    CAS  PubMed  Google Scholar 

  55. Pellegrini, G. et al. p63 identifies keratinocyte stem cells. Proc. Natl Acad. Sci. USA 98, 3156–3161 (2001).

    CAS  PubMed  Google Scholar 

  56. Di Iorio, E. et al. Isoforms of DeltaNp63 and the migration of ocular limbal cells in human corneal regeneration. Proc. Natl Acad. Sci. USA 102, 9523–9528 (2005).

    PubMed  Google Scholar 

  57. Di Iorio, E. et al. Q-FIHC: quantification of fluorescence immunohistochemistry to analyse p63 isoforms and cell cycle phases in human limbal stem cells. Microsc. Res. Tech. 69, 983–991 (2006).

    PubMed  Google Scholar 

  58. Le, Q., Xu, J. & Deng, S. X. The diagnosis of limbal stem cell deficiency. Ocul. Surf. 16, 58–69 (2018).

    PubMed  Google Scholar 

  59. Dong, Y., Peng, H. & Lavker, R. M. Emerging therapeutic strategies for limbal stem cell deficiency. J. Ophthalmol. 2018, 7894647 (2018).

    PubMed  PubMed Central  Google Scholar 

  60. Fine, J. D. et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J. Am. Acad. Dermatol. 70, 1103–1126 (2014).

    PubMed  Google Scholar 

  61. Carulli, S., Contin, R., De Rosa, L., Pellegrini, G. & De Luca, M. The long and winding road that leads to a cure for epidermolysis bullosa. Regen. Med. 8, 467–481 (2013).

    CAS  PubMed  Google Scholar 

  62. Mavilio, F. et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat. Med. 12, 1397–1402 (2006).

    CAS  PubMed  Google Scholar 

  63. Bauer, J. W. et al. Closure of a large chronic wound through transplantation of gene-corrected epidermal stem cells. J. Invest. Dermatol. 137, 778–781 (2017).

    CAS  PubMed  Google Scholar 

  64. Siprashvili, Z. et al. Safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with recessive dystrophic epidermolysis bullosa. J. Am. Med. Assoc. 316, 1808–1817 (2016).

    Google Scholar 

  65. Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).

    CAS  PubMed  Google Scholar 

  66. Mascré, G. et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 257–262 (2012).

    PubMed  Google Scholar 

  67. Comai, G. & Tajbakhsh, S. Molecular and cellular regulation of skeletal myogenesis. Curr. Top. Dev. Biol. 110, 1–73 (2014).

    CAS  PubMed  Google Scholar 

  68. Miquerol, L. & Kelly, R. G. Organogenesis of the vertebrate heart. Wiley Interdiscip. Rev. Dev. Biol. 2, 17–29 (2013).

    CAS  PubMed  Google Scholar 

  69. Buckingham, M. Tissue differentiation: a personal account of research on myogenesis and cardiogenesis. Curr. Top. Dev. Biol. 116, 135–151 (2016).

    CAS  PubMed  Google Scholar 

  70. Chang, N. C. & Rudnicki, M. A. Satellite cells: the architects of skeletal muscle. Curr. Top. Dev. Biol. 107, 161–181 (2014).

    CAS  PubMed  Google Scholar 

  71. Mercola, M., Ruiz-Lozano, P. & Schneider, M. D. Cardiac muscle regeneration: lessons from development. Genes Dev. 25, 299–309 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Chong, J. J., Forte, E. & Harvey, R. P. Developmental origins and lineage descendants of endogenous adult cardiac progenitor cells. Stem Cell Res. 13, 592–614 (2014).

    CAS  PubMed  Google Scholar 

  73. Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Chien, K. R. et al. Regenerating the field of cardiovascular cell therapy. Nat. Biotechnol. 37, 232–237 (2019).

    CAS  PubMed  Google Scholar 

  75. Mauro, A. Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol. 9, 493–495 (1961).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Buckingham, M. & Rigby, P. W. Gene regulatory networks and transcriptional mechanisms that control myogenesis. Dev. Cell 28, 225–238 (2014).

    CAS  PubMed  Google Scholar 

  77. Zammit, P. S. et al. Muscle satellite cells adopt divergent fates: a mechanism for self-renewal? J. Cell Biol. 166, 347–357 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M. A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012).

    CAS  PubMed  Google Scholar 

  79. Guiraud, S. et al. The pathogenesis and therapy of muscular dystrophies. Annu. Rev. Genomics Hum. Genet. 16, 281–308 (2015).

    CAS  PubMed  Google Scholar 

  80. Partridge, T. A., Morgan, J. E., Coulton, G. R., Hoffman, E. P. & Kunkel, L. M. Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature 337, 176–179 (1989).

    CAS  PubMed  Google Scholar 

  81. Miller, R. G. et al. Myoblast implantation in Duchenne muscular dystrophy: the San Francisco study. Muscle Nerve 20, 469–478 (1997).

    CAS  PubMed  Google Scholar 

  82. Gussoni, E. et al. Normal dystrophin transcripts detected in Duchenne muscular dystrophy patients after myoblast transplantation. Nature 356, 435–438 (1992).

    CAS  PubMed  Google Scholar 

  83. Péault, B. et al. Stem and progenitor cells in skeletal muscle development, maintenance, and therapy. Mol. Ther. 15, 867–877 (2007).

    PubMed  Google Scholar 

  84. Périé, S. et al. Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study. Mol. Ther. 22, 219–225 (2014).

    PubMed  Google Scholar 

  85. Boyer, O. et al. Autologous myoblasts for the treatment of fecal incontinence: results of a phase 2 randomized placebo-controlled study (MIAS). Ann. Surg. 267, 443–450 (2018).

    PubMed  Google Scholar 

  86. Peters, K. M. et al. Autologous muscle derived cells for treatment of stress urinary incontinence in women. J. Urol. 192, 469–476 (2014).

    PubMed  Google Scholar 

  87. Lin, C. S. & Lue, T. F. Stem cell therapy for stress urinary incontinence: a critical review. Stem Cells Dev. 21, 834–843 (2012).

    CAS  PubMed  Google Scholar 

  88. Mitchell, K. J. et al. Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development. Nat. Cell Biol. 12, 257–266 (2010).

    CAS  PubMed  Google Scholar 

  89. Joe, A. W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Dellavalle, A. et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat. Cell Biol. 9, 255–267 (2007).

    CAS  PubMed  Google Scholar 

  91. Dellavalle, A. et al. Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nat. Commun. 2, 499 (2011).

    CAS  PubMed  Google Scholar 

  92. Cossu, G. et al. Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy. EMBO Mol. Med. 7, 1513–1528 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Clifford, D. M. et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst. Rev. 2012, CD006536 (2012).

    Google Scholar 

  94. Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).

    CAS  PubMed  Google Scholar 

  95. Zhang, Y., Mignone, J. & MacLellan, W. R. Cardiac Regeneration and Stem Cells. Physiol. Rev. 95, 1189–1204 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Harvey, R. P., Graham, R. M. & Pu, W. T. Introduction to the special issue on heart regeneration and rejuvenation. Stem Cell Res. 13, 521–522 (2014).

    PubMed  PubMed Central  Google Scholar 

  97. Gerbin, K. A. & Murry, C. E. The winding road to regenerating the human heart. Cardiovasc. Pathol. 24, 133–140 (2015).

    PubMed  PubMed Central  Google Scholar 

  98. Li, Y. et al. Genetic lineage tracing of non-myocyte population by dual recombinases. Circulation 138, 793–805 (2018).

    CAS  PubMed  Google Scholar 

  99. Lee, J. H., Protze, S. I., Laksman, Z., Backx, P. H. & Keller, G. M. Human pluripotent stem cell-derived atrial and ventricular cardiomyocytes develop from distinct mesoderm populations. Cell Stem Cell 21, 179–194.e174 (2017).

    CAS  PubMed  Google Scholar 

  100. Giacomelli, E., Mummery, C. L. & Bellin, M. Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes. Cell. Mol. Life Sci. 74, 3711–3739 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Yang, X., Pabon, L. & Murry, C. E. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114, 511–523 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Liu, Y. W. et al. Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat. Biotechnol. 36, 597–605 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Veerman, C. C. et al. Immaturity of human stem-cell-derived cardiomyocytes in culture: fatal flaw or soluble problem? Stem Cells Dev. 24, 1035–1052 (2015).

    CAS  PubMed  Google Scholar 

  104. Coulombe, K. L., Bajpai, V. K., Andreadis, S. T. & Murry, C. E. Heart regeneration with engineered myocardial tissue. Annu. Rev. Biomed. Eng. 16, 1–28 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Fu, J. D. & Srivastava, D. Direct reprogramming of fibroblasts into cardiomyocytes for cardiac regenerative medicine. Circ. J. 79, 245–254 (2015).

    PubMed  Google Scholar 

  106. Farouz, Y., Chen, Y., Terzic, A. & Menasché, P. Concise review: growing hearts in the right place: on the design of biomimetic materials for cardiac stem cell differentiation. Stem Cells 33, 1021–1035 (2015).

    CAS  PubMed  Google Scholar 

  107. D’Uva, G. et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat. Cell Biol. 17, 627–638 (2015).

    PubMed  Google Scholar 

  108. Mikkers, H. M., Freund, C., Mummery, C. L. & Hoeben, R. C. Cell replacement therapies: is it time to reprogram? Hum. Gene Ther. 25, 866–874 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Bianco, P. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19, 35–42 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Bianco, P., Robey, P. G. & Simmons, P. J. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2, 313–319 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Owen, M. & Friedenstein, A. J. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found. Symp. 136, 42–60 (1988).

    CAS  PubMed  Google Scholar 

  112. Bianco, P. & Robey, P.G. in Handbook of Adult and Fetal Stem Cells (eds Lanza, R. et al.) 415–424 (San Diego, Academic Press, 2004).

  113. Caplan, A. I. Mesenchymal stem cells. J. Orthop. Res. 9, 641–650 (1991).

    CAS  PubMed  Google Scholar 

  114. Bianco, P. & Robey, P. G. Skeletal stem cells. Development 142, 1023–1027 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Galipeau, J. & Sensébé, L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22, 824–833 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kuriyan, A. E. et al. Vision loss after intravitreal injection of autologous “stem cells” for AMD. N. Engl. J. Med. 376, 1047–1053 (2017).

    PubMed  PubMed Central  Google Scholar 

  117. Caplan, A. I. & Correa, D. The MSC: an injury drugstore. Cell Stem Cell 9, 11–15 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Phinney, D. G. & Prockop, D. J. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views. Stem Cells 25, 2896–2902 (2007).

    PubMed  Google Scholar 

  119. Bianco, P. et al. Regulation of stem cell therapies under attack in Europe: for whom the bell tolls. EMBO J. 32, 1489–1495 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Bartunek, J. et al. Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. Eur. Heart J. 38, 648–660 (2017).

    CAS  PubMed  Google Scholar 

  121. Herreros, M. D., Garcia-Arranz, M., Guadalajara, H., De-La-Quintana, P. & Garcia-Olmo, D. Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. Dis. Colon Rectum 55, 762–772 (2012).

    CAS  PubMed  Google Scholar 

  122. Sipp, D., Robey, P. G. & Turner, L. Clear up this stem-cell mess. Nature 561, 455–457 (2018).

    CAS  PubMed  Google Scholar 

  123. Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

    CAS  PubMed  Google Scholar 

  124. Sacchetti, B. et al. No identical “mesenchymal stem cells” at different times and sites: human committed progenitors of distinct origin and differentiation potential are incorporated as adventitial cells in microvessels. Stem Cell Reports 6, 897–913 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Shi, S. & Gronthos, S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J. Bone Miner. Res. 18, 696–704 (2003).

    PubMed  Google Scholar 

  126. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

    CAS  PubMed  Google Scholar 

  127. Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G. & Morrison, S. J. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154–168 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Guimaraes-Camboa, N. et al. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20, 345–359.e345 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Quarto, R. et al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N. Engl. J. Med. 344, 385–386 (2001).

    CAS  PubMed  Google Scholar 

  130. Lee, J. et al. Successful reconstruction of 15-cm segmental defects by bone marrow stem cells and resected autogenous bone graft in central hemangioma. J. Oral Maxillofac. Surg. 68, 188–194 (2010).

    PubMed  Google Scholar 

  131. Yamada, Y., Ueda, M., Hibi, H. & Baba, S. A novel approach to periodontal tissue regeneration with mesenchymal stem cells and platelet-rich plasma using tissue engineering technology: a clinical case report. Int. J. Periodontics Restorative Dent. 26, 363–369 (2006).

    PubMed  Google Scholar 

  132. Robey, P. G. Cell sources for bone regeneration: the good, the bad, and the ugly (but promising). Tissue Eng. Part B Rev. 17, 423–430 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Nakashima, M. et al. Pulp regeneration by transplantation of dental pulp stem cells in pulpitis: a pilot clinical study. Stem Cell Res. Ther. 8, 61 (2017).

    PubMed  PubMed Central  Google Scholar 

  134. Bachoud-Lévi, A. C. From open to large-scale randomized cell transplantation trials in Huntington’s disease: lessons from the multicentric intracerebral grafting in Huntington’s disease trial (MIG-HD) and previous pilot studies. Prog. Brain Res. 230, 227–261 (2017).

    PubMed  Google Scholar 

  135. Barker, R. A., Drouin-Ouellet, J. & Parmar, M. Cell-based therapies for Parkinson disease—past insights and future potential. Nat. Rev. Neurol. 11, 492–503 (2015).

    CAS  PubMed  Google Scholar 

  136. Barker, R. A., Parmar, M., Studer, L. & Takahashi, J. Human trials of stem cell-derived dopamine neurons for Parkinson’s disease: dawn of a new era. Cell Stem Cell 21, 569–573 (2017).

    CAS  PubMed  Google Scholar 

  137. Kalladka, D. et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet 388, 787–796 (2016).

    PubMed  Google Scholar 

  138. Lindvall, O. & Kokaia, Z. Stem cell research in stroke: how far from the clinic? Stroke 42, 2369–2375 (2011).

    PubMed  Google Scholar 

  139. Shirai, H. et al. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration. Proc. Natl Acad. Sci. USA 113, E81–E90 (2016).

    CAS  PubMed  Google Scholar 

  140. Whiting, P., Kerby, J., Coffey, P., da Cruz, L. & McKernan, R. Progressing a human embryonic stem-cell-based regenerative medicine therapy towards the clinic. Phil. Trans. R. Soc. Lond. B 370, 20140375 (2015).

    Google Scholar 

  141. Priest, C. A., Manley, N. C., Denham, J., Wirth, E. D. III & Lebkowski, J. S. Preclinical safety of human embryonic stem cell-derived oligodendrocyte progenitors supporting clinical trials in spinal cord injury. Regen. Med. 10, 939–958 (2015).

    CAS  PubMed  Google Scholar 

  142. da Cruz, L. et al. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat. Biotechnol. 36, 328–337 (2018).

    PubMed  Google Scholar 

  143. Mandai, M., Kurimoto, Y. & Takahashi, M. Autologous induced stem-cell-derived retinal cells for macular degeneration. N. Engl. J. Med. 377, 792–793 (2017).

    PubMed  Google Scholar 

  144. Damier, P., Hirsch, E. C., Agid, Y. & Graybiel, A. M. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 122, 1437–1448 (1999).

    PubMed  Google Scholar 

  145. Jenner, P. Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson’s disease. Curr. Opin. Neurol. 16 Suppl 1, S3–S7 (2003).

    PubMed  Google Scholar 

  146. Huot, P., Johnston, T. H., Koprich, J. B., Fox, S. H. & Brotchie, J. M. The pharmacology of L-DOPA-induced dyskinesia in Parkinson’s disease. Pharmacol. Rev. 65, 171–222 (2013).

    CAS  PubMed  Google Scholar 

  147. Lindvall, O. et al. Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease. A detailed account of methodology and a 6-month follow-up. Arch. Neurol. 46, 615–631 (1989).

    CAS  PubMed  Google Scholar 

  148. Lindvall, O. et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 247, 574–577 (1990).

    CAS  PubMed  Google Scholar 

  149. Kefalopoulou, Z. et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 71, 83–87 (2014).

    PubMed  PubMed Central  Google Scholar 

  150. Piccini, P. et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nat. Neurosci. 2, 1137–1140 (1999).

    CAS  PubMed  Google Scholar 

  151. Kordower, J. H. et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N. Engl. J. Med. 332, 1118–1124 (1995).

    CAS  PubMed  Google Scholar 

  152. Li, W. et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc. Natl Acad. Sci. USA 113, 6544–6549 (2016).

    CAS  PubMed  Google Scholar 

  153. Li, J. Y. et al. Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson’s disease. Mov. Disord. 25, 1091–1096 (2010).

    PubMed  Google Scholar 

  154. Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 14, 504–506 (2008).

    CAS  PubMed  Google Scholar 

  155. Ribeiro, D. et al. Efficient expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells by midbrain morphogens. Neurobiol. Dis. 49, 118–127 (2013).

    CAS  PubMed  Google Scholar 

  156. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  PubMed  Google Scholar 

  157. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Google Scholar 

  158. Kriks, S. et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 480, 547–551 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Kirkeby, A. et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 1, 703–714 (2012).

    CAS  PubMed  Google Scholar 

  160. Grealish, S. et al. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson’s disease. Cell Stem Cell 15, 653–665 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Kikuchi, T. et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature 548, 592–596 (2017).

    CAS  PubMed  Google Scholar 

  162. Kirkeby, A., Parmar, M. & Barker, R. A. Strategies for bringing stem cell-derived dopamine neurons to the clinic: a European approach (STEM-PD). Prog. Brain Res. 230, 165–190 (2017).

    PubMed  Google Scholar 

  163. Studer, L. Strategies for bringing stem cell-derived dopamine neurons to the clinic-The NYSTEM trial. Prog. Brain Res. 230, 191–212 (2017).

    PubMed  Google Scholar 

  164. Takahashi, J. Strategies for bringing stem cell-derived dopamine neurons to the clinic: the Kyoto trial. Prog. Brain Res. 230, 213–226 (2017).

    PubMed  Google Scholar 

  165. Abbott, A. Fetal-cell revival for Parkinson’s. Nature 510, 195–196 (2014).

    CAS  PubMed  Google Scholar 

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Acknowledgements

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

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Author notes

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

Authors and Affiliations

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

    Michele De Luca

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

    Alessandro Aiuti

  3. Vita-Salute San Raffaele University, Milan, Italy

    Alessandro Aiuti

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

    Giulio Cossu

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

    Malin Parmar

  6. Lund Stem Cell Center, Lund University, Lund, Sweden

    Malin Parmar

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

    Graziella Pellegrini

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

    Pamela Gehron Robey

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Correspondence to Michele De Luca.

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Competing interests

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

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

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