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  • Review Article
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Patient-specific pluripotent stem cells: promises and challenges

Nature Reviews Endocrinology volume 5, pages 195–203 (2009)Cite this article

Abstract

Tissue transplantation is a well-established tool for the treatment of degenerative and malignant disorders, yet its use in clinical practice is hampered by the need for human-leukocyte-antigen-compatible donors and a shortage of suitable graft tissue. The discovery of human embryonic stem cells a decade ago raised hopes that a universal resource for the cell-based treatment of various conditions would soon become available. Embryonic stem cells derived by somatic-cell nuclear transfer or parthenogenesis can provide human-leukocyte-antigen-matched cells, which may be transplanted without the need for immunosuppressive treatment. However, technical hurdles and ethical concerns about use of oocytes and involvement of embryos have limited the clinical use of these cells. An alternative approach involves adult somatic cells being reprogrammed to enter a pluripotent state. Such manipulation of these readily available cells has enabled derivation of patient-specific, pluripotent stem-cell lines, without progression through the blastocyst stage. This Review critically analyzes the currently available methods for the generation of pluripotent stem cells, and discusses prospects for their clinical use.

Key Points

  • Patient-specific, pluripotent stem cells are a potential resource for cell-replacement therapies in various degenerative or malignant disorders, and can be used without concomitant immunosuppressive therapy

  • Pluripotent stem cells are usually obtained by in vitro culture of the inner-cell mass of blastocyst-stage embryos but alternative methods have now been developed

  • Somatic-cell nuclear transfer can generate isogenic, pluripotent stem cells from mammalian species, but has low efficiency, requires oocyte donation, and has not yet been successfully performed with human cells

  • Direct oocyte activation (parthenogenesis) or isolation of specific testis-derived cells can result in human-leukocyte-antigen-matched, pluripotent stem cells; however, uniparental imprinting could limit their clinical application

  • Genetic modification with embryonic-stem-cell-specific proteins can reprogram human adult somatic cells to a pluripotent state, which thereby generates isogenic-induced, pluripotent stem cells without the involvement of oocytes or embryos

  • Current research aims to establish protocols that allow pluripotent stem-cell-derived therapies to enter clinical practice (for example, protocols for reprogramming adult somatic cells without viral integration or use of oncoproteins)

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Figure 1: Derivation of pluripotent stem cells.
Figure 2: Human-induced pluripotent stem cells growing on mouse embryonic fibroblast feeder cells.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Evans, M. J. & Kaufman M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).

    Article  CAS  PubMed  Google Scholar 

  3. Martin, G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634–7638 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brinster, R. L. The effect of cells transferred into the mouse blastocyst on subsequent development. J. Exp. Med. 140, 1049–1056 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nagy, A. et al. Embryonic stem cells alone are able to support fetal development in the mouse. Development 110, 815–821 (1990).

    CAS  PubMed  Google Scholar 

  6. Brivanlou, A. H. et al. Stem cells. Setting standards for human embryonic stem cells. Science 300, 913–916 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Lensch, M. W. et al. Teratoma formation assays with human embryonic stem cells: a rationale for one type of human–animal chimera. Cell Stem Cell 1, 253–258 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. De Coppi, P. et al. Isolation of amniotic stem cell lines with potential for therapy. Nat. Biotechnol. 25, 100–106 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Doetschman, T. C. et al. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J. Embryol. Exp. Morphol. 87, 27–45 (1985).

    CAS  PubMed  Google Scholar 

  10. Wiles, M. V. & Keller, G. Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture. Development 111, 259–267 (1991).

    CAS  PubMed  Google Scholar 

  11. Lengerke, C. et al. BMP and Wnt specify hematopoietic fate by activation of the Cdx–Hox pathway. Cell Stem Cell 2, 72–82 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Ueno, S. et al. Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proc. Natl Acad. Sci. USA 104, 9685–9690 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gadue, P. et al. Germ layer induction from embryonic stem cells. Exp. Hematol. 33, 955–964 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Gadue, P. et al. Wnt and TGF-β signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc. Natl Acad. Sci. USA 103, 16806–16811 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nostro, M. C. et al. Wnt, activin, and BMP signaling regulate distinct stages in the developmental pathway from embryonic stem cells to blood. Cell Stem Cell 2, 60–71 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Murry, C. E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Drukker, M. et al. Characterization of the expression of MHC proteins in human embryonic stem cells. Proc. Natl Acad. Sci. USA 99, 9864–9869 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sheldon, S. & Poulton K. HLA typing and its influence on organ transplantation. Methods Mol. Biol. 333, 157–174 (2006).

    CAS  PubMed  Google Scholar 

  19. Taylor, C. J. et al. Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 366, 2019–2025 (2005).

    Article  PubMed  Google Scholar 

  20. Briggs, R. & King T. J. Transplantation of living nuclei from blastula cells into enucleated frogs' eggs. Proc. Natl Acad. Sci. USA 38, 455–463 (1952).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gurdon, J. B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962).

    CAS  PubMed  Google Scholar 

  22. Gurdon, J. B. Adult frogs derived from the nuclei of single somatic cells. Dev. Biol. 4, 256–273 (1962).

    Article  CAS  PubMed  Google Scholar 

  23. Cibelli, J. Developmental biology. A decade of cloning mystique. Science 316, 990–992 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Wilmut, I. et al. Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Byrne, J. A. et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 450, 497–502 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Stojkovic, M. et al. Derivation of a human blastocyst after heterologous nuclear transfer to donated oocytes. Reprod. Biomed. Online 11, 226–231 (2005).

    Article  PubMed  Google Scholar 

  27. Rideout, W. M. 3rd et al. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 109, 17–27 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Kyba, M. et al. HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109, 29–37 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Hochedlinger, K & Jaenisch, R. Nuclear reprogramming and pluripotency. Nature 441, 1061–1067 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Kishigami, S. et al. Significant improvement of mouse cloning technique by treatment with trichostatin A after somatic nuclear transfer. Biochem. Biophys. Res. Commun. 340, 183–189 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Brambrink, T. et al. ES cells derived from cloned and fertilized blastocysts are transcriptionally and functionally indistinguishable. Proc. Natl Acad. Sci. USA 103, 933–938 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Egli, D. et al. Developmental reprogramming after chromosome transfer into mitotic mouse zygotes. Nature 447, 679–685 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Klimanskaya, I. et al. Human embryonic stem cell lines derived from single blastomeres. Nature 444, 481–485 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Rougier, N. & Werb, Z. Minireview: parthenogenesis in mammals. Mol. Reprod. Dev. 59, 468–474 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Revazova, E. S. et al. Patient-specific stem cell lines derived from human parthenogenetic blastocysts. Cloning Stem Cells 9, 432–449 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Cibelli, J. B. et al. Embryonic stem cells from parthenotes. Methods Enzymol. 418, 117–135 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Kim, K. et al. Histocompatible embryonic stem cells by parthenogenesis. Science 315, 482–486 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Kono, T. et al. Birth of parthenogenetic mice that can develop to adulthood. Nature 428, 860–864 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Thomson, J. A. & Solter, D. The developmental fate of androgenetic, parthenogenetic, and gynogenetic cells in chimeric gastrulating mouse embryos. Genes Dev. 2, 1344–1351 (1988).

    Article  CAS  PubMed  Google Scholar 

  40. Lengerke, C. et al. Differentiation potential of histocompatible parthenogenetic embryonic stem cells. Ann. NY Acad. Sci. 1106, 209–218 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Miller, R. A. & Ruddle, F. H. Pluripotent teratocarcinoma-thymus somatic cell hybrids. Cell 9, 45–55 (1976).

    Article  CAS  PubMed  Google Scholar 

  42. Cowan, C. A. et al. Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309, 1369–1373 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Yu, J. et al. Human embryonic stem cells reprogram myeloid precursors following cell–cell fusion. Stem Cells 24, 168–176 (2006).

    Article  PubMed  Google Scholar 

  44. Matsumura, H. et al. Targeted chromosome elimination from ES-somatic hybrid cells. Nat. Methods 4, 23–25 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Takahashi K & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Yamanaka, S. Pluripotency and nuclear reprogramming. Philos. Trans. R. Soc. Lond. Biol. Sci. 363, 2079–2087 (2008).

    Article  CAS  Google Scholar 

  47. Maherali, N. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55–70 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Okita, K. et al. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Meissner, A. et al. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat. Biotechnol. 25, 1177–1181 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  52. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Park, I. H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Park, I. H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Aoi, T. et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321, 699–702 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Eminli, S. et al. Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cells 26, 2467–2474 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Stadtfeld, M. et al. Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr. Biol. 18, 890–894 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hanna, J. et al. Direct reprogramming of terminally differentiated mature B–lymphocytes to pluripotency. Cell 133, 250–264 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Silva, J. et al. Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS Biol. 6, e253 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kim, J. B. et al. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454, 646–650 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Huangfu, D. et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat. Biotechnol. 26, 1269–1275 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Gidekel, S. et al. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 4, 361–370 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Huangfu, D. et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat. Biotechnol. 26, 795–797 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shi, Y. et al. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2, 525–528 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Stadtfeld, M. et al. Induced pluripotent stem cells generated without viral integration. Science 322, 945–949 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Okita, K. et al. Generation of mouse-induced pluripotent stem cells without viral vectors. Science 322, 949–953 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Zhou, Q. et al. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627–632 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jiang, Y. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Donovan, P. J. & de Miguel, M. P. Turning germ cells into stem cells. Curr. Opin. Genet. Dev. 13, 463–471 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Kanatsu-Shinohara, M. et al. Generation of pluripotent stem cells from neonatal mouse testis. Cell 119, 1001–1012 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Guan, K. et al. Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 440, 1199–1203 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Conrad, S. et al. Generation of pluripotent stem cells from adult human testis. Nature 456, 344–349 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

C Lengerke is supported by grants from the Deutsche Forschungsgemeinschaft (SFB773), the Max-Eder-Program of the Deutsche Krebshilfe and the Fortüne Program of the University of Tübingen. The authors thank Lothar Kanz (University of Tübingen Medical Center II) for critical reading of the manuscript and George Daley (Children's Hospital Boston) for providing the hFib2-iPS5 cell line.

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  1. Department of Hematology and Oncology, Laboratory for Developmental Biology, University of Tübingen Medical Center II, Tübingen, Germany

    Rouven Müller & Claudia Lengerke

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Correspondence to Claudia Lengerke.

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Müller, R., Lengerke, C. Patient-specific pluripotent stem cells: promises and challenges. Nat Rev Endocrinol 5, 195–203 (2009). https://doi.org/10.1038/nrendo.2009.18

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