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Embryonic stem cells as a source of models for drug discovery

Nature Reviews Drug Discovery volume 6, pages 605–616 (2007)Cite this article

Abstract

Embryonic stem cells (ESCs) will become a source of models for a wide range of adult differentiated cells, providing that reliable protocols for directed differentiation can be established. Stem-cell technology has the potential to revolutionize drug discovery, making models available for primary screens, secondary pharmacology, safety pharmacology, metabolic profiling and toxicity evaluation. Models of differentiated cells that are derived from mouse ESCs are already in use in drug discovery, and are beginning to find uses in high-throughput screens. Before analogous human models can be obtained in adequate numbers, reliable methods for the expansion of human ESC cultures will be needed. For applications in drug discovery, involving either species, protocols for directed differentiation will need to be robust and affordable. Here, we explore current challenges and future opportunities in relation to the use of stem-cell technology in drug discovery, and address the use of both mouse and human models.

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Figure 1: Use of mouse ESCs, or committed precursor cells obtained from ESCs, in drug discovery and development.
Figure 2: Selection can be used to enrich populations with target cells.
Figure 3: General protocol for obtaining mouse dopaminergic neurons from mouse ESCs.
Figure 4: Results of a typical in vitro differentiation experiment for dopaminergic neurons.
Figure 5: General scheme for development of a drug discovery platform based on the use of transformed ESCs.

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References

  1. Hook, L., O'Brian, C. & Allsopp, T. E. ES cell technology: an introduction to genetic manipulation, differentiation, and therapeutic cloning. Adv. Drug Delivery Rev. 57, 1904–1917 (2005).

    Article  CAS  Google Scholar 

  2. Zhao, S. et al. Generation of embryonic stem cells and transgenic mice expressing green fluorescence protein in midbrain dopaminergic neurons. Eur. J. Neurosci. 19, 1133–1140 (2004).

    Article  PubMed  Google Scholar 

  3. Schindehutte, J. et al. In vivo and in vitro tissue-specific expression of green fluorescent protein using the CRE-lox system in mouse embryonic stem cells. Stem Cells 23, 10–15 (2005).

    Article  PubMed  CAS  Google Scholar 

  4. Elaut, G. et al. Molecular mechanisms underlying the dedifferentiation process of isolated hepatocytes and their cultures. Curr. Drug Metab. 7, 629–660 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Smith, A. G. et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336, 688–690 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Williams, R. L. et al. Myeloid leukemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336, 684–687 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. Niwa, H., Burdon, T., Chambers, I. & Smith, A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 12, 2048–2060 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 115, 281–292 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Ludwig, T. E. et al. Derivation of human embryonic stem cells in defined conditions. Nature Biotech. 24, 185–187 (2006).

    Article  CAS  Google Scholar 

  11. Trounson, A. The production and directed differentiation of human embryonic stem cells. Endocrine Rev. 27, 208–219 (2007).

    Article  Google Scholar 

  12. Thomson, J. A. & Odorico, J. S. Human embryonic stem cell and embryonic germ cell lines. Trends Biotechnol. 18, 53–57 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Daheron, L. et al. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells 22, 770–778 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Rosler, E. S. et al. Long-term culture of human embryonic stem cells in feeder-free conditions. Dev. Dyn. 229, 259–274 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Carpenter, M. K. et al. Properties of four human embryonic stem cell lines maintained in a feeder-free culture system. Dev. Dyn. 229, 243–258 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Xu, R. H. et al. Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nature Methods 2, 185–190 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Xu, C. et al. Basic fibroblast growth factor supports undifferentiated human embryonic stem cell growth without conditioned medium. Stem Cells 23, 315–323 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Pera, M. F. & Trounson, A. O. Human embryonic stem cells: prospects for development. Development 131, 5515–5525 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Pera, M. F. Stem cell culture, one step at a time. Nature Methods 2, 164–165 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Hoffman, L. M. & Carpenter, M. K. Characterization and culture of human embryonic stem cells. Nature Biotech. 23, 699–708 (2005).

    Article  CAS  Google Scholar 

  21. Xiao, L., Xuan, Y. & Sharkis, S. J. Activin A maintains self-renewal and regulates fibroblast growth factor, Wnt and bone morphogenetic protein pathways in human embryonic stem cells. Stem Cells 24, 1476–1486 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Beattie, G. M. et al. Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers. Stem Cells 23, 489–495 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. James, D., Levine, A. J., Besser, D. & Hemmati-Brivanlou, A. TGFβ/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryoinic stem cells. Development 132, 1273–1282 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Ogawa, K. et al. Activin-nodal signalling is involved in propagation of mouse embryonic stem cells. J. Cell Sci. 120, 55–65 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Vallier, L., Alexander, M. & Pedersen, R. A. Activin/nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J. Cell Sci. 118, 4495–4509 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Mallon, B. S., Park, K-Y., Che, K. G., Hamilton, R. S. & McKay, R. D. G. Toward xeno-free culture of human embryonic stem cells. Int. J. Biochem. Cell Biol. 38, 1063–1075 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lu, J., Hou, R., Booth, C. J., Yang, S-H. & Snyder, M. Defined culture conditions of human embryonic stem cells. Proc. Natl Acad. Sci. USA 103, 5688–5693 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yao, S. et al. Long-term self-renewal and directed differentiation of human embryonic stem cells in chemically defined conditions. Proc. Natl Acad. Sci. USA 103, 6907–6912 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Buzzard, J. J., Gough, N. M., Crook, J. M. & Colman, A. Karyotype of human ES cells during extended culture. Nature Biotech. 22, 381–382 (2004).

    Article  CAS  Google Scholar 

  30. Draper, J. S. et al. Recurrent gain of chromosomes 17q and12 in cultured human embryonic stem cells. Nature Biotech. 22, 53–54 (2004).

    Article  CAS  Google Scholar 

  31. Brimble. S. N. et al. Karyotypic stability, genotyping, differentiation, feeder-free maintenance, and gene expression sampling in three human embryonic stem cell lines derived prior to August 9, 2001. Stem Cells Dev. 13, 585–597 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Doetschman, T. C., Eistetter, H., Katz, M., Schmidt, W. & Kemler, R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of a visceral yolk sac, blood islands and myocardium. J. Embryol. Exp. Morphol. 87, 27–45 (1985).

    CAS  PubMed  Google Scholar 

  33. Smith, A. G. Embryo-derived stem cells: of mice and men. Annu. Rev. Cell Dev. Biol. 17, 435–462 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Gorba, T. & Allsopp, T. E. Pharmacological potential of embryonic stem cells. Pharmacol. Res. 47, 269–278 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Keller, G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 19, 1129–1155 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Nishikawa, S. I., Nishikawa, S., Hirashima, M., Matsuyoshi, N. & Kodama, H. Progressive lineage analysis by cell sorting and culture identifies FLK1+ve-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development 125, 1747–1757 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Yamashita, J. et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors, Nature 408, 92–96 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Tropepe, V. et al. Direct neural fate specification from embryonic stem cells: a primitive mammalian stem cell stage acquired through a default mechanism. Neuron 30, 65–78 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Bouhon, I. A, Kato, H., Chandran, S. & Allen, N. D. Neural differentiation of mouse embryonic stem cells in chemically defined medium. Brain Res. Bull. 68, 62–75 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Ying, Q-L., Stavridis, M., Griffiths, D., Li, M. & Smith, A. Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture, Nature Biotech. 21, 183–186 (2003).

    Article  CAS  Google Scholar 

  41. Li, M., Pevny, L., Lovell-Badge, R. & Smith, A. Generation of purified neural precursors from embryonic stem cells by lineage selection. Curr. Biol. 8, 971–974 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Klug, M. G., Soonpaa, M. H., Koh, G. Y. & Fields, L. J. Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J. Clin. Invest. 98, 216–224 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hancock, C. R., Wetherington, J. P., Lambert, N. A. & Condie, B. G. Neuronal differentiation of cryopreserved neural progenitor cells derived from mouse embryonic stem cells. Biochem. Biophys. Res. Commun. 271, 418–421 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Conti, L et al. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biology 3, 1594–1606 (2005).

    Article  CAS  Google Scholar 

  45. Maltsev, V. A., Rohwedel, J., Hescheler, J. & Wobus, A. M. Embryonic stem cells differentiate in vitro into cardiomyocytes representing sinusnodol, atrial and ventricular cell types. Mech. Dev. 44, 41–50 (1993).

    Article  CAS  PubMed  Google Scholar 

  46. Rohwedel, J. et al. Muscle cell differentiation of embryonic stem cells reflects myogenesis in vivo: developmentally regulated expression of myogenic determination genes and functional expression of ionic currents Dev. Biol. 164, 87–101 (1994).

    Article  CAS  PubMed  Google Scholar 

  47. Strübing, C. et al. Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons. Mech. Dev. 53, 275–287 (1995).

    Article  PubMed  Google Scholar 

  48. Bagutti, C., Wobus, A. M., Fässler, R. & Watt, F. M. Differentiation of embryonal stem cells into keratinocytes: comparison of wild-type and β1-integrin deficient cells. Dev. Biol. 179, 184–196 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Yamane, T., Hayashi, S. I., Mizoguchi, M., Yamazaki, H. & Kunisada, T. Derivation of melanocytes from embryonic stem cells in culture. Dev. Dyn. 216, 450–458 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Fairchild, P. J. et al. Directed differentiation of dendritic cells from mouse embryonic stem cells. Curr. Biol. 10, 1515–1518 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Nakano, T., Kodama, H. & Honjo T. In vitro development of primitive and definitive erythrocytes from different precursors. Science 272, 722–724 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Jones, E. A., Tosh, D., Wilson, D. I., Lindsay, S. & Forrester, L. M. Hepatic differentiation of murine embryonic stem cells. Exp. Cell Res. 272, 15–22 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Weintraub, H. et al. The myoD gene family: nodal point during specification of the muscle cell lineage. Science 251, 761–766 (1991).

    Article  CAS  PubMed  Google Scholar 

  54. Dekel, I., Magal, Y., Pearson-White, S., Emmerson, C. P. & Shani, M. Conditional conversion of ES cells to skeletal muscle by an exogenous myoD1 gene. New Biol. 4, 217–224 (1992).

    CAS  PubMed  Google Scholar 

  55. Levinson-Dushnik, M. & Benevisty, N. Involvement of hepatocyte nuclear factor 3 in endoderm differentiation of embryonic stem cells. Mol. Cell. Biol. 17, 3817–3822 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kim, J. H. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50–56 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. D'Souza, S. L., Elefanty, A. G. & Keller, G. SCL/Tal-1 is essential for hematopoietic commitment of the hemangioblast but not for its development. Blood 105, 3862–3870 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lacaud, G., Keller, G. & Kouskoff, V. Tracking mesoderm formation and specification to the hemangioblast in vitro. Trends Cardiovasc. Med. 14, 314–317 (2004).

    Article  PubMed  Google Scholar 

  59. Lee, S. H., Lumelsky, N., Studer, L., Auerbach, J. M. & McKay, R. D. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nature Biotech. 18, 675–679 (2000).

    Article  CAS  Google Scholar 

  60. Carpenter, M. K. et al. Enrichment of neurons and neural precursors from human embryonic stem cells. Exp. Neurol. 172, 383–397 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Park, C. H. et al. In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J. Neurochem. 92, 1265–1276 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Lang, R. J. et al. Electrical and neurotransmitter activity of mature neurons derived from mouse embryonic stem cells by Sox-1 lineage selection and directed differentiation. Eur. J. Neurosci. 20, 3209–3221 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Raye, W. S., Tochon-Danguy, N., Pouton, C. W. & Haynes, J. M. Heterogeneous population of dopaminergic neurons derived from mouse embryonic stem cells: preliminary phenotyping based on receptor expression & function. Eur. J. Neurosci. 25, 1961–1970 (2007).

    Article  PubMed  Google Scholar 

  64. Munoz-Sanjuan, I. & Brivanlou A. H. Neural induction, the default model and embryonic stem cells. Nature Rev. Neurosci. 3, 271–280 (2002).

    Article  CAS  Google Scholar 

  65. Rathjen, J. & Rathjen, P. J. Formation of neural precursor cell populations by differentiation of embryonic stem cells in vitro. Scientific WorldJournal 2, 690–700 (2002).

    Article  CAS  Google Scholar 

  66. Zhao, S., Nichols, J., Smith, A. G. & Li, M. SoxB transcription factors specify neurectodermal lineage choice in ES cells. Mol. Cell. Neurosci. 27, 332–342 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Aubert, J. et al. Screening for mammalian neural genes via fluorescence-activated cell sorter purification of neural precursors from Sox1-gfp knock-in mice. Proc. Natl Acad. Sci. USA 100, 11836–11841 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lang, K. J. D., Rathjen, J., Vassilieva, S. & Rathjen, P. D. Differentiation of embryonic stem cells to a neural fate: a route to re-building the nervous system. J. Neurosci. Res. 76, 184–192 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Kawasaki, H., Mizuseki, K. & Sasai, Y. Selective neural induction from ES cells by stromal cell-derived inducing activity and its potential therapeutic application in Parkinson's disease. Methods Mol. Biol. 185, 217–227 (2002).

    CAS  PubMed  Google Scholar 

  70. Kawasaki, H. et al. Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc. Natl Acad. Sci. USA 99, 1580–1585 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mizuseki, K. et al. Generation of neural crest-derived peripheral neurons and floor plate cells from mouse and primate embryonic stem cells. Proc. Natl Acad. Sci. USA 100, 5828–5833 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Barberi, T. et al. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in Parkinsonian mice. Nature Biotech. 21, 1200–1207 (2003).

    Article  CAS  Google Scholar 

  73. Jain, M., Armstrong, R. J. E., Tyers, P., Barker, R. A. & Rosser, A. E. GABAergic immunoreactivity is predominant in neurons derived from expanded human neural precursors in vitro. Exp. Neurol. 182, 113–123 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Perrier, A. L. et al. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc. Natl Acad. Sci. USA 101, 12543–12548 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yan, Y. et al. Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 23, 781–790 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Reubinoff, B. E. et al. Neural progenitors from human embryonic stem cells. Nature Biotech. 19, 1134–1140 (2001).

    Article  CAS  Google Scholar 

  77. Zhang, S. C., Wernig, M., Duncan, I. D., Brustle, O. & Thomson. J. A. In vitro differentiation of transplantable neural precursors from human embryonic stem cells, Nature Biotech. 19, 1129–1133 (2001).

    Article  CAS  Google Scholar 

  78. Ng, E. S, Davis, R. P., Azzola, L., Stanley, E. G. & Elefanty, A. G. Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust reproducible hematopoietic differentiation. Blood 106, 1601–1603 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Sauer, H. et al. Involvement of reactive oxygen species in cardiotrohin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells. Exp. Cell Res. 294, 313–324 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Kanno, S. et al. Nitric oxide facilitates cardiomyogenesis in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 101, 12277–12281 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kehat, I. et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J. Clin. Invest. 108, 407–414 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Xu, C., Police, S., Rao, N. & Carpenter, M. K. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ. Res. 91, 501–508 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. He, J-Q, Ma, Y., Lee, Y., Thomson, J. A. & Kamp, T. J. Human embryonic stem cells develop into multiple types of cardiac myocytes. Circ. Res. 93, 32–39 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Xue, T. et al. Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes. Circ. Res. 111, 11–20 (2005).

    Article  Google Scholar 

  85. Wobus, A. M., Wallukat, G. & Hescheler, J. Pluripotent mouse embryonic stem cells are able to differentiate into cardiomyocytes expressing chronotropic responses to adrenergic and cholinergic agents and Ca2+ channel blockers. Differentiation 48, 173–182 (1991).

    Article  CAS  PubMed  Google Scholar 

  86. Igelmund, P. et al. Action potential propagation failures in long-term recordings from embryonic stem cell-derived cardiomyocytes in tissue culture. Pflugers Arch. 437, 669–679 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Banach, K., Halbach, M. D., Hu, P., Hescheler, J. & Egert, U. Development of electrical activity in cardiac myocyte aggregates derived from mouse embryonic stem cells. Am. J. Physiol. Heart Circ. Physiol. 284, H2114–H2123 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Reppel, M., Boettinger, C. & Hescheler, J. β-Adrenergic and muscarinic modulation of human embryonic stem cell-derived cardiomyocytes. Cell. Physiol. Biochem. 14, 187–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Hescheler, J. et al. Determination of electrical properties of ES cell-derived cardiomyocytes using MEAs. J. Electrocardiol. 37 (Suppl.), 110–116 (2004).

    Article  PubMed  Google Scholar 

  90. Ali, N. et al. β-Adrenoceptor subtype dependence of chronotropy in mouse embryonic stem cell-derived cardiomyocytes. Basic Res. Cardiol. 99, 382–391 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Dolnikov, K. et al. Functional properties of human embryonic stem cell-derived cardiomyocytes. Ann. NY Acad. Sci. 1047, 66–75 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Dolnikov, K. et al. Functional properties of human embryonic stem cell-derived cardiomyocytes: intracellular Ca2+ handling and the role of sarcoplasmic reticulum in the contraction. Stem Cells 24, 236–245 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Lumelsky, N. et al. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292, 1389–1394 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Hori, Y. et al. Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc. Natl Acad. Sci. USA 99, 16105–16110 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Blyszczuk, P. et al. Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc. Natl Acad. Sci. USA 100, 998–1003 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Schmitt, R. M., Bruyns, E. & Snodgrass, H. R. Hematopoietic development of embryonic stem cells in vitro: cytokine and receptor gene expression. Genes Dev. 5, 728–740 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  98. Rambhatla, L., Chiu, C. P., Kundu, P., Peng, Y. & Carpenter, M. K. Generation of hepatocyte-like cells from human embryonic stem cells. Cell Transplant. 12, 1–11 (2003).

    Article  PubMed  Google Scholar 

  99. Kaufman, D. S. et al. Functional endothelial cells derived from rhesus monkey embryonic stem cells. Blood 103, 1325–1332 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Scholz, G. et al. Prevalidation of the embryonic stem cell test EST — a new in vitro embryotoxicity test. Toxicol. In Vitro 13, 675–681 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Laschinski, G., Vogel, R. & Spielman, H. Cytotoxicity test using blastocyst-derived euploid embryonal stem cells: a new approach to in vitro teratogenesis screening. Reprod. Toxicol. 5, 57–64 (1991).

    Article  CAS  PubMed  Google Scholar 

  102. Spielman, H., Pohl, I., Doring, B., Liebsch, M. & Moldenhauer, F. The embryonic stem cell test, an in vitro embryotoxicity test using two permanent mouse cell lines 3T3 fibroblasts and embryonic stem cells. Toxicol. In Vitro 10, 119–127 (1997).

    Google Scholar 

  103. Balls, M. & Hellstein, E. Statement on the scientific validity of the embryonic stem cell test (EST) — an in vitro test for embryotoxicity. Altern. Lab. Anim. 30, 265–268 (2002).

    Article  PubMed  Google Scholar 

  104. Lassar, A. B., Paterson, B. M. & Weintraub, H. Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts. Cell 47, 649–56 (1986).

    Article  CAS  PubMed  Google Scholar 

  105. Walsh, J. & Andrews, P. W. Expression of Wnt and Notch pathway genes in a pluripotent human embryonal carcinoma cell line and embryonic stem cell. APMIS 111, 197–210 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Tokar, E. J., Ancrile, B. B., Cunha, G. R. & Webber, M. M. Stem/progenitor and intermediate cell types and the origin of human prostate cancer. Differentiation 73, 463–473 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Lam, J. S. & Reiter, R. E. Stem cells in prostate and prostate cancer development. Urol. Oncol. 24, 131–140 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. van Es, J. H., Barker, N. & Clevers, H. You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr. Opin. Genet. Dev. 13, 28–33 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Blanpain, C., Horsley, V. & Fuchs, E. Epithelial stem cells: turning over new leaves. Cell 128, 445–458 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Druker, B. J. Perspectives on the development of a molecularly targeted agent. Cancer Cell 1, 31–36 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Albanell, J. & Adams, J. Bortezomib, a proteasome inhibitor, in cancer therapy: from concept to clinic. Drugs of the Future 27, 1079–1092 (2002).

    Article  CAS  Google Scholar 

  112. Maloney, A. & Workman, P. HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin. Biol. Ther. 2, 3–24 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Ding, S. et al. Synthetic small molecules that control stem cell fate. Proc. Natl Acad. Sci. USA 100, 7632–7637 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ding, S. & Schultz, P. G. A role for chemistry in stem cell biology. Nature Biotech. 22, 833–840 (2004).

    Article  CAS  Google Scholar 

  115. Takahashi, T. et al. Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 107, 1912–1916 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Wu, X., Ding, S., Ding, Q., Gray, N. S. & Schultz, P. G. Small molecules that induce cardiomyogenesis in embryonic stem cells. J. Am. Chem. Soc. 126, 1590–1591 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Chen, S., Zhang, Q., Wu, X., Schultz, P. G. & Ding, S. Dedifferentiation of lineage-committed cells by a small molecule. J. Am. Chem. Soc. 126, 410–411 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Ding, S. & Schultz, P. G. Small molecules and future regenerative medicine. Curr. Top. Med. Chem. 5, 383–395 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Shen, C-N., Slack, J. M. W. & Tosh, D. Molecular basis of transdifferentiation of pancreas to liver. Nature Cell Biol. 2, 879–887 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Skillington, J., Choy, J. & Derynck, R. Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes, J. Cell Biol. 159, 135–146 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wu, X., Ding, S., Ding, Q., Gray, N. S. & Schultz, P. G. A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells. J. Am. Chem. Soc. 124, 14520–14521 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Meijer, L. et al. GSK-3-selective inhibitors derived from Tyrian Purple indirubins. Chem. Biol. 10, 1255–1266 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A. H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signalling by a pharmacological GSK-3-specific inhibitor. Nature Med. 10, 55–63 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Chen, S. et al. Self-renewal of embryonic stem cells by a small molecule. Proc. Natl Acad. Sci. USA 103, 17266–17271 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Broxmeyer, H. E. et al. High efficiency recovery of functional hematopoietic progenitor and stem cells from human cord blood cryopreserved for 15 years. Proc. Natl Acad. Sci. USA 100, 645–650 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  128. Zuk, P. A. et al. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell 13, 4279–4295 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Murrell, W. et al. Multipotent stem cells from adult olfactory mucosa. Dev. Dyn. 233, 496–515 (2005).

    Article  PubMed  Google Scholar 

  130. Collas, P. Nuclear reprogramming in cell-free extracts. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358, 1389–1395 (2002).

    Article  CAS  Google Scholar 

  131. Gaustad, K. G., Boquest, A. C., Anderson, B. E., Gerdes, A. M. & Collas, P. Differentiation of human adipose tissue stem cells using extracts of rat cardiomyocytes. Biochem. Biophys. Res. Commun. 314, 420–427 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Hakelien, A. M., Gaustad, P. & Collas, P. Transient alteration of cell fate using a nuclear and cytoplasmic extract of an insulinoma cell line, Biochem. Biophys. Res. Commun. 316, 834–841 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Qin, M., Tai, G., Collas, P., Polak, J. M. & Bishop A. E. Cell extract-derived differentiation of embryonic stem cells. Stem Cells 23, 712–718 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Burke, Z. D., Shen, C. N., Ralphs, R. L. & Tosh, D. Characterization of liver function in transdifferentiated hepatocytes. J. Cell Physiol. 206, 47–59 (2006).

    Article  CAS  Google Scholar 

  135. Li, W. C., Horb, M. E., Tosh, D. & Slack, J. M. In vitro transdifferentiation of hepatoma cells into functional pancreatic cells. Mech. Dev. 122, 835–847 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Burke, Z. D. & Tosh, D. Therapeutic potential of transdifferentiated cells. Clin. Sci. 108, 309–321 (2005).

    Article  CAS  Google Scholar 

  137. Fu, J-D. et al. Crucial role of the sarcoplasmic reticulum in the developmental regulation of Ca2+ transients and contraction in cardiomyocytes derived from embryonic stem cells. FASEB J. 20, 181–183 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Warashina, M. et al. A synthetic small molecule that induces neuronal differentiation of adult hippocampal neural progenitor cells. Angew. Chem. Int. Ed. 45, 591–593 (2006).

    Article  CAS  Google Scholar 

  139. Engel, F. B. et al. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev. 19, 1175–1187 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Dezawa, M. et al. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation J. Clin. Invest. 113, 1701–1710 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Duval, D., Malaise, M., Reinhardt, B., Kedinger, C. & Boeuf, H. A p38 inhibitor allows to dissociate differentiation and apoptotic processes triggered upon LIF withdrawal in mouse embryonic stem cells Cell Death Differ. 11, 331–341 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Tseng, A. S., Engel, F. B. & Keating, M. T. The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem. Biol. 13 957–963 (2006).

    Article  CAS  PubMed  Google Scholar 

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  1. Colin W. Pouton and John M. Haynes are at the Department of Pharmaceutical Biology, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Melbourne, Australia.,

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Pouton, C., Haynes, J. Embryonic stem cells as a source of models for drug discovery. Nat Rev Drug Discov 6, 605–616 (2007). https://doi.org/10.1038/nrd2194

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