Archives of Pharmacal Research

, Volume 35, Issue 2, pp 281–297 | Cite as

Chemical biology in stem cell research



Stem cells are offering a considerable range of prospects to the biomedical research including novel platforms for disease models and drug discovery tools to cell transplantation and regenerative therapies. However, there are several obstacles to overcome to bring these potentials into reality. First, robust methods to maintain stem cells in the pluripotent state should be established and factors that are required to direct stem cell fate into a particular lineage should be elucidated. Second, both allogeneic rejection following transplantation and limited cell availability issues must be circumvented. These challenges are being addressed, at least in part, through the identification of a group of chemicals (small molecules) that possess novel activities on stem cell biology. For example, small molecules can be used both in vitro and/or in vivo as tools to promote proliferation of stem cells (self-renewal), to direct stem cells to a lineage specific patterns (differentiation), or to reprogram somatic cells to a more undifferentiated state (de-differentiation or reprogramming). These molecules, in turn, have provided new insights into the signaling mechanisms that regulate stem cell biology, and may eventually lead to effective therapies in regenerative medicine. In this review, we will introduce recent findings with regards to small molecules and their impact on stem cell self-renewal and differentiation.

Key words

Stem cell Chemical biology Drug discovery 


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  1. Adhikary, S. and Eilers, M., Transcriptional regulation and transformation by Myc proteins. Nat. Rev. Mol. Cell Biol., 6, 635–645 (2005).PubMedCrossRefGoogle Scholar
  2. Ahn, S. and Joyner, A. L., In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature, 437, 894–897 (2005).PubMedCrossRefGoogle Scholar
  3. Amabile, G., D’Alise, A. M., Iovino, M., Jones, P., Santaguida, S., Musacchio, A., Taylor, S., and Cortese, R., The Aurora B kinase activity is required for the maintenance of the differentiated state of murine myoblasts. Cell Death Differ., 16, 321–330 (2009).PubMedCrossRefGoogle Scholar
  4. Amit, M., Shariki, C., Margulets, V., and Itskovitz-Eldor, J., Feeder layer- and serum-free culture of human embryonic stem cells. Biol. Reprod., 70, 837–845 (2004).PubMedCrossRefGoogle Scholar
  5. Anastasia, L., Sampaolesi, M., Papini, N., Oleari, D., Lamorte, G., Tringali, C., Monti, E., Galli, D., Tettamanti, G., Cossu, G., and Venerando, B., Reversine-treated fibroblasts acquire myogenic competence in vitro and in regenerating skeletal muscle. Cell Death Differ., 13, 2042–2051 (2006).PubMedCrossRefGoogle Scholar
  6. Androutsellis-Theotokis, A., Leker, R. R., Soldner, F., Hoeppner, D. J., Ravin, R., Poser, S. W., Rueger, M. A., Bae, S. K., Kittappa, R., and McKay, R. D., Notch signalling regulates stem cell numbers in vitro and in vivo. Nature, 442, 823–826 (2006).PubMedCrossRefGoogle Scholar
  7. Ao, A., Hao, J., and Hong, C. C., Regenerative chemical biology: current challenges and future potential. Chem. Biol., 18, 413–424 (2011).PubMedCrossRefGoogle Scholar
  8. Araki, H., Mahmud, N., Milhem, M., Nunez, R., Xu, M., Beam, C. A., and Hoffman, R., Expansion of human umbilical cord blood SCID-repopulating cells using chromatinmodifying agents. Exp. Hematol., 34, 140–149 (2006).PubMedCrossRefGoogle Scholar
  9. Arya, P., Joseph, R., and Chou, D. T., Toward high-throughput synthesis of complex natural product-like compounds in the genomics and proteomics age. Chem. Biol., 9, 145–156 (2002).PubMedCrossRefGoogle Scholar
  10. Baer, A. S., Syed, Y. A., Kang, S. U., Mitteregger, D., Vig, R., Ffrench-Constant, C., Franklin, R. J., Altmann, F., Lubec, G., and Kotter, M. R., Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling. Brain, 132, 465–481 (2009).PubMedCrossRefGoogle Scholar
  11. Bass, A. J., Watanabe, H., Mermel, C. H., Yu, S., Perner, S., Verhaak, R. G., Kim, S. Y., Wardwell, L., Tamayo, P., Gat-Viks, I., Ramos, A. H., Woo, M. S., Weir, B. A., Getz, G., Beroukhim, R., O’Kelly, M., Dutt, A., Rozenblatt-Rosen, O., Dziunycz, P., Komisarof, J., Chirieac, L. R., Lafargue, C. J., Scheble, V., Wilbertz, T., Ma, C., Rao, S., Nakagawa, H., Stairs, D. B., Lin, L., Giordano, T. J., Wagner, P., Minna, J. D., Gazdar, A. F., Zhu, C. Q., Brose, M. S., Cecconello, I., Jr, U. R., Marie, S. K., Dahl, O., Shivdasani, R. A., Tsao, M. S., Rubin, M. A., Wong, K. K., Regev, A., Hahn, W. C., Beer, D. G., Rustgi, A. K., and Meyerson, M., SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat. Genet., 41, 1238–1242 (2009).PubMedCrossRefGoogle Scholar
  12. Beattie, G. M., Lopez, A. D., Bucay, N., Hinton, A., Firpo, M. T., King, C. C., and Hayek, A., Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers. Stem Cells, 23, 489–495 (2005).PubMedCrossRefGoogle Scholar
  13. Bendall, S. C., Stewart, M. H., Menendez, P., George, D., Vijayaragavan, K., Werbowetski-Ogilvie, T., Ramos-Mejia, V., Rouleau, A., Yang, J., Bosse, M., Lajoie, G., and Bhatia, M., IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature, 448, 1015–1021 (2007).PubMedCrossRefGoogle Scholar
  14. Benvenuti, S., Cellai, I., Luciani, P., Deledda, C., Baglioni, S., Giuliani, C., Saccardi, R., Mazzanti, B., Dal Pozzo, S., Mannucci, E., Peri, A., and Serio, M., Rosiglitazone stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells. J Endocrinol. Invest., 30, RC26–RC30 (2007).PubMedGoogle Scholar
  15. Berman, D. M., Karhadkar, S. S., Hallahan, A. R., Pritchard, J. I., Eberhart, C. G., Watkins, D. N., Chen, J. K., Cooper, M. K., Taipale, J., Olson, J. M., and Beachy, P. A., Medulloblastoma growth inhibition by hedgehog pathway blockade. Science, 297, 1559–1561 (2002).PubMedCrossRefGoogle Scholar
  16. Blackwell, H. E., Perez, L., Stavenger, R. A., Tallarico, J. A., Cope Eatough, E., Foley, M. A., and Schreiber, S. L., A one-bead, one-stock solution approach to chemical genetics: part 1. Chem. Biol., 8, 1167–1182 (2001).PubMedCrossRefGoogle Scholar
  17. Boitano, A. E., Wang, J., Romeo, R., Bouchez, L. C., Parker, A. E., Sutton, S. E., Walker, J. R., Flaveny, C. A., Perdew, G. H., Denison, M. S., Schultz, P. G., and Cooke, M. P., Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science, 329, 1345–1348 (2010).PubMedCrossRefGoogle Scholar
  18. Boland, M. J., Hazen, J. L., Nazor, K. L., Rodriguez, A. R., Gifford, W., Martin, G., Kupriyanov, S., and Baldwin, K. K., Adult mice generated from induced pluripotent stem cells. Nature, 461, 91–94 (2009).PubMedCrossRefGoogle Scholar
  19. Bone, H. K., Damiano, T., Bartlett, S., Perry, A., Letchford, J., Ripoll, Y. S., Nelson, A. S., and Welham, M. J., Involvement of GSK-3 in regulation of murine embryonic stem cell self-renewal revealed by a series of bisindolylmaleimides. Chem. Biol., 16, 15–27 (2009).PubMedCrossRefGoogle Scholar
  20. Bunin, B. A., Plunkett, M. J., and Ellman, J. A., The combinatorial synthesis and chemical and biological evaluation of a 1,4-benzodiazepine library. Proc. Natl. Acad. Sci. U. S. A., 91, 4708–4712 (1994).PubMedCrossRefGoogle Scholar
  21. Burba, I., Colombo, G. I., Staszewsky, L. I., De Simone, M., Devanna, P., Nanni, S., Avitabile, D., Molla, F., Cosentino, S., Russo, I., De Angelis, N., Soldo, A., Biondi, A., Gambini, E., Gaetano, C., Farsetti, A., Pompilio, G., Latini, R., Capogrossi, M. C., and Pesce, M., Histone deacetylase inhibition enhances self renewal and cardioprotection by human cord blood-derived CD34 cells. PLoS ONE, 6, e22158 (2011).Google Scholar
  22. Bushway, P. J. and Mercola, M., High-throughput screening for modulators of stem cell differentiation. Methods Enzymol., 414, 300–316 (2006).PubMedCrossRefGoogle Scholar
  23. Canudas, A. M., Di Giorgi-Gerevini, V., Iacovelli, L., Nano, G., D’Onofrio, M., Arcella, A., Giangaspero, F., Busceti, C., Ricci-Vitiani, L., Battaglia, G., Nicoletti, F., and Melchiorri, D., PHCCC, a specific enhancer of type 4 metabotropic glutamate receptors, reduces proliferation and promotes differentiation of cerebellar granule cell neuroprecursors. J. Neurosci., 24, 10343–10352 (2004).PubMedCrossRefGoogle Scholar
  24. Cartwright, P., McLean, C., Sheppard, A., Rivett, D., Jones, K., and Dalton, S., LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development, 132, 885–896 (2005).PubMedCrossRefGoogle Scholar
  25. Chambers, I., Colby, D., Robertson, M., Nichols, J., Lee, S., Tweedie, S., and Smith, A., Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell, 113, 643–655 (2003).PubMedCrossRefGoogle Scholar
  26. Chen, S., Zhang, Q., Wu, X., Schultz, P. G., and Ding, S., Dedifferentiation of lineage-committed cells by a small molecule. J. Am. Chem. Soc., 126, 410–411 (2004).PubMedCrossRefGoogle Scholar
  27. Chen, S., Do, J. T., Zhang, Q., Yao, S., Yan, F., Peters, E. C., Scholer, H. R., Schultz, P. G., and Ding, S., Self-renewal of embryonic stem cells by a small molecule. Proc. Natl. Acad. Sci. U. S. A., 103, 17266–17271 (2006).PubMedCrossRefGoogle Scholar
  28. Chen, S., Takanashi, S., Zhang, Q., Xiong, W., Zhu, S., Peters, E. C., Ding, S., and Schultz, P. G., Reversine increases the plasticity of lineage-committed mammalian cells. Proc. Natl. Acad. Sci. U. S. A., 104, 10482–10487 (2007).PubMedCrossRefGoogle Scholar
  29. Clemons, P. A., Koehler, A. N., Wagner, B. K., Sprigings, T. G., Spring, D. R., King, R. W., Schreiber, S. L., and Foley, M. A., A one-bead, one-stock solution approach to chemical genetics: part 2. Chem. Biol., 8, 1183–1195 (2001).PubMedCrossRefGoogle Scholar
  30. Colca, J. R. and Harrigan, G. G., Photo-affinity labeling strategies in identifying the protein ligands of bioactive small molecules: examples of targeted synthesis of drug analog photoprobes. Comb. Chem. High Throughput Screen, 7, 699–704 (2004).PubMedGoogle Scholar
  31. Cowan, C. A., Klimanskaya, I., McMahon, J., Atienza, J., Witmyer, J., Zucker, J. P., Wang, S., Morton, C. C., McMahon, A. P., Powers, D., and Melton, D. A., Derivation of embryonic stem-cell lines from human blastocysts. N. Engl. J. Med., 350, 1353–1356 (2004).PubMedCrossRefGoogle Scholar
  32. D’Alise, A. M., Amabile, G., Iovino, M., Di Giorgio, F. P., Bartiromo, M., Sessa, F., Villa, F., Musacchio, A., and Cortese, R., Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells. Mol. Cancer Ther., 7, 1140–1149 (2008).PubMedCrossRefGoogle Scholar
  33. Dennis, J. E. and Caplan, A. I., In Stem Cells Handbook., Sell, S. (Ed.). Human Press, Totowa, p. 107, (2004).Google Scholar
  34. Diamandis, P., Wildenhain, J., Clarke, I. D., Sacher, A. G., Graham, J., Bellows, D. S., Ling, E. K., Ward, R. J., Jamieson, L. G., Tyers, M., and Dirks, P. B., Chemical genetics reveals a complex functional ground state of neural stem cells. Nat. Chem. Biol., 3, 268–273 (2007).PubMedCrossRefGoogle Scholar
  35. Ding, S., Gray, N. S., Wu, X., Ding, Q., and Schultz, P. G., A combinatorial scaffold approach toward kinase-directed heterocycle libraries. J. Am. Chem. Soc., 124, 1594–1596 (2002).PubMedCrossRefGoogle Scholar
  36. Ding, S., Wu, T. Y., Brinker, A., Peters, E. C., Hur, W., Gray, N. S., and Schultz, P. G., Synthetic small molecules that control stem cell fate. Proc. Natl. Acad. Sci. U. S. A., 100, 7632–7637 (2003).PubMedCrossRefGoogle Scholar
  37. Ding, S. and Schultz, P. G., A role for chemistry in stem cell biology. Nat. Biotechnol., 22, 833–840 (2004).PubMedCrossRefGoogle Scholar
  38. Doble, B. W. and Woodgett, J. R., GSK-3: tricks of the trade for a multi-tasking kinase. J. Cell Sci., 116, 1175–1186 (2003).PubMedCrossRefGoogle Scholar
  39. Dravid, G., Ye, Z., Hammond, H., Chen, G., Pyle, A., Donovan, P., Yu, X., and Cheng, L., Defining the role of Wnt/betacatenin signaling in the survival, proliferation, and selfrenewal of human embryonic stem cells. Stem Cells, 23, 1489–1501 (2005).PubMedCrossRefGoogle Scholar
  40. Ehninger, A. and Trumpp, A., The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move in. J. Exp. Med., 208, 421–428 (2011).PubMedCrossRefGoogle Scholar
  41. Ertl, P., Jelfs, S., Muhlbacher, J., Schuffenhauer, A., and Selzer, P., Quest for the rings. In silico exploration of ring universe to identify novel bioactive heteroaromatic scaffolds. J. Med. Chem., 49, 4568–4573 (2006).PubMedCrossRefGoogle Scholar
  42. Evans, M. J. and Kaufman, M. H., Establishment in culture of pluripotential cells from mouse embryos. Nature, 292, 154–156 (1981).PubMedCrossRefGoogle Scholar
  43. Firestone, A. J. and Chen, J. K., Controlling destiny through chemistry: small-molecule regulators of cell fate. ACS Chem. Biol., 5, 15–34 (2010).PubMedCrossRefGoogle Scholar
  44. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., and Tsai, L. H., Recovery of learning and memory is associated with chromatin remodelling. Nature, 447, 178–182 (2007).PubMedCrossRefGoogle Scholar
  45. Foster, K. W., Liu, Z., Nail, C. D., Li, X., Fitzgerald, T. J., Bailey, S. K., Frost, A. R., Louro, I. D., Townes, T. M., Paterson, A. J., Kudlow, J. E., Lobo-Ruppert, S. M., and Ruppert, J. M., Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia. Oncogene, 24, 1491–1500 (2005).PubMedCrossRefGoogle Scholar
  46. Frank-Kamenetsky, M., Zhang, X. M., Bottega, S., Guicherit, O., Wichterle, H., Dudek, H., Bumcrot, D., Wang, F. Y., Jones, S., Shulok, J., Rubin, L. L., and Porter, J. A., Smallmolecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol., 1, 10 (2002).PubMedCrossRefGoogle Scholar
  47. Franklin, R. J. and Ffrench-Constant, C., Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci., 9, 839–855 (2008).PubMedCrossRefGoogle Scholar
  48. Gage, F. H., Mammalian neural stem cells. Science, 287, 1433–1438 (2000).PubMedCrossRefGoogle Scholar
  49. Garriga-Canut, M. and Orkin, S. H., Transforming acidic coiled-coil protein 3 (TACC3) controls friend of GATA-1 (FOG-1) subcellular localization and regulates the association between GATA-1 and FOG-1 during hematopoiesis. J. Biol. Chem., 279, 23597–23605 (2004).PubMedCrossRefGoogle Scholar
  50. Gidekel, S., Pizov, G., Bergman, Y., and Pikarsky, E., Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell, 4, 361–370 (2003).PubMedCrossRefGoogle Scholar
  51. Graf, T. and Enver, T., Forcing cells to change lineages. Nature, 462, 587–594 (2009).PubMedCrossRefGoogle Scholar
  52. Greber, B., Coulon, P., Zhang, M., Moritz, S., Frank, S., Muller-Molina, A. J., Arauzo-Bravo, M. J., Han, D. W., Pape, H. C., and Scholer, H. R., FGF signalling inhibits neural induction in human embryonic stem cells. EMBO J., 30, 4874–4884 (2011).PubMedCrossRefGoogle Scholar
  53. Grinshtein, N., Datti, A., Fujitani, M., Uehling, D., Prakesch, M., Isaac, M., Irwin, M. S., Wrana, J. L., Al-Awar, R., and Kaplan, D. R., Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells. Cancer Res., 71, 1385–1395 (2011).PubMedCrossRefGoogle Scholar
  54. Hao, J., Daleo, M. A., Murphy, C. K., Yu, P. B., Ho, J. N., Hu, J., Peterson, R. T., Hatzopoulos, A. K., and Hong, C. C., Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells. PLoS ONE, 3, e2904 (2008).Google Scholar
  55. Hao, Y., Creson, T., Zhang, L., Li, P., Du, F., Yuan, P., Gould, T. D., Manji, H. K., and Chen, G., Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J. Neurosci., 24, 6590–6599 (2004).PubMedCrossRefGoogle Scholar
  56. Hochedlinger, K., Yamada, Y., Beard, C., and Jaenisch, R., Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell, 121, 465–477 (2005).PubMedCrossRefGoogle Scholar
  57. Hong, J., Role of natural product diversity in chemical biology. Curr. Opin. Chem. Biol., 15, 350–354 (2011).PubMedCrossRefGoogle Scholar
  58. Horwitz, E. M., Prockop, D. J., Fitzpatrick, L. A., Koo, W. W., Gordon, P. L., Neel, M., Sussman, M., Orchard, P., Marx, J. C., Pyeritz, R. E., and Brenner, M. K., Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat. Med., 5, 309–313 (1999).PubMedCrossRefGoogle Scholar
  59. Hsieh, J., Nakashima, K., Kuwabara, T., Mejia, E., and Gage, F. H., Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc. Natl. Acad. Sci. U. S. A., 101, 16659–16664 (2004).PubMedCrossRefGoogle Scholar
  60. Hsieh, T. C., Traganos, F., Darzynkiewicz, Z., and Wu, J. M., The 2,6-disubstituted purine reversine induces growth arrest and polyploidy in human cancer cells. Int. J. Oncol., 31, 1293–1300 (2007).PubMedGoogle Scholar
  61. Huryn, D. M., Brodsky, J. L., Brummond, K. M., Chambers, P. G., Eyer, B., Ireland, A. W., Kawasumi, M., Laporte, M. G., Lloyd, K., Manteau, B., Nghiem, P., Quade, B., Seguin, S. P., and Wipf, P., Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators. Proc. Natl. Acad. Sci. U. S. A., 108, 6757–6762 (2011).PubMedCrossRefGoogle Scholar
  62. Ichida, J. K., Blanchard, J., Lam, K., Son, E. Y., Chung, J. E., Egli, D., Loh, K. M., Carter, A. C., Di Giorgio, F. P., Koszka, K., Huangfu, D., Akutsu, H., Liu, D. R., Rubin, L. L., and Eggan, K., A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell, 5, 491–503 (2009).PubMedCrossRefGoogle Scholar
  63. Jaenisch, R. and Young, R., Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell, 132, 567–582 (2008).PubMedCrossRefGoogle Scholar
  64. Jaiswal, N., Haynesworth, S. E., Caplan, A. I., and Bruder, S. P., Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro. J. Cell Biochem., 64, 295–312 (1997).PubMedCrossRefGoogle Scholar
  65. James, D., Levine, A. J., Besser, D., and Hemmati-Brivanlou, A., TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development, 132, 1273–1282 (2005).PubMedCrossRefGoogle Scholar
  66. Johnson, G. L. and Lapadat, R., Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science, 298, 1911–1912 (2002).PubMedCrossRefGoogle Scholar
  67. Jones, B. J. and McTaggart, S. J., Immunosuppression by mesenchymal stromal cells: from culture to clinic. Exp. Hematol., 36, 733–741 (2008).PubMedCrossRefGoogle Scholar
  68. Joubert, L., Foucault, I., Sagot, Y., Bernasconi, L., Duval, F., Alliod, C., Frossard, M. J., Pescini Gobert, R., Curchod, M. L., Salvat, C., Nichols, A., Pouly, S., Rommel, C., Roach, A., and Hooft van Huijsduijnen, R., Chemical inducers and transcriptional markers of oligodendrocyte differentiation. J. Neurosci. Res., 88, 2546–2557 (2010).PubMedGoogle Scholar
  69. Jung, D. W. and Williams, D. R., Novel chemically defined approach to produce multipotent cells from terminally differentiated tissue syncytia. ACS Chem. Biol., 6, 553–562 (2011).PubMedCrossRefGoogle Scholar
  70. Kim, Y. K., Choi, H. Y., Kim, N. H., Lee, W., Seo, D. W., Kang, D. W., Lee, H. Y., Han, J. W., Park, S. W., and Kim, S. N., Reversine stimulates adipocyte differentiation and downregulates Akt and p70(s6k) signaling pathways in 3T3-L1 cells. Biochem. Biophys. Res. Commun, 358, 553–558 (2007).PubMedCrossRefGoogle Scholar
  71. Knockaert, M., Wieking, K., Schmitt, S., Leost, M., Grant, K. M., Mottram, J. C., Kunick, C., and Meijer, L., Intracellular Targets of Paullones. Identification following affinity purification on immobilized inhibitor. J. Biol. Chem., 277, 25493–25501 (2002).PubMedCrossRefGoogle Scholar
  72. Laflamme, M. A. and Murry, C. E., Regenerating the heart. Nat. Biotechnol., 23, 845–856 (2005).PubMedCrossRefGoogle Scholar
  73. Laping, N. J., Grygielko, E., Mathur, A., Butter, S., Bomberger, J., Tweed, C., Martin, W., Fornwald, J., Lehr, R., Harling, J., Gaster, L., Callahan, J. F., and Olson, B. A., Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol. Pharmacol., 62, 58–64 (2002).PubMedCrossRefGoogle Scholar
  74. Lee, K. L., Lim, S. K., Orlov, Y. L., Yit le, Y., Yang, H., Ang, L. T., Poellinger, L., and Lim, B., Graded Nodal/Activin signaling titrates conversion of quantitative phospho-Smad2 levels into qualitative embryonic stem cell fate decisions. PLoS Genet., 7, e1002130 (2011).Google Scholar
  75. Li, J., Gao, G. D., and Yuan, T. F., Cell based vaccination using transplantation of iPSC-derived memory B cells. Vaccine, 27, 5728–5729 (2009).PubMedCrossRefGoogle Scholar
  76. Li, W., Wei, W., Zhu, S., Zhu, J., Shi, Y., Lin, T., Hao, E., Hayek, A., Deng, H., and Ding, S., Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell, 4, 16–19 (2009).PubMedCrossRefGoogle Scholar
  77. Lin, T., Ambasudhan, R., Yuan, X., Li, W., Hilcove, S., Abujarour, R., Lin, X., Hahm, H. S., Hao, E., Hayek, A., and Ding, S., A chemical platform for improved induction of human iPSCs. Nat. Methods, 6, 805–808 (2009).PubMedCrossRefGoogle Scholar
  78. Liu, A., Muggironi, M., Marin-Husstege, M., and Casaccia-Bonnefil, P., Oligodendrocyte process outgrowth in vitro is modulated by epigenetic regulation of cytoskeletal severing proteins. Glia, 44, 264–274 (2003).PubMedCrossRefGoogle Scholar
  79. Ludwig, T. E., Bergendahl, V., Levenstein, M. E., Yu, J., Probasco, M. D., and Thomson, J. A., Feeder-independent culture of human embryonic stem cells. Nat. Methods, 3, 637–646 (2006).PubMedCrossRefGoogle Scholar
  80. Lypowy, J., Chen, I. Y., and Abdellatif, M., An alliance between Ras GTPase-activating protein, filamin C, and Ras GTPase-activating protein SH3 domain-binding protein regulates myocyte growth. J. Biol. Chem., 280, 25717–25728 (2005).PubMedCrossRefGoogle Scholar
  81. Lyssiotis, C. A., Chrette, B. D., and Lairson, L. L., Title, In Lakshmipathy, U., Chesnut, J. D., and Thyagarajan, B. (Eds.). Wiley, New York, p. 51, (2009a).Google Scholar
  82. Lyssiotis, C. A., Foreman, R. K., Staerk, J., Garcia, M., Mathur, D., Markoulaki, S., Hanna, J., Lairson, L. L., Charette, B. D., Bouchez, L. C., Bollong, M., Kunick, C., Brinker, A., Cho, C. Y., Schultz, P. G., and Jaenisch, R., Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proc. Natl. Acad. Sci. U. S. A., 106, 8912–8917 (2009b).PubMedCrossRefGoogle Scholar
  83. Lyssiotis, C. A., Lairson, L. L., Boitano, A. E., Wurdak, H., Zhu, S., and Schultz, P. G., Chemical control of stem cell fate and developmental potential. Angew. Chem. Int. Ed. Engl., 50, 200–242 (2011).PubMedCrossRefGoogle Scholar
  84. MacDonald, J. L. and Roskams, A. J., Epigenetic regulation of nervous system development by DNA methylation and histone deacetylation. Prog. Neurobiol., 88, 170–183 (2009).PubMedCrossRefGoogle Scholar
  85. Maherali, N., Sridharan, R., Xie, W., Utikal, J., Eminli, S., Arnold, K., Stadtfeld, M., Yachechko, R., Tchieu, J., Jaenisch, R., Plath, K., and Hochedlinger, K., Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell, 1, 55–70 (2007).PubMedCrossRefGoogle Scholar
  86. McKeveney, P. J., Hodges, V. M., Mullan, R. N., Maxwell, P., Simpson, D., Thompson, A., Winter, P. C., Lappin, T. R., and Maxwell, A. P., Characterization and localization of expression of an erythropoietin-induced gene, ERIC-1/ TACC3, identified in erythroid precursor cells. Br. J. Haematol., 112, 1016–1024 (2001).PubMedCrossRefGoogle Scholar
  87. Mitsui, K., Tokuzawa, Y., Itoh, H., Segawa, K., Murakami, M., Takahashi, K., Maruyama, M., Maeda, M., and Yamanaka, S., The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell, 113, 631–642 (2003).PubMedCrossRefGoogle Scholar
  88. Miyabayashi, T., Teo, J. L., Yamamoto, M., McMillan, M., Nguyen, C., and Kahn, M., Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc. Natl. Acad. Sci. U. S. A., 104, 5668–5673 (2007).PubMedCrossRefGoogle Scholar
  89. Monje, M., Mitra, S. S., Freret, M. E., Raveh, T. B., Kim, J., Masek, M., Attema, J. L., Li, G., Haddix, T., Edwards, M. S., Fisher, P. G., Weissman, I. L., Rowitch, D. H., Vogel, H., Wong, A. J., and Beachy, P. A., Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc. Natl. Acad. Sci. U. S. A., 108, 4453–4458 (2011).PubMedCrossRefGoogle Scholar
  90. Murry, C. E. and Keller, G., Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell, 132, 661–680 (2008).PubMedCrossRefGoogle Scholar
  91. Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., and Yamanaka, S., Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol., 26, 101–106 (2008).PubMedCrossRefGoogle Scholar
  92. Nichols, J. and Ying, Q. L., Derivation and propagation of embryonic stem cells in serum- and feeder-free culture. Methods Mol. Biol., 329, 91–98 (2006).PubMedGoogle Scholar
  93. Niwa, H., Burdon, T., Chambers, I., and Smith, A., Selfrenewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev., 12, 2048–2060 (1998).PubMedCrossRefGoogle Scholar
  94. North, T. E., Goessling, W., Walkley, C. R., Lengerke, C., Kopani, K. R., Lord, A. M., Weber, G. J., Bowman, T. V., Jang, I. H., Grosser, T., Fitzgerald, G. A., Daley, G. Q., Orkin, S. H., and Zon, L. I., Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature, 447, 1007–1011 (2007).PubMedCrossRefGoogle Scholar
  95. Okita, K., Ichisaka, T., and Yamanaka, S., Generation of germline-competent induced pluripotent stem cells. Nature, 448, 313–317 (2007).PubMedCrossRefGoogle Scholar
  96. Oliveira, F., Bellesini, L., Defino, H., da Silva Herrero, C., Beloti, M., and Rosa, A., Hedgehog signaling and osteoblast gene expression are regulated by purmorphamine in human mesenchymal stem cells. J. Cell. Biochem., 113, 204–208 (2012).PubMedCrossRefGoogle Scholar
  97. Peled, T., Landau, E., Prus, E., Treves, A. J., Nagler, A., and Fibach, E., Cellular copper content modulates differentiation and self-renewal in cultures of cord blood-derived CD34+ cells. Br. J. Haematol., 116, 655–661 (2002).PubMedCrossRefGoogle Scholar
  98. Peled, T., Landau, E., Mandel, J., Glukhman, E., Goudsmid, N. R., Nagler, A., and Fibach, E., Linear polyamine copper chelator tetraethylenepentamine augments long-term ex vivo expansion of cord blood-derived CD34+ cells and increases their engraftment potential in NOD/SCID mice. Exp. Hematol., 32, 547–555 (2004a).PubMedCrossRefGoogle Scholar
  99. Peled, T., Mandel, J., Goudsmid, R. N., Landor, C., Hasson, N., Harati, D., Austin, M., Hasson, A., Fibach, E., Shpall, E. J., and Nagler, A., Pre-clinical development of cord bloodderived progenitor cell graft expanded ex vivo with cytokines and the polyamine copper chelator tetraethylenepentamine. Cytotherapy, 6, 344–355 (2004b).PubMedCrossRefGoogle Scholar
  100. Piekorz, R. P., Hoffmeyer, A., Duntsch, C. D., McKay, C., Nakajima, H., Sexl, V., Snyder, L., Rehg, J., and Ihle, J. N., The centrosomal protein TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis. EMBO J., 21, 653–664 (2002).PubMedCrossRefGoogle Scholar
  101. Pieters, T., Haenebalcke, L., Hochepied, T., D’Hont, J., Haigh, J. J., van Roy, F., and van Hengel, J., Efficient and User-Friendly Pluripotin-based Derivation of Mouse Embryonic Stem Cells. Stem Cell Rev., DOI 10.1007/ s12015-011-9323-x (2011).Google Scholar
  102. 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., and Marshak, D. R., Multilineage potential of adult human mesenchymal stem cells. Science, 284, 143–147 (1999).PubMedCrossRefGoogle Scholar
  103. Qi, X., Li, T. G., Hao, J., Hu, J., Wang, J., Simmons, H., Miura, S., Mishina, Y., and Zhao, G. Q., BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proc. Natl. Acad. Sci. U. S. A., 101, 6027–6032 (2004).PubMedCrossRefGoogle Scholar
  104. Rosania, G. R., Chang, Y. T., Perez, O., Sutherlin, D., Dong, H., Lockhart, D. J., and Schultz, P. G., Myoseverin, a microtubule-binding molecule with novel cellular effects. Nat. Biotechnol., 18, 304–308 (2000).PubMedCrossRefGoogle Scholar
  105. Sachinidis, A., Sotiriadou, I., Seelig, B., Berkessel, A., and Hescheler, J., A chemical genetics approach for specific differentiation of stem cells to somatic cells: a new promising therapeutical approach. Comb. Chem. High Throughput Screen, 11, 70–82 (2008).PubMedCrossRefGoogle Scholar
  106. Saraiya, M., Nasser, R., Zeng, Y., Addya, S., Ponnappan, R. K., Fortina, P., Anderson, D. G., Albert, T. J., Shapiro, I. M., and Risbud, M. V., Reversine enhances generation of progenitor-like cells by dedifferentiation of annulus fibrosus cells. Tissue Eng. Part A, 16, 1443–1455 (2010).PubMedCrossRefGoogle Scholar
  107. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., and Brivanlou, A. H., Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat. Med., 10, 55–63 (2004).PubMedCrossRefGoogle Scholar
  108. Saxe, J. P., Wu, H., Kelly, T. K., Phelps, M. E., Sun, Y. E., Kornblum, H. I., and Huang, J., A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation. Chem. Biol., 14, 1019–1030 (2007).PubMedCrossRefGoogle Scholar
  109. Schneider, J. W., Gao, Z., Li, S., Farooqi, M., Tang, T. S., Bezprozvanny, I., Frantz, D. E., and Hsieh, J., Small-molecule activation of neuronal cell fate. Nat. Chem. Biol., 4, 408–410 (2008).PubMedCrossRefGoogle Scholar
  110. Shen, S., Li, J., and Casaccia-Bonnefil, P., Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. J. Cell Biol., 169, 577–589 (2005).PubMedCrossRefGoogle Scholar
  111. Shi, Y., Desponts, C., Do, J. T., Hahm, H. S., Scholer, H. R., and Ding, S., Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with smallmolecule compounds. Cell Stem Cell, 3, 568–574 (2008a).PubMedCrossRefGoogle Scholar
  112. Shi, Y., Do, J. T., Desponts, C., Hahm, H. S., Scholer, H. R., and Ding, S., A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell, 2, 525–528 (2008b).PubMedCrossRefGoogle Scholar
  113. Sinha, S. and Chen, J. K., Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat. Chem. Biol., 2, 29–30 (2006).PubMedCrossRefGoogle Scholar
  114. Spangrude, G. J., Heimfeld, S., and Weissman, I. L., Purification and characterization of mouse hematopoietic stem cells. Science, 241, 58–62 (1988).PubMedCrossRefGoogle Scholar
  115. Styner, M., Sen, B., Xie, Z., Case, N., and Rubin, J., Indomethacin promotes adipogenesis of mesenchymal stem cells through a cyclooxygenase independent mechanism. J. Cell. Biochem., 111, 1042–1050 (2010).PubMedCrossRefGoogle Scholar
  116. Takahashi, K. and Yamanaka, S., Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676 (2006).PubMedCrossRefGoogle Scholar
  117. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S., Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–872 (2007).PubMedCrossRefGoogle Scholar
  118. Taylor, S. M. and Jones, P. A., Multiple new phenotypes induced in 10T1/2 and 3T3 cells treated with 5-azacytidine. Cell, 17, 771–779 (1979).PubMedCrossRefGoogle Scholar
  119. Tesar, P. J., Chenoweth, J. G., Brook, F. A., Davies, T. J., Evans, E. P., Mack, D. L., Gardner, R. L., and McKay, R. D., New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature, 448, 196–199 (2007).PubMedCrossRefGoogle Scholar
  120. Thomas, G. L. and Johannes, C. W., Natural product-like synthetic libraries. Curr. Opin. Chem. Biol., 15, 516–522 (2011).PubMedCrossRefGoogle Scholar
  121. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., and Jones, J. M., Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145–1147 (1998).PubMedCrossRefGoogle Scholar
  122. Thorne, N., Auld, D. S., and Inglese, J., Apparent activity in high-throughput screening: origins of compound-dependent assay interference. Curr. Opin. Chem. Biol., 14, 315–324 (2010).PubMedCrossRefGoogle Scholar
  123. Vallier, L., Alexander, M., and Pedersen, R. A., Activin/ Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J. Cell Sci., 118, 4495–4509 (2005).PubMedCrossRefGoogle Scholar
  124. Wagers, A. J. and Conboy, I. M., Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis. Cell, 122, 659–667 (2005).PubMedCrossRefGoogle Scholar
  125. Warashina, M., Min, K. H., Kuwabara, T., Huynh, A., Gage, F. H., Schultz, P. G., and Ding, S., A synthetic small molecule that induces neuronal differentiation of adult hippocampal neural progenitor cells. Angew. Chem. Int. Ed. Engl., 45, 591–593 (2006).PubMedCrossRefGoogle Scholar
  126. Weissman, I. L., Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science, 287, 1442–1446 (2000).PubMedCrossRefGoogle Scholar
  127. Wernig, M., Meissner, A., Cassady, J. P., and Jaenisch, R., c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell, 2, 10–12 (2008).PubMedCrossRefGoogle Scholar
  128. West, M. D., Sargent, R. G., Long, J., Brown, C., Chu, J. S., Kessler, S., Derugin, N., Sampathkumar, J., Burrows, C., Vaziri, H., Williams, R., Chapman, K. B., Larocca, D., Loring, J. F., and Murai, J., The ACTCellerate initiative: large-scale combinatorial cloning of novel human embryonic stem cell derivatives. Regen. Med., 3, 287–308 (2008).PubMedCrossRefGoogle Scholar
  129. Wu, X., Ding, S., Ding, Q., Gray, N. S., and Schultz, P. G., A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells. J. Am. Chem. Soc., 124, 14520–14521 (2002).PubMedCrossRefGoogle Scholar
  130. Wu, X., Walker, J., Zhang, J., Ding, S., and Schultz, P. G., Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway. Chem. Biol., 11, 1229–1238 (2004).PubMedCrossRefGoogle Scholar
  131. Wurdak, H., Zhu, S., Min, K. H., Aimone, L., Lairson, L. L., Watson, J., Chopiuk, G., Demas, J., Charette, B., Halder, R., Weerapana, E., Cravatt, B. F., Cline, H. T., Peters, E. C., Zhang, J., Walker, J. R., Wu, C., Chang, J., Tuntland, T., Cho, C. Y., and Schultz, P. G., A small molecule accelerates neuronal differentiation in the adult rat. Proc. Natl. Acad. Sci. U. S. A., 107, 16542–16547 (2010).PubMedCrossRefGoogle Scholar
  132. Xu, Y., Shi, Y., and Ding, S., A chemical approach to stemcell biology and regenerative medicine. Nature, 453, 338–344 (2008).PubMedCrossRefGoogle Scholar
  133. Yang, M., Li, K., Ng, P. C., Chuen, C. K., Lau, T. K., Cheng, Y. S., Liu, Y. S., Li, C. K., Yuen, P. M., James, A. E., Lee, S. M., and Fok, T. F., Promoting effects of serotonin on hematopoiesis: ex vivo expansion of cord blood CD34+ stem/ progenitor cells, proliferation of bone marrow stromal cells, and antiapoptosis. Stem Cells, 25, 1800–1806 (2007).PubMedCrossRefGoogle Scholar
  134. Ying, Q. L., Nichols, J., Chambers, I., and 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).PubMedCrossRefGoogle Scholar
  135. Ying, Q. L., Wray, J., Nichols, J., Batlle-Morera, L., Doble, B., Woodgett, J., Cohen, P., and Smith, A., The ground state of embryonic stem cell self-renewal. Nature, 453, 519–523 (2008).PubMedCrossRefGoogle Scholar
  136. Young, J. C., Wu, S., Hansteen, G., Du, C., Sambucetti, L., Remiszewski, S., O’Farrell, A. M., Hill, B., Lavau, C., and Murray, L. J., Inhibitors of histone deacetylases promote hematopoietic stem cell self-renewal. Cytotherapy, 6, 328–336 (2004).PubMedCrossRefGoogle Scholar
  137. Yu, P. B., Hong, C. C., Sachidanandan, C., Babitt, J. L., Deng, D. Y., Hoyng, S. A., Lin, H. Y., Bloch, K. D., and Peterson, R. T., Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol., 4, 33–41 (2008).PubMedCrossRefGoogle Scholar
  138. Zaharevitz, D. W., Gussio, R., Leost, M., Senderowicz, A. M., Lahusen, T., Kunick, C., Meijer, L., and Sausville, E. A., Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res., 59, 2566–2569 (1999).PubMedGoogle Scholar
  139. Zhao, C., Deng, W., and Gage, F. H., Mechanisms and functional implications of adult neurogenesis. Cell, 132, 645–660 (2008).PubMedCrossRefGoogle Scholar
  140. Zheng, X. S., Chan, T. F., and Zhou, H. H., Genetic and genomic approaches to identify and study the targets of bioactive small molecules. Chem. Biol., 11, 609–618 (2004).PubMedCrossRefGoogle Scholar
  141. Zhou, B. B., Zhang, H., Damelin, M., Geles, K. G., Grindley, J. C., and Dirks, P. B., Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat. Rev. Drug Discov., 8, 806–823 (2009).PubMedCrossRefGoogle Scholar
  142. Zhou, Q., Dalgard, C. L., Wynder, C., and Doughty, M. L., Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells. BMC Neurosci., 12, 50 (2011).PubMedCrossRefGoogle Scholar
  143. Zhou, S., LeBoff, M. S., and Glowacki, J., Vitamin D metabolism and action in human bone marrow stromal cells. Endocrinology, 151, 14–22 (2010).PubMedCrossRefGoogle Scholar
  144. Zhu, S., Wurdak, H., Wang, J., Lyssiotis, C. A., Peters, E. C., Cho, C. Y., Wu, X., and Schultz, P. G., A small molecule primes embryonic stem cells for differentiation. Cell Stem Cell, 4, 416–426 (2009).PubMedCrossRefGoogle Scholar
  145. Zhu, S., Wurdak, H., and Schultz, P. G., Directed embryonic stem cell differentiation with small molecules. Future Med. Chem., 2, 965–973 (2010).PubMedCrossRefGoogle Scholar

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© The Pharmaceutical Society of Korea and Springer Netherlands 2012

Authors and Affiliations

  1. 1.Gyeonggi Bio-CenterGyeonggi Institute of Science and Technology PromotionSuwonKorea
  2. 2.College of PharmacyHanyang UniversityAnsanKorea

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