Abstract
Although stem cells hold considerable promise for the treatment of numerous diseases including cardiovascular disease, neurodegenerative disease, musculoskeletal disease, diabetes and cancer, obstacles such as the control of stem cell fate, allogenic rejection and limited cell availability must be overcome before their therapeutic potential can be realized. This requires an improved understanding of the signaling pathways that affect stem cell fate. Cell-based phenotypic and pathway-specific screens of natural products and synthetic compounds have recently provided a number of small molecules that can be used to selectively control stem cell proliferation and differentiation. Examples include the selective induction of neurogenesis and cardiomyogenesis in murine embryonic stem cells, osteogenesis in mesenchymal stem cells and dedifferentiation in skeletal muscle cells. Such molecules will likely provide new insights into stem cell biology, and may ultimately contribute to effective medicines for tissue repair and regeneration.
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References
Department of Health and Human Services. Stem cells: scientific progress and future research directions (DHHS, Washington, DC, 2001). http://www.nih.gov/news/stemcell/scireport.htm
Hubner, K. et al. Derivation of oocytes from mouse embryonic stem cells. Science 300, 1251–1256 (2003).
Toyooka, Y., Tsunekawa, N., Akasu, R. & Noce, T. Embryonic stem cells can form germ cells in vitro. Proc. Natl Acad. Sci. USA 100, 11457–11462 (2003).
Geijsen, N. et al. Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature 427, 148–154 (2004).
Draper, J.S. et al. Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nat. Biotechnol. 22, 53–54 (2004).
Jiang, Y. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49 (2002).
Hwang, W.S. et al. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science 303, 1669–1674 (2004).
Ehrlich, P. The Collected Papers of Paul Ehrlich in Four Volumes Including a Complete Bibliography. ed. Himmelweit, F. (Pergamon, London, 1956).
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).
Marks, P.A. et al. Histone deacetylases and cancer: causes and therapies. Nat. Rev. Cancer 1, 194–202 (2001).
Maloney, A. & Workman, P. HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin. Biol. Ther. 2, 3–24 (2002).
Druker, B.J. Perspectives on the development of a molecularly targeted agent. Cancer Cell 1, 31–36 (2002).
Albanell, J. & Adams, J. Bortezomib, a proteasome inhibitor, in cancer therapy: from concept to clinic. Drugs of the Future 27, 1079–1092 (2002).
Ding, S., Gray, N.S., Wu, X., Ding, Q. & Schultz, P.G. A combinatorial scaffold approach toward kinase-directed heterocycle libraries. J. Am. Chem. Soc. 124, 1594–1596 (2002).
Wichterle, H., Lieberam, I., Porter, J.A. & Jessell, T.M. Directed differentiation of embryonic stem cells into motor neurons. Cell 110, 385–397 (2002).
Ding, S. et al. Synthetic small molecules that control stem cell fate. Proc. Natl. Acad. Sci. USA 100, 7632–7637 (2003).
Wang, S. et al. Isolation of neuronal precursors by sorting embryonic forebrain transfected with GFP regulated by the Ta1 tubulin promoter. Nat. Biotechnol. 16, 196–201 (1998).
McBurney, M.W. P19 embryonal carcinoma cells. Int. J. Dev. Biol. 37, 135–140 (1993).
Murry, C.E. et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428, 664–668 (2004).
Balsam, L.B. et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428, 668–673 (2004).
Nygren, J.M. et al. Bone marrow–derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat. Med. 10, 494–501 (2004).
Beltramin, A.P. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776 (2003).
Oh, H. et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc. Natl. Acad. Sci. USA 100, 12313–12318 (2003).
Cai, C.-L. et al. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Developmental Cell 5, 877–889 (2003).
Takahashi, T. et al. Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 107, 1912–1916 (2003).
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).
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).
Dor, Y., Brown, J., Martinez, O.I. & Melton, D.A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–46 (2004).
Lumelsky, N. et al. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292, 1389–1394 (2001).
Hori, Y. et al. Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc. Natl. Acad. Sci. USA 99, 16105–16110 (2003).
Drucker, D. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol. Endocrinol. 17, 161–171 (2003).
Giannoukakis, N. Exenatide Amylin/Eli Lilly. Curr. Opin. Investig. Drugs 4, 459–465 (2003). (For comprehensive and updated reviews on glucagon-like peptides, go to http://www.glucagon.com.)
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).
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 signaling by a pharmacological GSK-3-specific inhibitor. Nat. Med. 10, 55–63 (2004).
Dennis, J.E. & Caplan, A.I. Bone marrow mesenchymal stem cells. in Stem Cells Handbook (ed. Sell, S.) 107–117 (Humana Press Inc., Totowa, NJ, 2004).
Jaiswal, N., Haynesworth, S.E., Caplan, A.I. & Bruder, S.P. Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro. J. Cell. Biochem. 64, 295–312 (1997).
Grigoriadis, A.E., Heersche, J.N. & Aubin, J.E. Differentiation of muscle, fat, cartilage, and bone from progenitor cells present in a bone-derived clonal cell population: effect of dexamethasone. J. Cell Biol. 106, 2139–2151 (1988).
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).
Gage, F.H. Neurogenesis in the adult brain. J. Neurosci. 22, 612–613 (2002).
Gabay, L., Lowell, S., Rubin, L.L. & Anderson, D.J. Deregulation of dorsoventral patterning by FGF confers trilineage differentiation capacity on CNS stem cells in vitro. Neuron 40, 485–499 (2003).
Berman, D.M. et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297, 1559–1561 (2002).
Pardal, R., Clarke, M.F. & Morrison, S.J. Applying the principles of stem-cell biology to cancer. Nat. Rev. Cancer 3, 895–902 (2003).
Frank-Kamenetsky, M. et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1, 10 (2002).
Palmer, T.D., Takahashi, J. & Gage, F.H. The adult rat hippocampus contains primordial neural stem cells. Mol. Cell Neurosci. 8, 389–404 (1997).
Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).
Brockes, J.P. Amphibian limb regeneration: rebuilding a complex structure. Science 276, 81–87 (1997).
Terada, N. et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416, 542–545 (2002).
Ying, Q.-L, Nichols, J., Evans, E.P. & Smith, A.G. Changing potency by spontaneous fusion. Nature 416, 545–548 (2002).
Vassilopoulos, G., Wang, P.R. & Russell, D.W. Transplanted bone marrow regenerates liver by cell fusion. Nature 422, 901–904 (2003).
Wang, X. et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422, 897–901 (2003).
Weimann, J.M., Johansson, C.B., Trejo, A. & Blau, H.M. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat. Cell Biol. 5, 959–66 (2003).
Xie, H., Ye, M., Feng, R. & Graf, T. Stepwise reprogramming of B cells into macrophages. Cell 117, 663–676 (2004).
Jang, Y.-Y., Collector, M.I., Baylin, S.B., Mae Diehl, A. & Sharkis, S.J. Hematopoietic stem cells convert into liver cells within days without fusion. Nat. Cell Biol. 6, 532–539 (2004).
Lanza, R.P. et al. Generation of histocompatible tissues using nuclear transplantation. Nat. Biotechnol. 20, 665–666 (2002).
Eggan, K. et al. Mice cloned from olfactory sensory neurons. Nature 428, 44–49 (2004).
Håkelien, A.-M. et al. Reprogramming fibroblasts to express T-cell functions using cell extracts. Nat. Biotechnol. 20, 460–466 (2002).
Zhang, Z., Yuan, X.M., Li, L.H. & Xie, F.P. Transdifferentiation in neoplastic development and its pathological implication. Histol. Histopathol. 16, 1249–1262 (2001).
Odelberg, S.J., Kollhoff, A. & Keating, M.T. Dedifferentiation of mammalian myotubes induced by msx1. Cell 103, 1099–109 (2000).
McGann, C.J., Odelberg, S.J. & Keating, M.T. Mammalian myotube dedifferentiation induced by newt regeneration extract. Proc. Natl. Acad. Sci. USA 98, 13699–13704 (2001).
Rosania, G.R. et al. Myoseverin, a microtubule-binding molecule with novel cellular effects. Nat. Biotechnol. 18, 304–308 (2000).
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).
Shen, C.-N., Slack, J.M.W. & Tosh, D. Molecular basis of transdifferentiation of pancreas to liver. Nat. Cell Biol. 2, 879–887 (2000).
Skillington, J., Choy, L. & Derynck, R. Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J. Cell Biol. 159, 135–146 (2002).
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Ding, S., Schultz, P. A role for chemistry in stem cell biology. Nat Biotechnol 22, 833–840 (2004). https://doi.org/10.1038/nbt987
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DOI: https://doi.org/10.1038/nbt987
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