Abstract
Heart failure is one of the major causes of death in the Western world because cardiac muscle loss is largely irreversible and can lead to a relentless decline in cardiac function. Novel therapies are needed since the only therapy to effectively replace lost myocytes today is transplantation of the entire heart. The advent of embryonic and induced pluripotent stem cell (ESC/iPSC) technologies offers the unprecedented possibility of devising cell replacement therapies for numerous degenerative disorders. Not only are ESCs and iPSCs a plausible source of cardiomyocytes in vitro for transplantation, they are also useful tools to elucidate the biology of stem cells that reside in the adult heart and define signaling molecules that might enhance the limited regenerative capability of the adult human heart. Here, we review the extracellular factors that control stem cell cardiomyogenesis and describe new approaches that combine embryology with stem cell biology to discover drug-like small molecules that stimulate cardiogenesis and potentially contribute to the development of pharmaceutical strategies for heart muscle regeneration.
Similar content being viewed by others
References
AHA (2010). AHA Update 2010. http://www.aha.org.
Olson, E. N., & Schneider, M. D. (2003). Sizing up the heart: development redux in disease. Genes & Development, 17, 1937–1956.
Kehat, I., Gepstein, A., Spira, A., Itskovitz-Eldor, J., & Gepstein, L. (2002). High-resolution electrophysiological assessment of human embryonic stem cell-derived cardiomyocytes: a novel in vitro model for the study of conduction. Circulation Research, 91, 659–661.
Binah, O., et al. (2007). Functional and developmental properties of human embryonic stem cells-derived cardiomyocytes. Journal of Electrocardiology, 40, S192–S196.
Kita-Matsuo, H., et al. (2009). Lentiviral vectors and protocols for creation of stable hESC lines for fluorescent tracking and drug resistance selection of cardiomyocytes. PLoS ONE, 4, e5046.
Liu, J., Fu, J. D., Siu, C. W., & Li, R. A. (2007). Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation. Stem cells (Dayton, Ohio), 25, 3038–3044.
Dolnikov, K., et al. (2006). Functional properties of human embryonic stem cell-derived cardiomyocytes: intracellular Ca2+ handling and the role of sarcoplasmic reticulum in the contraction. Stem cells (Dayton, Ohio), 24, 236–245.
Laflamme, M. A., et al. (2005). Formation of human myocardium in the rat heart from human embryonic stem cells. The American Journal of Pathology, 167, 663–671.
Germanguz, I., et al. (2011). Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells. J Cell Mol Med, 15, 38–51.
Laflamme, M. A., et al. (2007). Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nature Biotechnology, 25, 1015–1024.
van Laake, L. W., Passier, R., Doevendans, P. A., & Mummery, C. L. (2008). Human embryonic stem cell-derived cardiomyocytes and cardiac repair in rodents. Circulation Research, 102, 1008–1010.
Xu, C., Police, S., Rao, N., & Carpenter, M. K. (2002). Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circulation Research, 91, 501–508.
Yang, L., et al. (2008). Human cardiovascular progenitor cells develop from a KDR + embryonic-stem-cell-derived population. Nature, 453, 524–528.
Bergmann, O., et al. (2009). Evidence for cardiomyocyte renewal in humans. Science, 324, 98–102.
Hsieh, P. C., et al. (2007). Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nature Medicine, 13, 970–974.
Bersell, K., Arab, S., Haring, B., & Kuhn, B. (2009). Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell, 138, 257–270.
Kuhn, B., et al. (2007). Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Natural Medicines, 13, 962–969.
Zhang, Y., et al. (2010). Dedifferentiation and proliferation of mammalian cardiomyocytes. PLoS One, 5, e12559.
Wojakowski, W., et al. (2004). Mobilization of CD34/CXCR4+, CD34/CD117+, c-met + stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation, 110, 3213–3220.
Limana, F., et al. (2010). Myocardial infarction induces embryonic reprogramming of epicardial c-kit(+) cells: role of the pericardial fluid. J Mol Cell Cardiol, 48, 609–618.
Di Meglio, F., et al. (2010). Epicardial cells are missing from the surface of hearts with ischemic cardiomyopathy: a useful clue about the self-renewal potential of the adult human heart? Int J Cardiol, 145(2), e44–e46.
Beltrami, A. P., et al. (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell, 114, 763–776.
Oh, H., et al. (2003). Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proceedings of the National Academy of Sciences of the United States of America, 100, 12313–12318.
Laugwitz, K. L., et al. (2005). Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature, 433, 647–653.
Hierlihy, A. M., Seale, P., Lobe, C. G., Rudnicki, M. A., & Megeney, L. A. (2002). The post-natal heart contains a myocardial stem cell population. FEBS Letters, 530, 239–243.
Messina, E., et al. (2004). Isolation and expansion of adult cardiac stem cells from human and murine heart. Circulation Research, 95, 911–921.
Smith, R. R., et al. (2007). Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation, 115, 896–908.
Poss, K. D., Wilson, L. G., & Keating, M. T. (2002). Heart regeneration in zebrafish. Science, 298, 2188–2190.
Zhang, M., et al. (2001). Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. Journal of Molecular and Cellular Cardiology, 33, 907–921.
Fransioli, J., et al. (2008). Evolution of the c-kit-positive cell response to pathological challenge in the myocardium. Stem Cells, 26, 1315–1324.
Kubo, H., et al. (2008). Increased cardiac myocyte progenitors in failing human hearts. Circulation, 118, 649–657.
Raya, A., et al. (2003). Activation of Notch signaling pathway precedes heart regeneration in zebrafish. Proceedings of the National Academy of Sciences of the United States of America, 100(Suppl 1), 11889–11895.
Kikuchi, K., et al. (2010). Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature, 464, 601–605.
Jopling, C., et al. (2010). Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature, 464, 606–609.
MacLellan, W. R., & Schneider, M. D. (2000). Genetic dissection of cardiac growth control pathways. Annual Review of Physiology, 62, 289–320.
Rubart, M., & Field, L. J. (2006). Cardiac regeneration: repopulating the heart. Annual Review of Physiology, 68, 29–49.
Gadue, P., Huber, T. L., Paddison, P. J., & Keller, G. M. (2006). Wnt and TGF-{beta} 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(45), 16806–16811.
Lindsley, R. C., Gill, J. G., Kyba, M., Murphy, T. L., & Murphy, K. M. (2006). Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm. Development, 133, 3787–3796.
D'Amour, K. A., et al. (2005). Efficient differentiation of human embryonic stem cells to definitive endoderm. Nature Biotechnology, 23, 1534–1541.
Yasunaga, M., et al. (2005). Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nature Biotechnology, 23, 1542–1550.
Willems, E., & Leyns, L. (2008). Patterning of mouse embryonic stem cell-derived pan-mesoderm by Activin A/Nodal and Bmp4 signaling requires Fibroblast Growth Factor activity. Differentiation, 76, 745–759.
Marvin, M. J., Di Rocco, G., Gardiner, A., Bush, S. M., & Lassar, A. B. (2001). Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes & Development, 15, 316–327.
Schneider, V. A., & Mercola, M. (2001). Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes & Development, 15, 304–315.
Foley, A. C., Korol, O., Timmer, A. M., & Mercola, M. (2007). Multiple functions of Cerberus cooperate to induce heart downstream of Nodal. Developmental Biology, 303, 57–65.
Foley, A. C., & Mercola, M. (2005). Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex. Genes & Development, 19, 387–396.
Naito, A. T., et al. (2006). Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis. Proceedings of the National Academy of Sciences of the United States of America, 103, 19812–19817.
Ueno, S., et al. (2007). Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104, 9685–9690.
Kitamura, R., et al. (2007). Stage-specific role of endogenous Smad2 activation in cardiomyogenesis of embryonic stem cells. Circulation Research, 101, 78–87.
Chen, V. C., Stull, R., Joo, D., Cheng, X., & Keller, G. (2008). Notch signaling respecifies the hemangioblast to a cardiac fate. Nature Biotechnology, 26, 1169–1178.
Qyang, Y., et al. (2007). The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway. Cell Stem Cell, 1, 165–179.
Kwon, C., et al. (2007). Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors. Proceedings of the National Academy of Sciences of the United States of America, 104, 10894–10899.
Tirosh-Finkel, L., et al. (2010). BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors. Development, 137, 2989–3000.
Campa, V. M., et al. (2008). Notch activates cell cycle reentry and progression in quiescent cardiomyocytes. The Journal of Cell Biology, 183, 129–141.
Collesi, C., Zentilin, L., Sinagra, G., & Giacca, M. (2008). Notch1 signaling stimulates proliferation of immature cardiomyocytes. The Journal of Cell Biology, 183, 117–128.
Xu, Y., Shi, Y., & Ding, S. (2008). A chemical approach to stem-cell biology and regenerative medicine. Nature, 453, 338–344.
Kattman, S. J., et al. (2011). Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell, 8, 228–240.
Zeineddine, D., et al. (2006). Oct-3/4 dose dependently regulates specification of embryonic stem cells toward a cardiac lineage and early heart development. Developmental Cell, 11, 535–546.
Takahashi, T., et al. (2003). Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation, 107, 1912–1916.
Sadek, H., et al. (2008). Cardiogenic small molecules that enhance myocardial repair by stem cells. Proceedings of the National Academy of Sciences of the United States of America, 105, 6063–6068.
Bushway, P. J., Mercola, M., & Price, J. H. (2008). A comparative analysis of standard microtiter plate reading versus imaging in cellular assays. Assay and Drug Development Technologies, 6, 557–567.
Wu, X., Ding, S., Ding, Q., Gray, N. S., & Schultz, P. G. (2004). Small molecules that induce cardiomyogenesis in embryonic stem cells. Journal of the American Chemical Society, 126, 1590–1591.
Wei, Z. L., et al. (2004). Isoxazolyl-serine-based agonists of peroxisome proliferator-activated receptor: design, synthesis, and effects on cardiomyocyte differentiation. Journal of the American Chemical Society, 126, 16714–16715.
Dinsmore, J., et al. (1996). Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. Cell Transplantation, 5, 131–143.
De Tullio, M. C., & Arrigoni, O. (2004). Hopes, disillusions and more hopes from vitamin C. Cellular and Molecular Life Sciences, 61, 209–219.
Bushway, P. J., & Mercola, M. (2006). High-throughput screening for modulators of stem cell differentiation. Methods in Enzymology, 414, 300–316.
Frormann, S. & Jas, G (2002). Natural Products and Combinatorial Chemistry: the comeback of nature in drug discovery. Business Briefing Future Drug Discovery, 84–90.
Rishton, G. M. (2003). Nonleadlikeness and leadlikeness in biochemical screening. Drug Discovery Today, 8, 86–96.
Feher, M., & Schmidt, J. M. (2003). Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. Journal of Chemical Information and Computer Sciences, 43, 218–227.
Hann, M. M., Leach, A. R., & Harper, G. (2001). Molecular complexity and its impact on the probability of finding leads for drug discovery. Journal of Chemical Information and Computer Sciences, 41, 856–864.
Teague, S. J., Davis, A. M., Leeson, P. D., & Oprea, T. (1999). The design of leadlike combinatorial libraries. Angewandte Chemie (International Ed. in English), 38, 3743–3748.
Newman, D. J., Cragg, G. M., & Snader, K. M. (2003). Natural products as sources of new drugs over the period 1981–2002. Journal of Natural Products, 66, 1022–1037.
Gupta, S., Maurya, M. R., & Subramaniam, S. (2010). Identification of crosstalk between phosphoprotein signaling pathways in RAW 264.7 macrophage cells. PLoS Comput Biol, 6, e1000654.
Pradervand, S., Maurya, M. R., & Subramaniam, S. (2006). Identification of signaling components required for the prediction of cytokine release in RAW 264.7 macrophages. Genome Biology, 7, R11.
Brill, L. M., et al. (2009). Phosphoproteomic analysis of human embryonic stem cells. Cell Stem Cell, 5, 204–213.
Van Hoof, D., et al. (2009). Phosphorylation dynamics during early differentiation of human embryonic stem cells. Cell Stem Cell, 5, 214–226.
Chen, B., et al. (2009). Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nature Chemical Biology, 5, 100–107.
Chi, X., et al. (2003). Expression of Nkx2-5-GFP bacterial artificial chromosome transgenic mice closely resembles endogenous Nkx2-5 gene activity. Genesis, 35, 220–226.
Craig, P. N. (1971). Interdependence between physical parameters and selection of substituent groups for correlation studies. Journal of Medicinal Chemistry, 14, 680–684.
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 46, 3–26.
Cashman, J. R., & MacDougall, J. M. (2005). Dynamic medicinal chemistry in the elaboration of morphine-6-glucuronide analogs. Current Topics in Medicinal Chemistry, 5, 585–594.
Domian, I. J., et al. (2009). Generation of functional ventricular heart muscle from mouse ventricular progenitor cells. Science, 326, 426–429.
Acknowledgments
This work was supported by grants from the NIH (R37HL59502, R33HL088266) and California Institute for Regenerative Medicine (CIRM) (RC1001321) to MM; CIRM (SEED RS1001691) and T Foundation to JRC; and CIRM Training Grant T2-00004 and American Heart Association for postdoctoral grant to EW.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Willems, E., Lanier, M., Forte, E. et al. A Chemical Biology Approach to Myocardial Regeneration. J. of Cardiovasc. Trans. Res. 4, 340–350 (2011). https://doi.org/10.1007/s12265-011-9270-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12265-011-9270-6