Natural and Synthetic Regulators of Embryonic Stem Cell Cardiogenesis
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Debilitating cardiomyocyte loss underlies the progression to heart failure. Although there have been significant advances in treatment, current therapies are intended to improve or preserve heart function rather than regenerate lost myocardium. A major hurdle in implementing a cell-based regenerative therapy is the inefficient differentiation of cardiomyocytes from either endogenous or exogenous stem cell sources. Moreover, cardiomyocytes that develop in human embryonic stem cell (hESC) or human-induced pluripotent stem cell (hIPSC) cultures are comparatively immature, even after prolonged culture, and differences in their calcium handling, ion channel, and force generation properties relative to adult cardiomyocytes raise concerns of improper integration and function after transplantation. Thus, the discovery of natural and novel small molecule synthetic regulators of differentiation and maturation would accelerate the development of stem-cell-based myocardial therapies. Here, we document recent advances in defining natural signaling pathways that direct the multistep cardiomyogenic differentiation program and the development of small molecules that might be used to enhance differentiation as well as the potential characteristics of lead candidates for pharmaceutical stimulation of endogenous myocardial replacement.
KeywordsCardiomyocyte Embryonic stem cell Chemical screening
Our research cited in this review was conducted in collaboration with the laboratories of Dr. Marcia I. Dawson (Burnham Institute), Dr. John Cashman (Human Biomolecular Research Institute), Dr. Clemencia Pinilla, and Dr. Richard Houghten (Torrey Pines Institute for Molecular Studies) and supported by research grants from the NIH/NHLBI and California Institute for Regenerative Medicine. This work was funded by grant support from the California Institute for Regenerative Medicine (CIRM) (RC1-00132-1), the NIH National Heart, Lung and Blood Institute (R37HL059502, R33HL088266), and Mather’s Charitable Foundation to MM and CIRM fellowship (T2-00004) to EW.
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