Computational and Experimental Modeling of Cardiomyocyte Proliferation

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Summary Heart failure arises in large part due to the very limited ability of cardiomyocytes to regenerate following injury. Recent studies have identified some molecular regulators of cardiomyocyte proliferation in mammals, but the field lacks an understanding of how these and yet-to-be identified components work as a system to regulate cardiomyocyte proliferation. A better understanding of the pathways that control CM proliferation and cell cycle exit is needed in order to develop strategies that stimulate CM proliferation as a regenerative therapy. Here, we integrate innovative computational and experimental methods to develop a systems-level understanding of cardiomyocyte proliferation. First, we develop a literature-based computational model of the molecular network, comprising known regulators of cardiomyocyte proliferation. This network model is expanded mechanistically to include novel regulators of cardiomyocyte proliferation that we have discovered through a genome-wide phenotypic screen, including several in a TGF-beta module. Model-predicted regulators within this TGF-beta module are validated experimentally in mouse cardiomyocytes, human induced pluripotent stem-cell derived cardiomyocytes, and an in vivo mouse model of cardiac regeneration. Overall, this study will provide novel candidate therapeutic targets for cardiomyocyte proliferation, the first mechanistic model integrating these candidates and known regulators of cardiomyocyte proliferation, and experimental validation that the model can predict network perturbations that enhance cardiomyocyte proliferation in vitro and in vivo.