Dynamic map illuminates Hippo to cMyc module crosstalk driving cardiomyocyte proliferation

Cardiac diseases are characterized by the inability of adult mammalian hearts to overcome the loss of cardiomyocytes (CMs). Current knowledge in cardiac regeneration lacks a clear understanding of the molecular systems determining whether CMs will progress through the cell cycle to proliferate. Here, we developed a computational model of cardiac proliferation signaling that identifies key regulators and provides a systems-level understanding of the cardiomyocyte proliferation regulatory network. This model defines five regulatory networks (DNA replication, mitosis, cytokinesis, growth factor, hippo pathway) of cardiomyocyte proliferation, which integrates 72 nodes and 88 reactions. The model correctly predicts 72 of 76 (94.7%) independent experiments from the literature. Network analysis predicted key signaling regulators of DNA replication (e.g., AKT, CDC25A, Cyclin D/CDK4, E2F), mitosis (e.g., Cyclin B/CDK2, CDC25B/C, PLK1), and cytokinesis, whose functions varied depending on the environmental context. Regulators of DNA replication were found to be highly context-dependent, while regulators of mitosis and cytokinesis were context-independent. We also predicted that in response to the YAP-activating compound TT-10, the Hippo module crosstalks with the growth factor module via PI3K, cMyc, and FoxM1 to drive proliferation. This prediction was validated with inhibitor experiments in primary rat cardiomyocytes and further supported by re-analysis of published data on YAP-stimulated mRNA and open chromatin of Myc from mouse hearts. This study contributes a systems framework for understanding cardiomyocyte proliferation and identifies potential therapeutic regulators that induce cardiomyocyte proliferation.