Summary of signaling pathways regulating cardiomyocyte proliferation. Hippo/YAP signaling is inactive when p-YAP is bound to the dystrophin glycoprotein complex (DGC). Binding of Agrin to the DGC leads to the translocation of p-YAP to the cytoplasm, phosphorylation of YAP is regulated by the kinase complex (Mst1/Lats2/Salv), and dephosphorylation of p-YAP by PP1/PP2A or others results in YAP activation and translocation to the nucleus. FGF signaling activates the MAPK pathway and induces the expression of Dusp6, a negative regulator of pERK, and Dusp6 protein is post-transcriptionally modified and degraded by H₂O₂. The PI3K-AKT signaling is regulated by NRG1/ErbB2/4, periostin/integrin, small molecule carbocyclin, and Wnt signaling pathways, which fine-tune β-catenin activity and its translocation into the nucleus. Binding of ligands such as Delta/Jagged to Notch receptors leads to Notch intracellular domain (NICD) activation and translocation to the nucleus. Together with injury-induced activation of chromatin remodeling factor Brg1/Dnmt3ab, the Yap/pERK-β-catenin/NICD activation in the nucleus regulates the expression of cell-cycle regulators including cyclins and cyclin inhibitors

Working model of injury-induced cardiomyocyte proliferation. Injury signals trigger the cell-cycle re-entry of CMs, leading to the formation of mononuclear, polynuclear, or polyploidy CMs. De-differentiation signals together with extracellular matrix (ECM) re-organization then regulate the generation of putative de-differentiated CMs, which have evident changes in mitochondrial morphology, disassembled sarcomeres, and reduced cell adhesion. Finally, reprogramming signals and mitogens drive the formation of putative progenitors and cell division