Molecular regulation of myocardial proliferation and regeneration

Abstract

Heart regeneration is a fascinating and complex biological process. Decades of intensive studies have revealed a sophisticated molecular network regulating cardiac regeneration in the zebrafish and neonatal mouse heart. Here, we review both the classical and recent literature on the molecular and cellular mechanisms underlying heart regeneration, with a particular focus on how injury triggers the cell-cycle re-entry of quiescent cardiomyocytes to replenish their massive loss after myocardial infarction or ventricular resection. We highlight several important signaling pathways for cardiomyocyte proliferation and propose a working model of how these injury-induced signals promote cardiomyocyte proliferation. Thus, this concise review provides up-to-date research progresses on heart regeneration for investigators in the field of regeneration biology.

Keywords: Cardiac regeneration; Cardiomyocyte proliferation; Mouse; Signaling pathways; Zebrafish.

Fig. 1

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

Fig. 2

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