Hippo pathway effector Yap promotes cardiac regeneration

TLDR

The adult mammalian heart has limited regenerative capacity, whereas the neonatal heart can regenerate through cardiomyocyte proliferation, a process promoted by the Hippo pathway effector Yap via insulin‑like growth factor and Wnt signaling. The study aims to identify critical regulators of cardiomyocyte proliferation and quiescence, focusing on the role of Yap in cardiac regeneration. Loss of Yap or its paralog Taz causes dose‑dependent cardiac defects, Yap deletion blocks neonatal regeneration and induces fibrosis, while constitutively active Yap drives adult heart regeneration and improves contractility after infarction by activating embryonic and proliferative gene programs, establishing Yap as a key regulator of cardiac regeneration.

Abstract

The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.