ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation

Abstract

The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3β/β-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

“…This is further supported by another study where they showed that Nrg1 lost its ability to promote cardiomyocyte proliferation after P7, concomitant with the postnatal down-regulation of its receptor Erbb2 (D'Uva et al, 2015).…”

“…Interestingly, overexpression of constitutively active Erbb2 promoted neonatal and adult cardiomyocyte proliferation as well as adult cardiac function following MI (D'Uva et al, 2015).…”

Endothelial Derived Neuregulin-1 may be Important for Cardioprotection Induced by Ischemic Preconditioning

“…Fang et al (17) had confirmed that NRG-1 can protect myocardium from IRI through a PI3K/Akt pathway. D' Uva et al (29) showed that selectively activating ErbB2 receptors on the myocardium can induce cardiomyocyte proliferation and improve the recovery of cardiac function, with less infarct size, more vascularization and less scarring.…”

Viability testing to guide myocardial revascularisation in patients with heart failure

“…[17] In animal models of regeneration, cardiomyocyte dedifferentiation (with sarcomere disassembly) occurs as the first stage of proliferation and is triggered by hypoxia. [18,19] In humans, proliferation may stall due to persistent hypoxia or limited energetic substrate. [20,21] Following revascularisation, cardiomyocyte re-differentiation and proliferation has been observed, which may underlie functional recovery [22].…”