ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation

Gabriele D'Uva, Alla Aharonov, Mattia Lauriola, David Kain, Yfat Yahalom-Ronen, Silvia Carvalho, Karen Weisinger, Elad Bassat, Dana Rajchman, Oren Yifa, Marina Lysenko, Tal Konfino, Julius Hegesh, Ori Brenner, Michal Neeman, Yosef Yarden, Jonathan Leor, Rachel Sarig, Richard P. Harvey, Eldad Tzahor

Research output: Contribution to journalArticlepeer-review

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 GSK3 2/2-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.

Original languageEnglish
Pages (from-to)627-638
Number of pages12
JournalNature Cell Biology
Volume17
Issue number5
DOIs
StatePublished - 5 May 2015
Externally publishedYes

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