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Nat Cell Biol. 2015 May;17(5):627-38. doi: 10.1038/ncb3149. Epub 2015 Apr 6.

ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation.

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Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
1] Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel [2] Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, 40138 Bologna, Italy.
Tamman Cardiovascular Research Institute, Leviev Heart Center, Chaim Sheba Medical Center, Tel Aviv 52621, Israel.
Department of Pediatric Cardiology, Chaim Sheba Medical Center, Tel Aviv 52621, Israel.
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
1] Victor Chang Cardiac Research Institute, Darlinghurst 2010, Australia [2] St Vincent's Clinical School, University of New South Wales, Kensington 2052, Australia [3] School of Biological and Biomolecular Sciences, University of New South Wales, Kensington 2052, Australia.


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.

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