期刊
NATURE CELL BIOLOGY
卷 17, 期 5, 页码 627-U207出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3149
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资金
- European Research Council
- Israel Science Foundation
- Louis and Fannie Tolz Elollaborative Research Project
- Estate of Jack Gitlitz
- National Health and Medical Research Council (NHMRC) of Australia [573705, 573732]
- Australian Research Council Special Initiative in Stem Cell Science (Stem Cells 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 GSK beta/beta-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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