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

doi:10.1038/ncb3149

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

527 Scopus citations

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 language	English
Pages (from-to)	627-638
Number of pages	12
Journal	Nature Cell Biology
Volume	17
Issue number	5
DOIs	https://doi.org/10.1038/ncb3149
State	Published - 5 May 2015
Externally published	Yes

Funding

Funders	Funder number
European Research Council, Israel Science Foundation
Australian Research Council Special Initiative in Stem Cell Science
European Commission	281289
National Health and Medical Research Council	573705, 573732

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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D'Uva, G., Aharonov, A., Lauriola, M., Kain, D., Yahalom-Ronen, Y., Carvalho, S., Weisinger, K., Bassat, E., Rajchman, D., Yifa, O., Lysenko, M., Konfino, T., Hegesh, J., Brenner, O., Neeman, M., Yarden, Y., Leor, J., Sarig, R., Harvey, R. P., & Tzahor, E. (2015). ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nature Cell Biology, 17(5), 627-638. https://doi.org/10.1038/ncb3149

@article{d21dbde418a34fdbb75d3769e994cabd,

title = "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 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.",

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

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year = "2015",

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doi = "10.1038/ncb3149",

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D'Uva, G, Aharonov, A, Lauriola, M, Kain, D, Yahalom-Ronen, Y, Carvalho, S, Weisinger, K, Bassat, E, Rajchman, D, Yifa, O, Lysenko, M, Konfino, T, Hegesh, J, Brenner, O, Neeman, M, Yarden, Y, Leor, J, Sarig, R, Harvey, RP & Tzahor, E 2015, 'ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation', Nature Cell Biology, vol. 17, no. 5, pp. 627-638. https://doi.org/10.1038/ncb3149

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T1 - ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation

AU - D'Uva, Gabriele

AU - Aharonov, Alla

AU - Lauriola, Mattia

AU - Kain, David

AU - Yahalom-Ronen, Yfat

AU - Carvalho, Silvia

AU - Weisinger, Karen

AU - Bassat, Elad

AU - Rajchman, Dana

AU - Yifa, Oren

AU - Lysenko, Marina

AU - Konfino, Tal

AU - Hegesh, Julius

AU - Brenner, Ori

AU - Neeman, Michal

AU - Yarden, Yosef

AU - Leor, Jonathan

AU - Sarig, Rachel

AU - Harvey, Richard P.

AU - Tzahor, Eldad

PY - 2015/5/5

Y1 - 2015/5/5

N2 - 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.

AB - 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.

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SN - 1465-7392

VL - 17

SP - 627

EP - 638

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 5

ER -

ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation

Abstract

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