ERBB2 triggers mammalian heart regeneration by promoting cardiorlyocyte dedifferentiation and proliferation
ERBB2 triggers mammalian heart regeneration by promoting cardiorlyocyte dedifferentiation and proliferation
复制标题
DOI：
10.1038/ncb3149
复制
发表时间：
2015-05-01
影响因子：
21.3
通讯作者：
Tzahor, Eldad
中科院分区：
文献类型：
--
作者：
D'Uva, Gabriele;Aharonov, Alla;Tzahor, Eldad
小鼠新生心脏可以通过心肌细胞（CM）增殖在损伤后再生，尽管这种能力在生命的第一周后显著降低。神经调节蛋白-1（NRG 1）给药已被提出作为促进心脏再生的策略。在这里，使用功能丧失和获得的遗传工具，我们探讨了NRG 1辅助受体ERBB 2在心脏再生中的作用。NRG 1诱导的CM增殖在出生后一周由于ERBB 2表达的减少而减少。CM特异性Erbb 2基因敲除表明，ERBB 2是胚胎/新生儿阶段CM增殖所必需的。在新生儿、青少年和成人CM中诱导组成性活性ERBB 2（caERBB 2）导致心脏肥大，其特征在于广泛的CM肥大、去分化和增殖，由ERK、AKT和GSK β/β-连环蛋白信号通路差异介导。心肌梗死后瞬时诱导caERBB 2触发CM去分化和增殖，然后再分化和再生。因此，ERBB 2是CM增殖所必需的，并且足以重新激活出生后CM增殖和再生潜能。
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.