Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart.
Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart.
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DOI：
10.1161/circresaha.110.218487
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发表时间：
2010-08-06
影响因子：
20.1
通讯作者：
Leri A
中科院分区：
文献类型：
--
作者：
Urbanek K;Cabral-da-Silva MC;Ide-Iwata N;Maestroni S;Delucchi F;Zheng H;Ferreira-Martins J;Ogórek B;D'Amario D;Bauer M;Zerbini G;Rota M;Hosoda T;Liao R;Anversa P;Kajstura J;Leri A
发育中的心脏生理性肥大被认为是在没有心肌细胞形成的情况下，先前存在的胎儿心肌细胞体积增加的产物。在这项研究中，我们测试了小鼠心脏在出生时是否拥有心脏干细胞(CSCs)池，这些干细胞在出生后分化为肌细胞，有助于实质细胞室的扩张。我们发现，新生心脏含有一群c-kit阳性的CSCs，它们是谱系阴性的、自我更新的和多潜能的。CSCs表达Notch1受体，并显示其活性片段N1ICD的核定位。在60%的病例中，N1ICD与NKX2.5的存在相结合，表明CSCs对心肌细胞谱系的承诺受到Notch1的调控。重要的是，N1ICD在新生CSCs中的过表达显著增加了瞬时扩增心肌细胞的比例。为了确定这些体外研究结果在体内是否具有功能上的对应性，通过给新生小鼠注射γ分泌酶抑制剂来阻断Notch通路。这种干预导致了扩张性肌病的发展和高死亡率。心室失代偿的特征是放大的肌细胞减少了62%，导致心肌细胞数量减少了54%。随着Notch阻断的停止和心肌细胞再生的恢复，心脏解剖和功能基本恢复。NOTCH1信号是CSC生长和分化的关键决定因素，当这一系列事件改变时，心肌生成受到损害，生理性心肌肥厚被预防，危及生命的肌病发生。
Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation. In this study, we tested whether the mouse heart possesses at birth a pool of cardiac stem cells (CSCs) which differentiate into myocytes contributing to the expansion of the parenchymal cell compartment postnatally. We have found that the newborn heart contains a population of c-kit-positive CSCs which are lineage negative, self-renewing and multipotent. CSCs express the Notch1 receptor and show the nuclear localization of its active fragment, N1ICD. In 60% of cases, N1ICD was coupled with the presence of Nkx2.5 indicating that the commitment of CSCs to the myocyte lineage is regulated by Notch1. Importantly, overexpression of N1ICD in neonatal CSCs expanded significantly the proportion of transit amplifying myocytes. To establish whether these in vitro findings had a functional counterpart in vivo, the Notch pathway was blocked in newborn mice by administration of a γ-secretase inhibitor. This intervention resulted in the development of a dilated myopathy and high mortality. Ventricular decompensation was characterized by a 62% reduction in amplifying myocytes which resulted in a 54% decrease in myocyte number. Following cessation of Notch blockade and recovery of myocyte regeneration, cardiac anatomy and function were largely restored. Notch1 signaling is a critical determinant of CSC growth and differentiation and when this cascade of events is altered cardiomyogenesis is impaired, physiological cardiac hypertrophy is prevented and a life threatening myopathy supervenes.