TAp63 Is Important for Cardiac Differentiation of Embryonic Stem Cells and Heart Development
TAp63 Is Important for Cardiac Differentiation of Embryonic Stem Cells and Heart Development
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DOI：
10.1002/stem.723
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发表时间：
2011-11-01
期刊：
影响因子：
5.2
通讯作者：
Aberdam, Daniel
中科院分区：
文献类型：
--
作者：
Rouleau, Matthieu;Medawar, Alain;Aberdam, Daniel
P63是P53家族中的一员，对皮肤形态发生和上皮干细胞的维持至关重要。在这里，我们报告了一个意想不到的TAp63在心脏发生中的作用。P63基因缺失的小鼠在胚胎心脏发育中表现出严重的缺陷，包括双侧脑室扩张、小梁形成缺陷和异常间隔。伴随而来的是肌原纤维紊乱、线粒体紊乱和自发性钙尖峰减少。通过胚胎干细胞(ESCs)的使用，我们发现TAp63缺乏阻止了关键心脏基因的表达和心肌细胞的产生。TAp63由内皮细胞表达。P63基因敲除的胚胎干细胞与野生型胚胎干细胞共培养，补充激活素A，或过表达GATA-6挽救心脏发生。因此，TAp63通过调节内皮细胞因子的表达，以非细胞自主的方式发挥作用。我们的发现揭示了p63在心脏发生中的关键作用，这可能与人类心脏病有关。干细胞2011；29：1672-1683
p63, a member of the p53 family, is essential for skin morphogenesis and epithelial stem cell maintenance. Here, we report an unexpected role of TAp63 in cardiogenesis. p63 null mice exhibit severe defects in embryonic cardiac development, including dilation of both ventricles, a defect in trabeculation and abnormal septation. This was accompanied by myofibrillar disarray, mitochondrial disorganization, and reduction in spontaneous calcium spikes. By the use of embryonic stem cells (ESCs), we show that TAp63 deficiency prevents expression of pivotal cardiac genes and production of cardiomyocytes. TAp63 is expressed by endodermal cells. Coculture of p63-knockdown ESCs with wildtype ESCs, supplementation with Activin A, or overexpression of GATA-6 rescue cardiogenesis. Therefore, TAp63 acts in a non-cell-autonomous manner by modulating expression of endodermal factors. Our findings uncover a critical role for p63 in cardiogenesis that could be related to human heart disease. STEM CELLS 2011;29:1672-1683