Cell Stem Cell ( IF 23.9 ) Pub Date : 2020-08-17 , DOI: 10.1016/j.stem.2020.07.015 Yifei Miao 1 , Lei Tian 2 , Marcy Martin 3 , Sharon L Paige 4 , Francisco X Galdos 4 , Jibiao Li 5 , Alyssa Klein 3 , Hao Zhang 2 , Ning Ma 2 , Yuning Wei 6 , Maria Stewart 7 , Soah Lee 4 , Jan-Renier Moonen 3 , Bing Zhang 8 , Paul Grossfeld 9 , Seema Mital 10 , David Chitayat 11 , Joseph C Wu 2 , Marlene Rabinovitch 3 , Timothy J Nelson 12 , Shuyi Nie 5 , Sean M Wu 4 , Mingxia Gu 1
Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterized by abnormalities in the left ventricle, associated valves, and ascending aorta. Studies have shown intrinsic myocardial defects but do not sufficiently explain developmental defects in the endocardial-derived cardiac valve, septum, and vasculature. Here, we identify a developmentally impaired endocardial population in HLHS through single-cell RNA profiling of hiPSC-derived endocardium and human fetal heart tissue with an underdeveloped left ventricle. Intrinsic endocardial defects contribute to abnormal endothelial-to-mesenchymal transition, NOTCH signaling, and extracellular matrix organization, key factors in valve formation. Endocardial abnormalities cause reduced cardiomyocyte proliferation and maturation by disrupting fibronectin-integrin signaling, consistent with recently described de novo HLHS mutations associated with abnormal endocardial gene and fibronectin regulation. Together, these results reveal a critical role for endocardium in HLHS etiology and provide a rationale for considering endocardial function in regenerative strategies.
中文翻译:
内在心内膜缺陷导致左心发育不良综合征。
左心发育不全综合征(HLHS)是一种复杂的先天性心脏病,其特征是左心室、相关瓣膜和升主动脉异常。研究表明存在固有的心肌缺陷,但不能充分解释心内膜衍生的心脏瓣膜、隔膜和脉管系统的发育缺陷。在这里,我们通过 hiPSC 衍生的心内膜和左心室发育不全的人胎儿心脏组织的单细胞 RNA 分析,确定了 HLHS 中发育受损的心内膜群体。内在性心内膜缺陷导致异常的内皮-间质转化、NOTCH 信号传导和细胞外基质组织,这些是瓣膜形成的关键因素。心内膜异常通过破坏纤连蛋白-整合素信号传导导致心肌细胞增殖和成熟减少,与异常心内膜基因和纤连蛋白调节相关的从头HLHS 突变。总之,这些结果揭示了心内膜在 HLHS 病因学中的关键作用,并为在再生策略中考虑心内膜功能提供了依据。