Cell stem cell · 2020
Intrinsic Endocardial Defects Contribute to Hypoplastic Left Heart Syndrome.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Miao Yifei, Tian Lei, Martin Marcy, Paige Sharon L, Galdos Francisco X, Li Jibiao, Klein Alyssa, Zhang Hao, Ma Ning, Wei Yuning, Stewart Maria, Lee Soah, Moonen Jan-Renier, Zhang Bing, Grossfeld Paul, Mital Seema, Chitayat David, Wu Joseph C, Rabinovitch Marlene, Nelson Timothy J, Nie Shuyi, Wu Sean M, Gu Mingxia
Аннотация
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.