Title: Intrinsic Endocardial Defects Contribute to Hypoplastic Left Heart Syndrome
Author: Yifei Miao, Lei Tian, Marcy Martin, Sharon L. Paige, Francisco X. Galdos, Jibiao Li, Alyssa Klein, Hao Zhang, Ning Ma, Yuning Wei, Maria Stewart, Soah Lee, Jan-Renier Moonen, Bing Zhang, Paul Grossfeld, Seema Mital, David Chitayat, Joseph C. Wu, Marlene Rabinovitch, Timothy J. Nelson, Shuyi Nie, Sean M. Wu, Mingxia Gu
Abstract: Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterizedby abnormalities in the left ventricle, associated valves, and ascending aorta. Studieshave shown intrinsic myocardial defects but do not sufficiently explain developmentaldefects in the endocardial-derived cardiac valve, septum, and vasculature. Here, weidentify a developmentally impaired endocardial population in HLHS through single-cellRNA profiling of hiPSC-derived endocardium and human fetal heart tissue with an underdevelopedleft ventricle. Intrinsic endocardial defects contribute to abnormal endothelial-to-mesenchymaltransition, NOTCH signaling, and extracellular matrix organization, key factors invalve formation. Endocardial abnormalities cause reduced cardiomyocyte proliferationand maturation by disrupting fibronectin-integrin signaling, consistent with recentlydescribed de novo HLHS mutations associated with abnormal endocardial gene and fibronectin regulation.Together, these results reveal a critical role for endocardium in HLHS etiology andprovide a rationale for considering endocardial function in regenerative strategies.