Combined Treatment of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates

作者：Yu‐Che Cheng, Marvin L. Hsieh, Chen‐Ju Lin, Cindy M. Chang, Ching-Ying Huang, Riley Puntney, Amy Moy, Chien-Yu Ting, Darien Zhing Herr Chan, Martin W. Nicholson, Po‐Ju Lin, Hung-Chih Chen, Gina C. Kim, Jianhua Zhang, Jennifer Coonen, Puja Basu, Heather A. Simmons, Yen-Wen Liu, Timothy A. Hacker, Timothy J. Kamp, Patrick C.H. Hsieh · 发表于：Circulation · 年份：2023 · DOI：10.1161/circulationaha.122.061736 · 被引用次数：76 · 研究领域：Pluripotent Stem Cells Research、Congenital heart defects research、Mesenchymal stem cell research

BACKGROUND: Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs. METHODS: We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesi...