Congenital heart defects are the most common human birth defect, but our understanding of their origins is limited by the accuracy of in vitro human heart models. This study reports a method to generate developmentally relevant human heart organoids via self-assembly using human pluripotent stem cells. The method is fully defined, efficient, reproducible, and compatible with high-content approaches. Organoids are generated through a three-step Wnt signaling modulation strategy. These organoids are comparable to age-matched human fetal cardiac tissues at the transcriptomic, structural, and cellular levels. They develop sophisticated internal chambers, well-organized cardiac cell types, recapitulate heart field formation, develop a complex vasculature, and exhibit robust functional activity. The organoid platform also recreates complex metabolic disorders associated with congenital heart defects, as demonstrated by an in vitro model of pregestational diabetes-induced congenital heart defects.

Yonatan R. Lewis-Israeli, Aaron H. Wasserman, Mitchell A. Gabalski, Brett D. Volmert, Yixuan Ming, Kristen A. Ball, Weiyang Yang, Jinyun Zou, Guangming Ni, Natalia Pajares, Xanthippi Chatzistavrou, Wen Li, Chao Zhou, Aitor Aguirre