YAP/TEAD3 signal mediates cardiac lineage commitment of human-induced pluripotent stem cells.

Abstract

Cardiomyocytes differentiated from human-induced pluripotent stem cells (hiPSCs) hold great potential for therapy of heart diseases. However, the underlying mechanisms of its cardiac differentiation have not been fully elucidated. Hippo-YAP signal pathway plays important roles in cell differentiation, tissue homeostasis, and organ size. Here, we identify the role of Hippo-YAP signal pathway in determining cardiac differentiation fate of hiPSCs. We found that cardiac differentiation of hiPSCs were significantly inhibited after treatment with verteporfin (a selective and potent YAP inhibitor). During hiPSCs differentiation from mesoderm cells (MESs) into cardiomyocytes, verteporfin treatment caused the cells retained in the earlier cardiovascular progenitor cells (CVPCs) stage. Interestingly, during hiPSCs differentiation from CVPC into cardiomyocytes, verteporfin treatment induced cells dedifferentiation into the earlier CVPC stage. Mechanistically, we found that YAP interacted with transcriptional enhanced associate domain transcription factor 3 (TEAD3) to regulate cardiac differentiation of hiPSCs during the CVPC stage. Consistently, RNAi-based silencing of TEAD3 mimicked the phenotype as the cells treated with verteporfin. Collectively, our study suggests that YAP-TEAD3 signaling is important for cardiomyocyte differentiation of hiPSCs. Our findings provide new insight into the function of Hippo-YAP signal in cardiovascular lineage commitment.