Yes-associated protein mediates human embryonic stem cell-derived cardiomyocyte proliferation: Involvement of epidermal growth factor receptor signaling.

Unlike mature cardiomyocytes, human pluripotent stem cell-derived cardiomyocytes exhibit higher proliferative capacity; however, the underlying mechanisms involved are yet to be elucidated. Here, we revealed that the Yes-associated protein (YAP) plays a critical role in regulating cell proliferation in association with epidermal growth factor receptor (EGFR) in human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Our results show that low-density culture significantly promotes the proliferation of hESC-CMs via YAP. Interestingly, the low-density culture-induced YAP expression further induced EGFR expression, without any alterations in the activity of EGFR and its two major downstream kinases, ERK, and AKT. However, treatment of a low-density-culture of hESC-CMs with epidermal growth factor (EGF) increased proliferation via phosphorylation of EGFR, ERK, and AKT, and the EGF-induced phosphorylation of EGFR, ERK, and AKT was significantly higher in low-density hESC-CMs than in high-density hESC-CMs. Furthermore, the EGF-induced activation of EGFR, ERK, and AKT increased YAP expression and subsequently proliferation. In conclusion, YAP mediates both low-density culture-induced and EGF-induced proliferation of hESC-CMs in low-density culture conditions.