【Background】

Mammalian cardiomyocytes (CM) largely cease to proliferate after birth. So far, several pathways, including activation of yes-associated protein (YAP) signaling and inhibition of glycogen synthase kinase (GSK)-3 signaling (i.e., activation of β-catenin), have been identified as candidate pathways that promote CM proliferation. The aim of this study is to clarify the crosstalk between these two signaling pathways.

【Methods/Results】

Consistent with previous reports, immunofluorescence (IF) with cell cycle marker revealed GSK-3 inhibitors (GSK3I) increased proliferation of neonatal rat CM (NRCM) and human iPS-derived CM (hiPSCM) under sparse culture condition. IF also revealed YAP is endogenously activated in NRCM and hiPSCM. YAP knock-down or pharmacological inhibition of YAP reduced GSK3I-induced CM proliferation without suppressing the β-catenin activation, suggesting endogenous activity of YAP potentiated the proliferative effects of GSK3I. Under dense culture condition of hiPSCM, GSK3I alone could not induce the CM proliferation; however, YAP activation by knocking down α-catenin restored their proliferative effects.

【Conclusion】

The activation of YAP potentiates GSK3I-induced proliferation of CM, proposing a novel strategy for the CM amplification.