HIF2α induces cardiomyogenesis via Wnt/β-catenin signaling in mouse embryonic stem cells

Background: Embryonic stem cells (ESCs) are pluripotent stem cells and can differentiate into cardiomyocytes when cultured in appropriate conditions. The function of hypoxia-inducible factors (HIFs) has been identified in directing the formation of cardiac lineages. The purpose of this study was to investigate the ability of HIF2 alpha to induce differentiation of ESCs into cardiomyocytes and to explore the potential underlying molecular mechanisms. Methods: Cardiac differentiation from mouse ESCs was analyzed using the "hanging drop" method, and success was determined by assaying the numbers of beating embryoid bodies and the expression level of cardiac markers. The expression of HIF2 alpha was then manipulated during cardiac differentiation with piggyBac transposon and the lentivirus system. The underlying mechanism was finally examined via administering selective inhibitors of the Wnt/beta-catenin signaling pathway. Results: Overexpressing HIF2 alpha can significantly drive mouse ESCs to form cardiomyocytes. Contrarily, knockdown of HIF2 alpha inhibits the emergence of cardiac cells. In addition, the cardiomyogenesis-promoting effect of HIF2 alpha occurred by increasing the protein level of beta-catenin, an effector that contributes to cardiac differentiation at an early stage of ESC differentiation. Conclusion: HIF2 alpha has a cardiomyogenesis-promoting effect in ESCs via enhancing the activation of the Wnt/beta-catenin signaling pathway. Our results may be beneficial for generating and applying cardiomyocytes from ESCs safely and effectively in the future.