Manipulating the Hippo-Yap signal cascade in stem cells for heart regeneration

The Hippo-Yap pathway was originally recognized as a crucial signal cascade controlling organ size, and more recently identified as an important component involved in the regulation of cardiomyocyte survival, proliferation, and regeneration. Negative stress responses can activate mammalian sterile 20-like kinase 1 (Mst1) to suppress protective autophagy and promote cardiomyocyte apoptosis via phosphorylation and inhibition of Bcl-xL. Moreover, decreased Yap activity and nuclear entry will decrease upon Mst1 activation, ultimately suppressing cardiomyocytes proliferation and regeneration. Based on these observations, there are potential therapeutic opportunities in cardiac structural and functional regeneration post myocardium infarction to be gained by manipulation of the Hippo-Yap signal cascade. This review will summarize the main components of the Hippo-Yap pathway and their molecular biological functions. It will then highlight the role of these signal modules in the acquisition of stem cell pluripotency, cardiogenic differentiation, cardiomyocyte proliferation and maturation, and mitochondrial biogenesis in cardiac stem cells. Finally, it will discuss the potential for future studies of Hippo-Yap pathway using induced pluripotent stem cell (iPSC) technology.