Heart failure due to cardiomyocyte loss after ischemic heart disease is the leading cause of death in the United States in large part because heart muscle regenerates poorly. The endogenous mechanisms preventing mammalian cardiomyocyte regeneration are poorly understood. Hippo signaling, an ancient organ size control pathway, is a kinase cascade that inhibits developing cardiomyocyte proliferation but it has not been studied postnatally or in fully mature adult cardiomyocytes. Here, we investigated Hippo signaling in adult cardiomyocyte renewal and regeneration. We found that unstressed Hippo-deficient adult mouse cardiomyocytes re-enter the cell cycle and undergo cytokinesis. Moreover, Hippo deficiency enhances cardiomyocyte regeneration with functional recovery after adult myocardial infarction as well as after postnatal day eight (P8) cardiac apex resection and P8 myocardial infarction. In damaged hearts, Hippo mutant cardiomyocytes also have elevated proliferation. Our findings reveal that Hippo signaling is an endogenous repressor of adult cardiomyocyte renewal and regeneration. Targeting the Hippo pathway in human disease might be beneficial for the treatment of heart disease.
Author contributions
T.H. and Y.M. designed and performed experiments and analyzed data; J.L. and G.T. performed experiments and analyzed data; J.T.W. and R.L.J. provided reagents; J.F.M. designed and supervised experiments and analyzed data; T.H., Y.M. and J.F.M. wrote the manuscript.
Funding
This work was supported by grants from the National Institutes of Health (NIH) [R56DK094865 to R.L.J.; 1U01HL087365 to J.T.W.; 5T32HL007676-23 to J.L.], the Vivian L. Smith Foundation [J.F.M.], the Cancer Prevention Research Institute of Texas (CPRIT) [P120138 IIRA to R.L.J.], and the American Heart Association (AHA) [AHA10POST4140029 and AHA12POST11760019 to T.H.; AHA NCRP SDG 0930240N to Y.M.]. Deposited in PMC for release after 12 months.
