miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway

Understanding the mechanisms that control human cardiomyocyte proliferation might be applicable to regenerative medicine. We screened a whole genome collection of human miRNAs, identifying 96 to be capable of increasing proliferation (DNA synthesis and cytokinesis) of human iPSC-derived cardiomyocytes. Chemical screening and computational approaches indicated that most of these miRNAs (67) target different components of the Hippo pathway and that their activity depends on the nuclear translocation of the Hippo transcriptional effector YAP. 53 of the 67 miRNAs are present in human iPSC cardiomyocytes, yet anti-miRNA screening revealed that none are individually essential for basal proliferation of hiPSC cardiomyocytes despite the importance of YAP for proliferation. We propose a model in which multiple endogenous miRNAs redundantly suppress Hippo signaling to sustain the cell cycle of immature cardiomyocytes. Diez-Cuñado et al. show that a large set of miRNAs are individually sufficient to promote cell division of immature human cardiomyocytes. Most of these miRNAs act by repressing Hippo and activating YAP, defining Hippo/YAP as a central node controlling cardiomyocyte proliferation and as a promising target to achieve therapeutic cardiac regeneration.