Large-scale microRNA functional high-throughput screening identifies miR-515-3p and miR-519e-3p as inducers of human cardiomyocyte proliferation

Ischemic cardiomyopathy, driven by loss of cardiomyocytes and inadequate pro-liferative response, persists to be a major global health problem. Using a func-tional high-throughput screening, we assessed differential proliferative potential of 2019 miRNAs after transient hypoxia by transfecting both miR-inhibitor and miR-mimic libraries in human iPSC-CM. Whereas miR-inhibitors failed to enhance EdU uptake, overexpression of 28 miRNAs substantially induced proliferative ac-tivity in hiPSC-CM, with an overrepresentation of miRNAs belonging to the primate-specific C19MC-cluster. Two of these miRNAs, miR-515-3p and miR-519e-3p, increased markers of early and late mitosis, indicative of cell division, and substantially alter signaling pathways relevant for cardiomyocyte prolifera-tion in hiPSC-CM.

Automated summary

Ischemic cardiomyopathy, driven by loss of cardiomyocytes and inadequate proliferative response, is a major global health problem. Functional high-throughput screening revealed that overexpression of certain miRNAs, especially miR-515-3p and miR-519e-3p from the C19MC-cluster, enhanced proliferative activity in hiPSC-CM and altered signaling pathways relevant for cardiomyocyte proliferation.