A large-scale functional high-throughput screening identifies miR-515 and miR-519e as potent inducers of human iPSC-cardiomyocyte proliferation

Abstract Introduction Ischemic heart failure persists as a global health problem despite optimized medical and adjunctive device therapies. Loss of cardiomyocytes in the absence proliferative response comprise major contributor to pathological remodeling death this patient population. Experimental studies have shown that microRNAs (miRNAs) may be used therapeutic option reinduce adult cardiomyocyte proliferation. Purpose This study thought evaluate potential human after overexpression inhibition 2019 miRNAs. Methods To identify miRNAs regulate proliferation, we performed functional high-throughput screenings iPSC-derived (hiPSC-CM) transient hypoxia. Herein, miRNA-mimics for anti-miRs were individually transfected examine EdU-incorporation hiPSC-CM. MiR-mimic-515 miR-mimic-519e induced highest EdU-uptake, further assessed by immunostaining molecular methods markers indicative early late mitosis. In addition, RNA-Sequencing hiPSC-CM miR-515 miR-519e was differential gene expression miRNA-modulated pathways involved Results Using screening, hypoxia transfecting both miR-inhibitor miR-mimic libraries (hiPSC-CM). Overexpression 28 substantially activity hiPSC-CM, with an overrepresentation belonging C19MC-cluster adjacent miR-371–373 family. Two these miRNAs, increased mitosis, additive turnover Aurora B-kinase midbodies, cell division. These findings supported using qRT-PCR, Western blot, showing substantial alterations signaling relevant proliferation iPSC-CM. Conclusion Collectively, results support critical role induction under hypoxic conditions, such present patients ischemia-driven cardiomyopathy. Funding Acknowledgement Type funding sources: Foundation. Main source(s): work German Centre Cardiovascular Research (DZHK), Deutsche Stiftung für Herzforschung (DSHF) OPO