In situ maturated early-stage human induced pluripotent stem cell-derived cardiomyocytes improve cardiac function by enhancing segmentary contraction in infarcted rats

Abstract

The scant ability of cardiomyocytes to proliferate makes heart regeneration one of the biggest challenges of science. Current therapies do not contemplate heart re-muscularization. In this scenario, stem cell-based approaches have been proposed to overcome the lack of regeneration. We hypothesize PluriCell hiPSC-derived cardiomyocytes (hiPSC-CMs) could enhance rats cardiac function after myocardial infarction (MI). Animals were subjected to permanent occlusion of the Left-Ventricle (LV) anterior descending coronary artery (LAD). Seven days after MI, Early-stage hiPSC-CMs were injected intramyocardially. Rats were subjected to Echocardiography pre- and post-treatment. Thirty days after injections, treated rats displayed 6.2% human cardiac grafts, which were characterized molecularly. Left ventricle ejection fraction (LVEF) was improved by 7.8% in cell-injected rats, while placebo controls showed an 18.2% deterioration. Also, cell-treated rats displayed a 92% and 56% increase in radial and circumferential strains, respectively. Human cardiac grafts maturate in situ, preserving proliferation with 10% Ki67 and 3% PHH3 positive nuclei. Grafts were perfused by host vasculature with no evidence for immune rejection nor ectopic tissue formations. Our findings support PluriCell hiPSC-CMs as an alternative therapy to treat MI. The next steps of preclinical development include efficacy studies in large animals on the path to clinical-grade regenerative therapy targeting human patients.