Abstract 10786: Cardiac Muscle Patches Containing Four Types of Cardiac Cells Derived From Human Pluripotent Stem Cells Improve Recovery From Cardiac Injury

Abstract

Introduction: We have shown that human cardiac muscle patches (hCMPs) containing three different types of cardiac cells—cardiomyocytes (CMs), smooth-muscle cells (SMCs), and endothelial cells (ECs), all of which were differentiated from human pluripotent stem cells (hPSCs)—significantly improved cardiac function, infarct size, and hypertrophy in a pig model of myocardial infarction (MI). However, hPSC-CMs are phenotypically immature, which may lead to arrythymogenic concerns; thus, since hPSC-derived cardiac fibroblasts (hPSC-CFs) appear to enhance the maturity of hPSC-CMs, we compared hCMPs containing hPSC-CMs, -SMCs, -ECs, and -CFs (4TCC-hCMPs) with a second hCMP construct that lacked hPSC-CFs but was otherwise identical (3TCC-hCMPs). Methods: hCMPs were generated in a fibrin scaffold. MI was induced in SCID mice through permanent coronary artery (LAD) ligation, followed by treatment with cardiac muscle patches. Animal groups included: MI heart treated with 3TCC-hCMP; with 4TCC-hCMP; MI heart treated with no patch (MI group) and sham group. Cardiac function was evaluated via echocardiography, and cell engraftment rate while infarct size was evaluated histologically at four weeks after patch transplantation. Results: The results from experiments in cultured hCMPs demonstrate: 1) that structural, metabolic, and ion-channel markers for CM maturation were significantly more abundant in 4TCC-hCMPs; and 2) that conduction velocities and action-potential durations were significantly greater in hPSC-CMs from 4TCC-hCMPs (18 cm/s ± 0.72 vs. 31 cm/s ± 3.23, p<0.005, 3TCC vs. 4TCC). Furthermore, when 3TCC- and 4TCC-hCMPs were compared in a mouse MI model, measures of cardiac function ( EF: 41.55% ± 0.92 vs. 49.18% ± 0.86, p<0.05, 3TCC vs. 4TCC), infarct size (39.23% ± 4.28 vs. 22.72% ± 0.98, p<0.05, 3TCC vs. 4TCC), hypertrophy, and CM engraftment were significantly better in animals treated with 4TCC-hCMPs than in the 3TCC-hCMP-treatment group (8.56% ± 1.79 vs. 15.99% ± 1.56, p<0.05, 3TCC vs. 4TCC). Conclusions: These results demonstrate that the inclusion of hPSC-CFs in hCMP manufacture promotes hPSC-CM maturation and increases the efficacy of hCMPs for myocardial repair.