Functional Consequences of Human Induced Pluripotent Stem Cell Therapy

Abstract

Background— The use of cells derived from human induced pluripotent stem cells as cellular therapy for myocardial injury has yet to be examined in a large-animal model. Methods and Results— Immunosuppressed Yorkshire pigs were assigned to 1 of 3 groups: A myocardial infarction group (MI group; distal left anterior descending coronary artery ligation and reperfusion; n=13); a cell-treatment group (MI with 4×10 6 vascular cells derived from human induced pluripotent stem cells administered via a fibrin patch; n=14); and a normal group (n=15). At 4 weeks, left ventricular structural and functional abnormalities were less pronounced in hearts in the cell-treated group than in MI hearts ( P <0.05), and these improvements were accompanied by declines in scar size (10.4±1.6% versus 8.3±1.1%, MI versus cell-treatment group, P <0.05). The cell-treated group displayed a significant increase in vascular density and blood flow (0.83±0.11 and 1.05±0.13 mL·min −1 ·g −1 , MI versus cell-treatment group, P <0.05) in the periscar border zone (BZ), which was accompanied by improvements in systolic thickening fractions (infarct zone, −10±7% versus 5±5%; BZ, 7±4% versus 23±6%; P <0.05). Transplantation of vascular cells derived from human induced pluripotent stem cells stimulated c-kit + cell recruitment to BZ and the rate of bromodeoxyuridine incorporation in both c-kit + cells and cardiomyocytes ( P <0.05). Using a magnetic resonance spectroscopic saturation transfer technique, we found that the rate of ATP hydrolysis in BZ of MI hearts was severely reduced, and the severity of this reduction was linearly related to the severity of the elevations of wall stresses ( r =0.82, P <0.05). This decline in BZ ATP utilization was markedly attenuated in the cell-treatment group. Conclusions— Transplantation of vascular cells derived from human induced pluripotent stem cells mobilized endogenous progenitor cells into the BZ, attenuated regional wall stress, stimulated neovascularization, and improved BZ perfusion, which in turn resulted in marked increases in BZ contractile function and ATP turnover rate.