Abstract
Introduction: Stem-cell-based therapies provide promise for the treatment of ischemic myocardial injury, but the number of cells that remain engrafted at the site of administration is exceptionally low, which is believed to limit the effectiveness of treatment. In this study, we investigated whether the number of engrafted human induced-pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) can be increased via overexpression of the cell-cycle activator cyclin D2 (CCND2) and if so, whether this increase is accompanied by improvements in myocardial recovery. Experiments were conducted in a large-animal (swine) model of myocardial injury. Methods and results: CCND2-overexpressing hiPSC-CMs (CCND2 OE CMs) were constructed via lentiviral transfection; then, myocardial infarction (MI) was surgically induced in swine, and the animals were randomly assigned to treatment with CCND2 OE CMs (i.e., the MI+CCND2 OE CM group), wild-type hiPSC-CMs (the MI+CCND2 WT CM group), or neither experimental treatment (the MI group); the cells were injected into five sites (6х10 6 cells/site) surrounding the infarct. Four weeks after MI, measurements of the heart-weight to bodyweight ratio (HW/BW), cardiac function (determined via magnetic resonance imaging), and vascularity (CD31 staining) were significantly better in MI+CCND2 OE CM animals than in the CCND2 WT CM group. HW/BW was also significantly lower in both cell-treatment groups than in MI animals, and CCND2 overexpression was associated with increases in both hiPSC-CM engraftment (mRNA levels) and cell-cycle activity (ki67 and phosphorylated histone 3 levels). Conclusion: Experiments in a large-animal MI model indicated that CCND2 overexpression in transplanted hiPSC-CMs was associated with increases in cell-cycle activity and the number of engrafted cells, as well as improvements in cardiac function, hypertrophy, and vascularity.
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