Cardiac injury and the inability of adult hearts to regenerate drive the progression of heart failure. Stem cell therapies to replace the damaged tissue and improve cardiac function are limited by incomplete differentiation of stem cells into mature adult cardiomyocytes, poor revascularization of the grafted tissue, immunogenicity of grafted cells and their low engraftment efficacy, and induction of ventricular arrhythmias. In a recent study, Cheng et al. show that treating mice or non-primate hearts with a combination of stem cell-derived cardiomyocytes and endothelial cells improves cardiac structure and function after injury.
First, the researchers characterized the effects of human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) on hiPSC-derived cardiomyocytes (hiPSC-CMs) and found that their coculture increased sarcomere length, expression of the gap junction protein connexin 43, calcium handling and the maturation of cardiomyocytes through cell-to-cell contacts. Human iPSC-CMs and iPSC-ECs were injected alone or together into the border zone of the infarcted hearts of NOD–SCID mice. The highest improvement in cardiac function and the lowest number of arrhythmic incidences after myocardial infarction were observed in mice that received the combination of iPSC-CMs and iPSC-ECs, compared with treatment with vehicle control or either endothelial cells or cardiomyocytes alone. Histology analysis of the infarcted area showed that the combined injection of cardiomyocytes and endothelial cells reduced infarct size, and increased vascular density within the infarct area and the cell engraftment. These effects occurred independently of cardiomyocyte proliferation, which indicates a higher survival rate of the injected cardiomyocytes through increased endothelial cell-induced angiogenesis. In return, cardiomyocytes promoted angiogenesis and maturation of neovessels.
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