Potent Immunomodulation and Angiogenic Effects of Mesenchymal Stem Cells versus Cardiomyocytes Derived from Pluripotent Stem Cells for Treatment of Heart Failure

Abstract

Heart failure (HF) following myocardial infarction (MI) is the leading cause of mortality and morbidity worldwide. Cell-based therapeutics has been explored as a potential approach to replenish the lost cardiomyocyte and restore cardiac function in HF. But the optimal cell type remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes(hESCCMs) and human induced pluripotent stem cell-derived mesenchymal stem cells(hiPSC-MSCs) in a porcine model of HF. Eight weeks after induction of MI, animals with left ventricular ejection fraction(LVEF) <40% were randomly assigned to receive direct intramyocardial injection of saline; 2×108 hESC-CMs or 2×108 hiPSC MSCs. All animals underwent serial echocardiography and hemodynamic evaluation to assess LV function after cell transplantation. The hearts were harvested for immunohistochemical evaluation after assessment of ventricular tachyarrhythmia (VT) induced by invivo programmed electrical stimulation.At 8-weeks post-transplantation, LVEF, maximal positive pressure derivative and end systolic pressure-volume relationship were significantly higher in the hiPSC-MSC group but not in the hESC-CM group compared with the MI group. The incidence of early spontaneous VT episodes was higher in the hESC-CM group but the incidence of inducible VT was similar among the different groups. Histological examination showed no tumor formation but hiPSCMSCs exhibited a stronger survival capacity by activating regulatory T cells and reducing the inflammatory cells. In-vitro study showed that hiPSC-MSCs were insensitive to pro-inflammatory Interferon-gamma induced Human Leukocyte Antigen Class-II expression compared with hESC-CMs. Moreover, hiPSC-MSCs also significantly enhanced angiogenesis compared with other groups via increasing expression of distinct angiogenic factors. Our results demonstrate that transplantation of hiPSC-MSCs does not increase proarrhythmia or tumor formation; and superior to hESC-CMs for improvement of cardiac function in HF due to their immunomodulation that improves in-vivo survival and enhanced angiogenesis via paracrine effects.