Immunomodulation by systemic administration of human-induced pluripotent stem cell-derived mesenchymal stromal cells to enhance the therapeutic efficacy of cell-based therapy for treatment of myocardial infarction

Rationale: Poor survival and engraftment are major hurdles of stem cell therapy in the treatment of myocardial infarction (MI). We sought to determine whether pre-transplantation systemic intravenous administration of human induced pluripotent stem cell (hiPSC)-derived mesenchymal stromal cells (hiPSC-MSCs) could improve the survival of hiPSC-MSCs or hiPSC-derived cardiomyocytes (hiPSC-CMs) following direct intramyocardial transplantation in a mouse model of MI. Methods: Mice were randomized to undergo intravenous administration of saline or 5x10(5) hiPSC-MSCs one week prior to MI, induced by ligation of the left anterior descending coronary artery. Mice were further assigned to undergo direct intramyocardial transplantation of hiPSC-MSCs (1x10(6)) or hiPSC-CMs (1x10(6)) 10 minutes following MI. Echocardiographic and invasive hemodynamic assessment were performed to determine cardiac function. In-vivo fluorescent imaging analysis, immunofluorescence staining and polymerase chain reaction were performed to detect cell engraftment. Flow cytometry of splenic regulatory T cells (Tregs) and natural killer (NK) cells was performed to assess the immunomodulatory effects. Results: Pre-transplantation systemic administration of hiPSC-MSCs increased systemic Tregs activation, decreased the number of splenic NK cells and inflammation, and enhanced survival of transplanted hiPSC-MSCs and hiPSC-CMs. These improvements were associated with increased neovascularization and decreased myocardial inflammation and apoptosis at the peri-infract zone with consequent improved left ventricular function four weeks later. Co-culture of splenic CD4 cells with hiPSC-MSCs also modulated their cytokine expression profile with a decreased level of interferon-gamma, tumor necrosis factor-alpha, and interleukin (IL)-17A, but not IL-2, IL-6 and IL-10. Conclusion: Pre-transplantation systemic intravenous administration of hiPSC-MSCs induced immunomodulation and facilitated the survival of intramyocardially transplanted cells to improve cardiac function in MI.