Immunomodulatory effects of hiPSC-MSCs on the therapeutic efficacy of cell-based therapy for cardiovascular diseases

Abstract

Regenerative therapies, which aim at regeneration and repair of ischemic tissue by administration of exogenous cells, have been investigated as a promising treatment to restore blood perfusion and improve physiological function in ischemic cardiovascular diseases, such as myocardial infarction (MI) and peripheral artery diseases (PADs). Unfortunately, clinical and preclinical studies that focus on transplantation of mesenchymal stem cells (MSCs) or cardiomyocytes (CMs) for MI, have failed to conclude the benefits of cell-based therapies due to inconsistencies in the quality and number of cell populations. The low engraftment and survival of transplanted cells hampers the therapeutic efficacy of cell-based therapies. Systemic intravenous infusion of MSCs has been investigated as an immunomodulatory therapy to facilitate the survival of solid organ grafts. In this thesis, we sought to determine whether systemic intravenous infusion of human induced pluripotent stem cell (hiPSC)-derived MSCs (hiPSC-MSCs) could improve the survival of direct locally transplanted cells in the treatment of ischemic cardiovascular diseases including MI and hind-limb ischemia.

The immunomodulatory effects of systemic intravenous infusion of hiPSC-MSCs on intramyocardially transplanted hiPSC-CMs or hiPSC-MSCs were investigated in a mouse model of MI. Intramyocardial transplantation of hiPSC-CMs or hiPSC-MSCs with or without systemic intravenous infusion of hiPSC-MSCs improved cardiac function relative to the MI group. In addition, systemic intravenous infusion of hiPSC-MSCs further improved cardiac function 4 weeks after intramyocardial transplantation of hiPSC-CMs or hiPSC-MSCs. The improved cardiac function was associated with improved engraftment and survival of intramyocardially transplanted hiPSC-CMs or hiPSC-MSCs. The immunomodulatory effects of repeated systemic intravenous infusion of hiPSC-MSCs on intramuscularly transplanted hiPSC-MSCs were investigated in a mouse model of hind-limb ischemia. Compared with ischemia group, intramuscular transplantation of hiPSC-MSCs with or without systemic intravenous infusion of hiPSC-MSCs once, every week or every 3 days significantly increased blood perfusion in the ischemic hind limbs and these therapeutic effects were enhanced by a single or repeated intravenous infusion of hiPSC-MSCs. Moreover, intramuscular transplantation of hiPSC-MSCs with repeated intravenous hiPSC-MSCs infusion further improved the blood perfusion, compared with mice treated with intramuscular transplantation of hiPSC-MSCs and a single intravenous infusion of hiPSC-MSCs.

The mechanisms underlying the immunomodulatory effects of systemic intravenous infusion of hiPSC-MSCs were further investigated. The immunomodulatory effects of intravenous infusion of hiPSC-MSCs were orchestrated by increased systemic Tregs and decreased splenic NK cells as well as polarization of M2 macrophages. In addition, our in-vitro study proved that co-culture of CD4 positive splenocytes with hiPSC-MSCs significantly reduced pro-inflammatory cytokines secretion including that of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-17A.

In conclusion, we provide proof-of-principle evidence that systemic intravenous infusion of hiPSC-MSCs to enhance the therapeutic efficacy of cell-based treatment for cardiovascular disease. The immunomodulatory effects of hiPSC-MSCs can be enhanced by repeated intravenous infusion.