Regulatory T Cells Boost Efficacy of Post-Infarction Pluripotent Stem Cell-Derived Cardiovascular Progenitor Cell Transplants.

Cell therapy is promising for heart failure treatment, with growing interest in cardiovascular progenitor cells (CPCs) from pluripotent stem cells. A major challenge is managing the immune response, due to their allogeneic source. Regulatory T cells (Treg) offer an alternative to pharmacological immunosuppression by inducing immune tolerance. This study assesses whether Treg therapy can mitigate the xeno-immune response, improving cardiac outcomes in a mouse model of human CPC intramyocardial transplantation. CPCs stimulated immune responses in allogeneic and xenogeneic settings, causing proliferation in T cell subsets. Tregs showed immunosuppressive effects on T lymphocyte populations when co-cultured with CPCs. Post infarction, CPCs were transplanted intramyocardially into an immune-competent mouse model 3 weeks after myocardial infarction. Human or murine Tregs were intravenously administered on transplantation day and three days later. Control groups received CPCs without Tregs or saline (PBS). CPCs with Tregs improved LV systolic function in three weeks, linked to reduced myocardial fibrosis and enhanced angiogenesis. This was accompanied by decreased splenocyte NK cell populations and pro-inflammatory cytokine levels in cardiac tissue. Treg therapy with CPC transplantation enhances cardiac functional and structural outcomes in mice. Though it does not directly avert graft rejection, it primarily affects NKG2D+ cytotoxic cells, indicating systemic immune modulation and remote heart repair benefits.