HLA-E^high/HLA-G^high/HLA-II^low Human iPSC-Derived Cardiomyocytes Exhibit Low Immunogenicity for Heart Regeneration

Although human pluripotent stem cells (hPSCs)-derived cardiomyocytes (hPSC-CMs) can remuscularize infarcted hearts and restore post-infarct cardiac function, post-transplant rejection resulting from human leukocyte antigen (HLA) mismatching is an enormous obstacle. It is crucial to identify hypoimmunogenic hPSCs for allogeneic cell therapy. This study is conducted to demonstrate the immune privilege of HLA-E^high/HLA-G^high/HLA-II^low human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs). Ischemia-reperfusion surgery is done to create transmural myocardial infarction in rats. At post-infarct 4 days, hPSC-CMs (1.0×10⁷ cells per kg), including human embryonic stem cell-derived cardiomyocytes (hESC-CMs), HLA-Elow/HLA-Glow/HLA-IIhigh hiPSC-CMs, and HLA-E^high/HLA-G^high/HLA-II^low hiPSC-CMs, are injected into the infarcted myocardium. Under the treatment of very low dose cyclosporine A (CsA), only HLA-E^high/HLA-G^high/HLA-II^low hiPSC-CMs survive in vivo and improved post-infarct cardiac function with infarct size reduction. HLA-E^high/HLA-G^high/HLA-II^low hiPSC-CMs activate the SHP-1 signaling pathway of natural killer (NK) cells and cytotoxic T cells to evade attack by NK cells and cytotoxic T cells. Herein, it is demonstrated that using a clinically relevant CsA dose, HLA-E^high/HLA-G^high/HLA-II^low hiPSC-CMs repair the infarcted myocardium and restore the post-infarct heart function. HLA-E^high/HLA-G^high/HLA-II^low hiPSCs are less immunogenic and may serve as platforms for regeneration medicine.