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

Although human induced pluripotent stem cells (hiPSCs)-derived cardiomyocytes (hiPSC-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 of cell therapy. Therefore, it is crucial to identify hypoimmunogenic hiPSCs for allogeneic cell therapy. We conducted this study to demonstrate the immune privilege of HLA-E high /HLA-G high /HLA-II low hiPSC-derived cardiomyocytes (hiPSC-CMs) in vitro. Then we did ischemia-reperfusion surgery to create transmural myocardial infarction in rats. At post-infarct 4 days, we injected hPSC-CMs (1.0×10 7  cells/kg), including human embryonic stem cell-derived cardiomyocytes (hESC-CMs), hiPSC-CMs and HLA-E high /HLA-G high /HLA-II low hiPSC-CMs, into the infarcted myocardium. Compared with hESC-CMs and hiPSC-CMs, under the treatment of very low dose cyclosporine A (CsA), only HLA-E high /HLA-G high /HLA-II low hiPSC-CM survived in vivo, remuscularized the infarcted myocardium with infarct size reduction and improved post-infarct cardiac function. HLA-E high /HLA-G high /HLA-II low hiPSC-CMs evaded attack by natural killer (NK) cells and cytotoxic T cells because these hiPSC-CMs activated the SHP-1 signaling pathway of NK cells and cytotoxic T cells which downregulated STAT-1 and NF-κB expression. Herein, we demonstrated that using clinically relevant CsA dose, HLA-E high /HLA-G high /HLA-II low hiPSC-CMs repaired the infarcted myocardium and restored 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. This article is protected by copyright. All rights reserved.