Abstract 15490: Immunogenic Verification of MHC-homo iPS Cell-derived Cardiomyocytes Transplantation to an MHC-matched Non-human Primate Ischemic Cardiomyopathy Model: Pre-clinical Study for Allogenic Therapy Using iPS Cells

Abstract

Introduction: Derivatives of allogeneic induced pluripotent stem cell (iPSC) are promising in clinical application of iPSC-based cardiac regeneration therapy. Although major histocompatibility complex (MHC)-matched allogeneic implantation (MMAI) is theoretically useful in minimizing immune rejection against the graft, graft survival or therapeutic efficacy of MMAI is poorly understood. Hypothesis: We herein hypothesized that MMAI of iPSC-derived cardiomyocytes (CM)-sheet may be therapeutically effective in a non-human primate ischemic cardiomyopathy model. Methods: iPSCs constitutively expressing GFP were established from Macaca fascicularis with homozygous MHC haplotypes, named “HT1”. Cardiomyogenic differentiation was induced in vitro. Heterozygous HT1 Macaca fascicularis ischemic model was made by ligation of left anterior descending artery (LAD) for 2 weeks, followed by transplantation of the derivatives containing 1.0х107 cells to the cardiac surface as MMAI with tacrolimus, mycophenolate mofetil and prednisolone given. Results: LAD ligation for 2 weeks successfully resulted in decrease of left ventricular ejection fraction (LVEF, 50.4±0.5% to 24.9±1.6%), increase of LV end-systolic volume (ESV, 3.2±0.4 mL to 8.2±0.4 mL) and LV global wall stress (GWS, 106±8 kdyne/cm2 to 203±22 kdyne/cm2). At 4 weeks after transplantation, GFP intensity of the graft was 3.6-fold greater in the MMAI group than the sham, although GFP intensity was not different between the two at 2 months, as assessed by stereomicroscope. LVEF, LVESV and GWS were recovered in the MMAI group at 1 month after the transplantation and then preserved until 5 months (LVEF; 32.4% and 33.8%, LVESV; 7.1 and 7.8 mL, GWS; 156.4 and 165.9 kdyne/cm2, respectively), whereas the sham group showed progressive functional deterioration at 1 and 5 months (LVEF; 20.9% and 21.5%, LVESV; 9.2 and 11.6 mL, GWS; 218.6 and 265.3 kdyne/cm2, respectively). Conclusions: Ischemic cardiomyopathy model was established in a non-human primate, for which MHC-homo-iPSCs-CM sheets were successfully transplanted as MMAI, inducing functional recovery with persistent presence of the graft. It was suggested that MHC-homo-iPSCs may be useful to realize iPSC-based cardiac regenerative therapy.