Abstract

Preclinical Transplantation Study of iPS Cell-Derived Cardiomyocytes in Non-Human Primate

Yuji Shiba, Professor, Department of Regenerative Science and Medicine, Shinshu University

Induced pluripotent stem cells (iPSCs) have promising potential as a source of autologous patient-specific cardiomyocytes for cardiac repair, obviously providing a major benefit in terms of immune rejection. However, autologous transplantation comes with substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy, surprisingly few immunological studies have been carried out with iPSCs. Here, we established an allogeneic transplantation model using cynomolgus monkey, whose MHC structure is identical to that of humans. iPSCs were generated from fibroblasts from an animal with a homozygous MHC haplotype (HT4), and the cells were differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intramyocardial injection of the iPSC-CMs. The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection under treatment of clinically relevant doses of methylprednisolone and tacrolimus, and they showed indisputable electrical integration with host cardiomyocytes as assessed by use of our novel fluorescent calcium indicator, G-CaMP7.09. In addition, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks post transplantation; however, the incidence of ventricular tachycardia was transiently but significantly increased when compared to the vehicle-treated control. MHC-matched allogeneic transplantation of iPSC-CMs regenerates infarcted non-human primate heart. Further research to control post-transplant arrhythmias is warranted.