Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts

Abstract

Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy, few immunological studies have been carried out with iPSCs. Here we describe an allogeneic transplantation model established using the cynomolgus monkey (Macaca fascicularis), the MHC structure of which is identical to that of humans. Fibroblast-derived iPSCs were generated from a MHC haplotype (HT4) homozygous animal and subsequently differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intra-myocardial injection of iPSC-CMs. The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection in monkeys treated with clinically relevant doses of methylprednisolone and tacrolimus, and showed electrical coupling with host cardiomyocytes as assessed by use of the fluorescent calcium indicator G-CaMP7.09. Additionally, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks after transplantation; however, the incidence of ventricular tachycardia was transiently, but significantly, increased when compared to vehicle-treated controls. Collectively, our data demonstrate that allogeneic iPSC-CM transplantation is sufficient to regenerate the infarcted non-human primate heart; however, further research to control post-transplant arrhythmias is necessary.

Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection

“…Vascular sequestration of immunoglobulins and complement activators could have important implications for cell therapies. A recent study reported that allogeneic-induced pluripotent stem cell-derived cardiomyocytes could regenerate nonhuman primate myocardium when directly injected in infarcted heart (48). Allogeneic cardiomyocytes survived for 12 weeks with no evidence of immune rejection in immunosuppressed monkeys.…”

Recent Progress Using Pluripotent Stem Cells for Cardiac Regenerative Therapy

“…51 Further, we transplanted monkey iPS cell-derived CMs expressing a brighter Ca indicator, G-CaMP7.09, into infarcted monkey hearts and found electrical coupling; however, electrical conduction was delayed when the heart rate was increased by electrical stimulation. 52 This slower propagation likely reflects insufficient gap junction development in the graft.…”

“…51 Subsequently, our group showed that iPSC-CM transplantation significantly increased ventricular tachycardia incidence in a monkey model of acute MI. 51, 52 Inconsistent results are most likely because of differences in heart sizes and beating rates. In small animals, electrical reentry is less likely to occur because of the small heart size.…”

“…Our group transplanted MHCmatched monkey PSC-CMs into injured monkey hearts with mild immunosuppression and observed long-term graft survival without acute rejection. 52 Currently, several groups are generating iPS cells from individuals with homozygous HLA alleles to provide off-the-shelf iPS cells for which HLA will be matched with multiple recipients. 80, 81 In Japan, 50 donor iPSC lines are needed to match >90% of the Japanese population, requiring 24,000 donors for screening.…”

Cardiac regeneration using HLA-matched induced pluripotent stem cells—no monkey business, but still a long and winding road ahead

“…In a recent study, Shiba and colleagues (6) addressed some of these issues using a non-human primate model of myocardial infarction.…”