RRC ID 47680
Author Shiba Y, Gomibuchi T, Seto T, Wada Y, Ichimura H, Tanaka Y, Ogasawara T, Okada K, Shiba N, Sakamoto K, Ido D, Shiina T, Ohkura M, Nakai J, Uno N, Kazuki Y, Oshimura M, Minami I, Ikeda U.
Title Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts.
Journal Nature
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.
Volume 538(7625)
Pages 388-391
Published 2016-10-20
DOI 10.1038/nature19815
PII nature19815
PMID 27723741
MeSH Animals Cell Differentiation Cell Survival Female Fibroblasts / cytology Graft Survival Haplotypes Heart / physiology* Immunosuppressive Agents Induced Pluripotent Stem Cells / cytology* Macaca fascicularis Major Histocompatibility Complex / genetics Male Myocardial Contraction / physiology Myocardial Infarction / pathology Myocardial Infarction / physiopathology Myocardial Infarction / therapy* Myocytes, Cardiac / cytology* Myocytes, Cardiac / immunology Myocytes, Cardiac / metabolism Myocytes, Cardiac / transplantation* Regeneration / physiology* Tachycardia, Ventricular / etiology Tachycardia, Ventricular / physiopathology Time Factors Transplantation, Homologous
IF 41.577
Times Cited 18
WOS Category CARDIAC & CARDIOVASCULAR SYSTEMS
Resource
DNA material G-CaMP7.09 (RDB14612)