title: 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.
authors.affiliation: Institute for Biomedical Sciences, Shinshu University, Matsumoto 390-8621, Japan.|Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shiba
authors.affiliation: Department of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Toshihito
authors.initials: T
authors.lastname: Gomibuchi
authors.affiliation: Department of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Tatsuichiro
authors.initials: T
authors.lastname: Seto
authors.affiliation: Department of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Department of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Ichimura
authors.affiliation: Department of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Ogasawara
authors.affiliation: Department of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Okada
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shiba
authors.affiliation: Ina Research Inc., Ina 399-4501, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Ina Research Inc., Ina 399-4501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ido
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, Isehara 259-1193, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiina
authors.affiliation: Brain Science Institute, Saitama University, Saitama 338-8570, Japan.|Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ohkura
authors.affiliation: Brain Science Institute, Saitama University, Saitama 338-8570, Japan.|Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nakai
authors.affiliation: Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan.
authors.forename: Narumi
authors.initials: N
authors.lastname: Uno
authors.affiliation: Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.affiliation: Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Itsunari
authors.initials: I
authors.lastname: Minami
authors.affiliation: Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Uichi
authors.initials: U
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006085:Graft Survival; D006239:Haplotypes; D006321:Heart / Q000502:physiology*; D007166:Immunosuppressive Agents; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008252:Macaca fascicularis; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D012038:Regeneration / Q000502:physiology*; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents