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MHC-mismatched Allotransplantation of Induced Pluripotent Stem Cell-derived Cardiomyocyte Sheets to Improve Cardiac Function in a Primate Ischemic Cardiomyopathy Model

Kashiyama, Noriyuki MD, PhD1; Miyagawa, Shigeru MD, PhD1; Fukushima, Satsuki MD, PhD2; Kawamura, Takuji MD, PhD1; Kawamura, Ai MD, PhD1; Yoshida, Shohei MD1; Eiraku, Seiko MD, PhD1; Harada, Akima BD1; Matsunaga, Keiko MD3,4; Watabe, Tadashi MD, PhD3,4; Toda, Koichi MD, PhD1; Hatazawa, Jun MD, PhD3,4,5; Sawa, Yoshiki MD, PhD1

doi: 10.1097/TP.0000000000002765
Original Basic Science—General

Background. Although allogeneic-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) exhibit potential in cardiomyogenesis for heart failure, whether major histocompatibility complex (MHC)-matched allogenic iPSC implantation (MMAI) minimizes immune rejection for cell survival or functional recovery remains unknown. We herein explored whether MMAI with an iPSC-CM sheet is stable for a longer period and therapeutically more effective than MHC-mismatched AI in a primate ischemic cardiomyopathy model.

Methods. Green fluorescent protein-transfected iPSC-CM sheets, derived from cynomolgus macaques with homozygous MHC haplotypes ‘‘HT1,’’ were transplanted on the left ventricle, generated by ligating the left anterior descending artery for 2 weeks in an ischemic model with or without heterozygous HT1 as MMAI and MHC-mismatched AI. Sham models were made by opening the chest at 14 days after left anterior descending ligation without any treatment.

Results. Stereomicroscopy revealed that at 4 months after transplantation, green fluorescent protein intensity was higher in the MMAI group than in the MHC-mismatched AI group and the sham group. Immunohistochemistry staining revealed that host immune reaction with CD3-positive cells was stronger in MHC-mismatched AI than in MMAI at 3 months. Cardiac function improved both in MMAI and MHC-mismatched AI at 1 month after transplantation and was preserved until 6 months, whereas in the sham group, functional deterioration progressed over time.

Conclusions. Although MHC-homo-iPSCs are preferred to avoid immune rejection, MHC-mismatched iPSC-CMs can also induce comparable cardiac functional recovery at late follow-up, suggesting that MHC-mismatched iPSC-based cardiac regenerative therapy with immunosuppressants is a feasible option for treating heart failure in clinical settings.

1 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

2 Department of Cardiovascular Surgery, National Cardiovascular Center, Osaka, Japan.

3 Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka, Japan.

4 PET Molecular Imaging Center, Osaka University Graduate School of Medicine, Osaka, Japan.

5 Immunology Frontier Research Center, Osaka University, Osaka, Japan.

Received 29 November 2018. Revision received 27 March 2019.

Accepted 7 April 2019.

This work was supported by the Japan Science and Technology Agency as a part of the project, Center for the Development of Myocardial Regenerative Treatments Using iPS Cells.

The authors declare no funding or conflicts of interest.

N.K. performed all the experiments, collected and/or assembled all the data, wrote the article, and prepared the figures. S.M. provided financial support and helped to set up all the experiments and contributed to data analysis and interpretation. S.F., T.K., A.K., S.Y., A.H., and K.T. helped data analysis and interpretation. S.E. provided study materials. K.M., T.W., and J.H. contributed to the analysis of cardiac perfusion in experimental animals by positron emission tomography scanning. Y.S. is the corresponding author and conceived and designed the study and provided financial support.

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Correspondence: Yoshiki Sawa, MD, PhD, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Yamadaoka, 2-2, Suita-city, Osaka 565-0087, Japan. (

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