Enhanced Therapeutic Effects of Human iPS Cell Derived-Cardiomyocyte by Combined Cell-Sheets with Omental Flap Technique in Porcine Ischemic Cardiomyopathy Model

Masashi Kawamura,Yoshiki Sawa,Yoshinori Yoshida,Kenji Miki,Tatsuya Shimizu,Teruo Okano,Shinya Yamanaka,Shunsuke Funakoshi,Koichi Toda,Takashi Daimon,Atsuhiro Saito,Satsuki Fukushima,Shigeru Miyagawa

doi:10.1038/s41598-017-08869-z

Abstract

Transplant of human induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) cell-sheet is a promising approach for treating ischemic cardiomyopathy (ICM). However, poor blood supply to the transplanted cell-sheet is a concern related to the effectiveness and durability of the treatment. Herein, we hypothesized that the combined the omentum flap might enhance survival and the therapeutic effects of hiPS-CM cell-sheet transplant for ICM treatment. Treatment by Wnt signaling molecules in hiPS cells produced hiPS-CMs, which were magnetically labeled by superparamagnetic iron oxide (SPIO), followed by culture in the thermoresponsive dishes to generate hiPS-CMs cell-sheets. A porcine ICM model included 4 groups; sham operation, omentum flap only, cell-sheet only, or combination therapy. Ejection fraction (EF) was significantly greater in the cell-sheet only and combination group compared to the other groups during the follow-up period. At 3 months, the EF of the combination group was significantly greater than that of the cell-sheet only group. Consistently, the survival rate of the SPIO-labeled hiPS-CMs, as assessed by MRI, was significantly greater in the combination group than in the cell-sheet only group. This cell delivery system would be useful in optimizing the hiPS-CM cell-sheet transplant for treating severe heart failure.

Highlights

Human iPS-derived cardiomyocytes sheet for a porcine ischemic cardiomyopathy model[11], long-term engraftment of transplanted cells has remained to be concerned[11]
80% (84.6 ± 6.8%) of the human iPS (hiPS)-CMs were positive for cardiac troponin T, as determined by flow cytometry (Fig. 1a), and evidence of sarcomeres among the hiPS cell-derived cardiomyocytes (hiPS-CM) was demonstrated by immunocytochemistry with an anti-sarcomeric alpha actinin antibody (Fig. 1b)
It is demonstrated that the combination of hiPS-CM cell-sheet and the omentum flap had higher and longer therapeutic effects compared with the sole hiPS-CM cell-sheet therapy in a porcine ischemic cardiomyopathy model

Summary

Introduction

Human iPS-derived cardiomyocytes (hiPS-CMs) sheet for a porcine ischemic cardiomyopathy model[11], long-term engraftment of transplanted cells has remained to be concerned[11]. This poor engraftment of the transplanted cells is considered to be resulted from ischemia caused by poor vascularization of the transplanted sites and inflammation with attendant oxidative stress and release of cytotoxic cytokines[1,2,3]. We hypothesized that the pedicle omentum flap technique may enhance survival of hiPS-CMs and the therapeutic capacity of hiPS-CM sheet transplant in a porcine ischemic cardiomyopathy model. We compared survival of hiPS-CMs after transplantation in a diseased heart, with or without the pedicle omentum flap, and we investigated whether improvement of cardiac functions increased by the additive omentum flap compared with the hiPS-CM sheet itself in a porcine cardiomyopathy model

Methods

Results

Conclusion