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Abstract
Originally Published 6 November 2015
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Abstract 13789: Developing Xeno-Free Human Induced Pluripotent Stem Cell-Derived Cardiac Construct for Regeneration Therapy Using a Rat Myocardial Infarction Model

Abstract

Background: Use of induced pluripotent stem cells (hiPSC) is promising to establish cardiac regenerative medicine in clinical arena; however, safety is concerned by regulatory scientific view, including use of xeno-biological materials for production of the graft. We have explored synthetic small molecules, KY, instead of standard xeno-materials to induce cardiomyogenic differentiation, such as BMP4, Activin A or insulin. We herein studied therapeutic efficacy of hiPSC-derived cardiomyocytes (CMs) generated by xeno-free condition on chronic myocardial infarction (MI) in rat.
Methods: Lentivirus vector carrying Oct3/4, Sox2 and Klf4 was transfected in human dermal fibroblasts to establish hiPSC cell-line. KY was added to the hiPSCs, which displayed 80±10%-positivity in cardiac-troponin T. Scaffold-free cardiac graft was produced by hiPSC-CMs that were cultured in thermoresponsive dishes, and transplanted over the cardiac surface of athymic nude rats that were subjected to left coronary artery ligation 2 weeks prior to the treatment, or sham operation was performed.
Results: Echocardiographically, ejection fraction recovered after the treatment in the hiPSC-CM group (48±4% at baseline, 55±4% at 1 week, 55±4% at 2 weeks, and 56±3% at 4 weeks), whereas the sham group showed gradual reduction in ejection fraction (46±5% at baseline, 42±5% at 1 week, 38±4% at 2 weeks, and 34±6% at 4 weeks). Immunohistochemistry showed that cardiac-troponin T and human nuclear antigen double positive-hiPSC-CMs were present in the lateral cardiac surface in the hiPSC-CM hearts. In the hiPSC-CM group, collagen fibers significantly decreased in the infarct-border and remote areas (p<0.01 and p<0.01, respectively). CD31-positve capillary number in the infarct-border area was significantly greater in the hiPSC-CM group (p<0.01) than the sham group.
Conclusion: Transplantation of scaffold-free human iPSC-CMs grafts produced by xeno-free synthetic small molecules was effective on rat chronic MI heart, warranting further studies to optimize production of iPSC-based artificial cardiac graft for cardiac regeneration therapy.

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Published online: 6 November 2015
Published in print: 10 November 2015

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Keywords

  1. iPS
  2. Xeno-free
  3. Ischemic heart disease
  4. Regenerative therapy
  5. Angiogenesis

Authors

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Motoko Shiozaki
Cardiovascular Surgery, Osaka Univ Graduate Sch of Medicine, Osaka, Japan
Shigeru Miyagawa
Cardiovascular Surgery, Osaka Univ Graduate Sch of Medicine, Osaka, Japan
Satsuki Fukushima
Cardiovascular Surgery, Osaka Univ Graduate Sch of Medicine, Osaka, Japan
Itsunari Minami
Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto Univ, Kyoto, Japan
Keitaro Domae
Cardiovascular Surgery, Osaka Univ Graduate Sch of Medicine, Osaka, Japan
Shin Yajima
Cardiovascular Surgery, Osaka Univ Graduate Sch of Medicine, Osaka, Japan
Emiko Ito
Cardiovascular Surgery, Osaka Univ Graduate Sch of Medicine, Osaka, Japan
Kazuhiro Aiba
Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto Univ, Kyoto, Japan
Takashi Asada
Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto Univ, Kyoto, Japan
Norio Nakatsuji
Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto Univ, Kyoto, Japan
Yoshiki Sawa
Cardiovascular Surgery, Osaka Univ Graduate Sch of Medicine, Osaka, Japan

Notes

Author Disclosures: M. Shiozaki: None. S. Miyagawa: None. S. Fukushima: None. I. Minami: None. K. Domae: None. S. Yajima: None. E. Ito: None. K. Aiba: None. T. Asada: None. N. Nakatsuji: None. Y. Sawa: None.

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Abstract 13789: Developing Xeno-Free Human Induced Pluripotent Stem Cell-Derived Cardiac Construct for Regeneration Therapy Using a Rat Myocardial Infarction Model
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