Transplantation study of iPS cell-derived cardiomyocytes in non-human primates

• Project/Area Number: 17H04173
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Shinshu University
• Principal Investigator: Shiba Yuji 信州大学, 学術研究院医学系, 教授 (70613503)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2020: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2019: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: 再生医療 / 多能性幹細胞 / 心不全 / iPS細胞 / 心筋再生 / 虚血性心疾患 / 心筋梗塞 / 循環器内科学 / 再生医学

Outline of Final Research Achievements

We performed three experiments itemized below to facilitate cardiac regeneration with iPS cell-derived cardiomyocytes (iPSC-CMs).
1) Autologous transplantation study of iPSC-CMs in chronic infarct model of non-human primates: We have generated iPS cell lines from six animals and generated cardiomyocytes. 2) Establishment of immunosuppression protocol following iPSC-CMs: We generated monkey iPS cell lines expressing AKaluc for bioluminescent imaging. 3) Transplantation study of iPSC-derived ventricular cardiomyocytes to control post-transplantation arrhythmia: We transplanted iPSC-ventricular CMs into 5 monkeys and found that the recipients tended to show less incidence of ventricular arrhythmia compared to those transplatned with iPSC-CMs

Academic Significance and Societal Importance of the Research Achievements

心不全は患者数、死亡率ともに高く、心臓移植以外の根本的治療の開発が必要である。多能性幹細胞（ES細胞またはiPS細胞）を用いた心筋再生治療が期待され、複数の研究機関で臨床試験が開始されている。しかし、この治療が標準的な治療として定着するためには多くの課題が残されている。本研究成果により、より有効で安全性の高い心筋再生治療の開発が期待される。

Research Products

• [Journal Article] Pluripotent Stem Cells for Cardiac Regeneration ― Current Status, Challenges, and Future Perspectives ― (2020)
  • Author(s): Shiba Yuji
  • Journal Title: Circulation Journal Volume: 84 Issue: 12 Pages: 2129-2135
  • DOI: 10.1253/circj.CJ-20-0755
  • NAID: 130007942529
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-11-25
  • Peer Reviewed / Open Access
• [Journal Article] Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo (2020)
  • Author(s): Ichimura Hajime、Kadota Shin、Kashihara Toshihide、Yamada Mitsuhiko、Ito Kuniaki、Kobayashi Hideki、Tanaka Yuki、Shiba Naoko、Chuma Shinichiro、Tohyama Shugo、Seto Tatsuichiro、Okada Kenji、Kuwahara Koichiro、Shiba Yuji
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 11883-11883
  • DOI: 10.1038/s41598-020-68373-9
  • NAID: 120007006223
  • Peer Reviewed / Open Access
• [Journal Article] Heart regeneration using pluripotent stem cells (2020)
  • Author(s): Kadota Shin、Tanaka Yuki、Shiba Yuji
  • Journal Title: Journal of Cardiology Volume: 76 Issue: 5 Pages: 459-463
  • DOI: 10.1016/j.jjcc.2020.03.013
  • Peer Reviewed / Open Access
• [Journal Article] Pluripotent stem cell-derived cardiomyocyte transplantation for heart disease treatment. (2019)
  • Author(s): Kadota Shin, Shiba Yuji
  • Journal Title: Curr Cardiol Rep. Volume: 21 Issue: 8 Pages: 73-73
  • DOI: 10.1007/s11886-019-1171-3
  • Peer Reviewed / Open Access
• [Presentation] Cardiac Regeneration via Pluripotent Stem Cells. (2021)
  • Author(s): Shiba Yuji
  • Organizer: Myocardial Ischemia Symposium in Korea 2021
  • Int'l Joint Research / Invited
• [Presentation] 霊長類を用いた心筋再生治療の開発 (2021)
  • Author(s): 柴 祐司
  • Organizer: 第20回日本再生医療学会総会
  • Invited
• [Presentation] Primate model for allogeneic transplantation study of iPS cell-derived cardiomyocytes. (2021)
  • Author(s): 柴 祐司
  • Organizer: 第85回日本循環器学会学術集会
  • Invited
• [Presentation] iPS細胞を用いた心筋梗塞治療 (2020)
  • Author(s): 柴 祐司
  • Organizer: 第19回日本再生医療学会総会
  • Invited
• [Presentation] Preclinical transplantation studies of pluripotent stem cell-derived cardiomyocytes for cardiac repair. (2020)
  • Author(s): Shiba Yuji
  • Organizer: Myocardial Ischemia Symposium in Korea 2020
  • Int'l Joint Research / Invited
• [Presentation] Cardiac Regeneration with Pluripotent Stem Cells : A New Paradigm (2020)
  • Author(s): 柴 祐司
  • Organizer: 第84回日本循環器学会学術集会
  • Invited
• [Presentation] Monkey model-based development of cardiomyocyte regeneration therapy. (2020)
  • Author(s): 柴 祐司
  • Organizer: 第84回日本循環器学会学術集会
  • Invited
• [Presentation] Allogenic translation study of pluropotent stem cell-derived cardiomyocytes in non-human primate. (2020)
  • Author(s): 柴 祐司
  • Organizer: 第24回日本心不全学会学術集会
  • Invited
• [Presentation] iPS細胞による心臓再生への挑戦 (2019)
  • Author(s): 柴 祐司
  • Organizer: 第30回日本医学会総会 2019 中部
  • Invited
• [Presentation] 多能性幹細胞を用いた心筋再生:霊長類を用いた前臨床試験 (2019)
  • Author(s): 柴 祐司
  • Organizer: 第67回日本心臓病学会学術集会
  • Invited
• [Presentation] ヒト以外の霊長類へのiPS細胞由来心筋細胞の移植に関する前臨床研究 (2019)
  • Author(s): 柴 祐司
  • Organizer: Cell & Gene Therapy Asia 2019
  • Invited
• [Presentation] Stem cell and regenerative medicine. (2019)
  • Author(s): Shiba Yuji
  • Organizer: The 12th APHRS Scientific Scession 2019
  • Int'l Joint Research / Invited
• [Presentation] Preclinical transplantation study of iPS cell-derived cardiomyosytes in non-human primate. (2019)
  • Author(s): Shiba Yuji
  • Organizer: The 1st Zhangjiang International Summit on Cell Therapy 2019
  • Int'l Joint Research / Invited