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Evaluation of Post-Transplant Arrhythmia in Human iPSC-Derived Purified Ventricular Cardiomyocytes

Research Project

Project/Area Number 19K22626
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 53:Organ-based internal medicine and related fields
Research InstitutionKeio University

Principal Investigator

Tohyama Shugo  慶應義塾大学, 医学部(信濃町), 講師 (90528192)

Co-Investigator(Kenkyū-buntansha) 柴 祐司  信州大学, 学術研究院医学系, 教授 (70613503)
Project Period (FY) 2019-06-28 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
KeywordsヒトiPS細胞 / 心筋細胞 / サル / 催不整脈作用 / 再生医療 / 移植 / カニクイザル
Outline of Research at the Start

ヒトiPS細胞は心筋細胞を含むさまざまな細胞へ分化することができるため、再生医療への応用が期待されているが、心臓再生医療を実現化するためには、移植後の催不整脈作用という課題を克服しなければならない。その課題を克服するために、京都大学iPS細胞研究所において作製されたHLAホモ接合体ヒト由来のiPS細胞から臨床グレードの心筋細胞(心筋含有率99%以上)を作製し (Cell Metab. 2016, Stem Cell Rep 2017)、直径200μmの微小組織球を作製した後、カニクイザル心筋梗塞モデルに免疫抑制剤投与下で移植し、催不整脈作用および心機能を評価することで、霊長類モデルにおける長期の安全性および有効性を評価する。

Outline of Final Research Achievements

Since human iPSCs can differentiate into various types of cells including cardiomyocytes, they are expected to be applied to regenerative medicine. However, to realize cardiac regenerative medicine, there is a risk of post-transplant arrhythmia. Therefore, we prepared purified ventricular cardiomyocytes from clinical-grade HLA homozygous human iPSCs by our developed clinical-grade culture system. Then, after production of cardiac spheroids, they were transplanted into cynomolgus monkey myocardial infarction models under immunosuppressive drug administration, and post-transplant arrhythmia and cardiac function were evaluated. As a result, we observed long-term engraftment of cardiac tissue and demonstrated that cardiac function was significantly improved and the risk of ventricular tachycardia was extremely low. Therefore, the transplanted purified ventricular cardiomyocytes were suitable for safer transplantation.

Academic Significance and Societal Importance of the Research Achievements

本研究において、臨床用iPS細胞を用いて臨床グレードの純化心筋細胞および微小心筋組織球を大量に作製し、カニクイザルに移植を行い、長期生着を達成しながら、心機能の改善および催不整脈作用の評価ができたことは非常に大きな意義があると考えられる。また、我々のシステムで作製したヒトiPS細胞由来心筋組織球を移植した際には催不整脈作用が既存の報告に比べて極めて少ないことも特筆すべきである。今後は、どのような特性を持つ心筋細胞を移植した場合に催不整脈作用を有するのかに関しても解明していく必要があると考えている。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (36 results)

All 2021 2020 2019

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (28 results) (of which Int'l Joint Research: 7 results,  Invited: 28 results) Book (3 results)

  • [Journal Article] Tryptophan Metabolism Regulates Proliferative Capacity of Human Pluripotent Stem Cells2021

    • Author(s)
      Shota Someya, Shugo Tohyama, Kotaro Kameda, Sho Tanosaki, Yuika Morita, Kazunori Sasaki, Moon Il Kang, Yoshikazu Kishino, Marina Okada, Hidenori Tani, Yusuke Soma, Kazuaki Nakajima, Tomohiko Umei, Otoya Sekine, Taijun Moriwaki, Hideaki Kanazawa, Eiji Kobayashi, Jun Fujita, Keiichi Fukuda
    • Journal Title

      iScience

      Volume: 24 Issue: 2 Pages: 102090-102090

    • DOI

      10.1016/j.isci.2021.102090

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intramyocardial Transplantation of Human iPS Cell?Derived Cardiac Spheroids Improves Cardiac Function in Heart?Failure Animals2021

    • Author(s)
      Kawaguchi Shinji、Soma Yusuke、Nakajima Kazuaki、Kanazawa Hideaki、Tohyama Shugo、Tabei Ryota、Hirano Akinori、Handa Noriko、Yamada Yoshitake、Okuda Shige,...........Shibata Rei、Murohara Toyoaki、Tabata Yasuhiko、Kobayashi Eiji、Shimizu Hideyuki、Fukuda Keiichi、Fujita Jun
    • Journal Title

      JACC: Basic to Translational Science

      Volume: 6 Issue: 3 Pages: 239-254

    • DOI

      10.1016/j.jacbts.2020.11.017

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fatty Acid Synthesis Is Indispensable for Survival of Human Pluripotent Stem Cells2020

    • Author(s)
      Sho Tanosaki, Shugo Tohyama, Jun Fujita, Hiroki Nakanishi, Takayo Ohto-Nakanishi, Tomohiko Akiyama, Yuika Morita, Yoshikazu Kishino, Marina Okada, Hidenori Tani, Yusuke Soma, Kazuaki Nakajima, Hideaki Kanazawa, Masahiro Sugimoto, Minoru S.H. Ko, Makoto Suematsu, Keiichi Fukuda
    • Journal Title

      iScience

      Volume: 23 Issue: 9 Pages: 101535-101535

    • DOI

      10.1016/j.isci.2020.101535

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Metabolic Regulation of Cardiac Differentiation and Maturation in Pluripotent Stem Cells: A Lesson from Heart Development2020

    • Author(s)
      Morita Y & Tohyama S.
    • Journal Title

      JMA Journal

      Volume: 3 Issue: 3 Pages: 193-200

    • DOI

      10.31662/jmaj.2020-0036

    • NAID

      130007905842

    • Related Report
      2020 Annual Research Report
    • 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

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 細胞の個性を生かした心臓再生医療2021

    • Author(s)
      遠山周吾
    • Organizer
      AMED再生・細胞医療・遺伝子治療公開シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ヒトiPS細胞を用いた 重症心不全に対する心臓再生医療2021

    • Author(s)
      遠山周吾
    • Organizer
      第24回日本心血管内分泌代謝学会学術総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ヒトiPS細胞を用いた重症心不全に対する心臓再生医療2021

    • Author(s)
      遠山周吾
    • Organizer
      第20回日本再生医療学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 多能性幹細胞の代謝機構に基づく機能制御と再生医療への応用2021

    • Author(s)
      遠山 周吾, 菱木 貴子, 飯島 寛, 的場 亮
    • Organizer
      第20回日本再生医療学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Cardiac Regenerative Therapy with Human Pluripotent Stem Cells for Heart Failure2021

    • Author(s)
      Shugo Tohyama, Sho Tanosaki, Yusuke Soma, Shota Someya, Hideaki Kanazawa, Jun Fujita, Keiichi Fukuda
    • Organizer
      The Japanese Circulation Society 2021
    • Related Report
      2020 Annual Research Report
    • 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.
    • Related Report
      2020 Annual Research Report
    • 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
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 細胞外代謝環境設計による再生医療用ヒト心筋細胞の大量製造2020

    • Author(s)
      遠山 周吾, 染谷 将太, 田野崎 翔, 藤田 淳, 福田 恵一
    • Organizer
      第19 回日本再生医療学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Cardiac Regenerative Therapy with Human Pluripotent Stem Cells2020

    • Author(s)
      Shugo Tohyama
    • Organizer
      The Japanese Circulation Society 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 多能性幹細胞における代謝機構に基づく機能制御とその応用2020

    • Author(s)
      遠山周吾
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 重症心不全に対するヒトiPS細胞由来心筋組織球移植療法の確立2020

    • Author(s)
      遠山周吾
    • Organizer
      第29回日本小児心筋疾患学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 代謝機構に基づくヒトiPS細胞由来心筋細胞の作製と心臓再生医療への応用2020

    • Author(s)
      遠山周吾
    • Organizer
      第24回日本心不全学会学術集会
    • Related Report
      2020 Annual Research Report
    • 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
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Preclinical transplantation studies of pluripotent stem cell-derived cardiomyocytes for cardiac repair.2020

    • Author(s)
      Yuji Shiba
    • Organizer
      Myocardial Ischemia Symposium in Korea 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Cardiac Regeneration with Pluripotent Stem Cells : A New Paradigm2020

    • Author(s)
      Yuji Shiba
    • Organizer
      The Japanese Circulation Society 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Monkey model-based development of cardiomyocyte regeneration therapy2020

    • Author(s)
      柴祐司
    • Organizer
      第84回日本循環器学会学術集会.
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Allogenic Transplantation of iPS Cell-Derived Cardiomyocytes Regenerates Primate Heart.2020

    • Author(s)
      柴祐司
    • Organizer
      第84回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
    • 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
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Cardiac Regeneration via Pluripotent Stem Cells2020

    • Author(s)
      Yuji Shiba
    • Organizer
      Myocardial Ischemia Symposium in Korea 2021
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ヒトiPS細胞由来の超高純度心筋組織球を用いた再生医療の現状と今後の展望2019

    • Author(s)
      遠山周吾
    • Organizer
      第67回日本心臓病学会学術集会
    • Related Report
      2019 Research-status Report
    • 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
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 細胞内代謝機構に基づくヒトiPS細胞由来心筋作製と心臓再生医療への応用2019

    • Author(s)
      遠山周吾
    • Organizer
      第53回河口湖心臓討論会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] ヒトiPS細胞由来超高純度心室筋細胞の大量作製と心臓再生医療への応用2019

    • Author(s)
      遠山周吾
    • Organizer
      第29回日本サイトメトリー学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 細胞内代謝機構に基づくヒトiPS由来心筋細胞の大量作製とその応用2019

    • Author(s)
      遠山周吾
    • Organizer
      第30回日本医学会総会(名古屋)
    • Related Report
      2019 Research-status Report
    • 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(名古屋)
    • Related Report
      2019 Research-status Report
    • 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
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Stem cell and regenerative medicine.2019

    • Author(s)
      Shiba Y.
    • Organizer
      The 12th APHRS Scientific Scession 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Preclinical transplantation study of iPS cell-derived cardiomyosytes in non-human primate.2019

    • Author(s)
      Shiba Y.
    • Organizer
      The 1st Zhangjiang International Summit on Cell Therapy 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Book] 心臓2020

    • Author(s)
      遠山周吾
    • Publisher
      日本心臓財団
    • Related Report
      2019 Research-status Report
  • [Book] 実験医学増刊号2019

    • Author(s)
      森田唯加、遠山周吾
    • Publisher
      羊土社
    • Related Report
      2019 Research-status Report
  • [Book] 腎と透析2019

    • Author(s)
      遠山周吾、福田恵一
    • Publisher
      東京医学社
    • Related Report
      2019 Research-status Report

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Published: 2019-07-04   Modified: 2024-12-25  

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