Novel method for treating myocardium infarction by using cardiac tissue ring matured by spontaneous traveling wave

• Project/Area Number: 19K12801
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 90120:Biomaterials-related
• Research Institution: Osaka University
• Principal Investigator: LI JUNJUN 大阪大学, 医学系研究科, 特任助教(非常勤) (10723786)
• Co-Investigator(Kenkyū-buntansha): 南 一成 大阪大学, 医学系研究科, 特任准教授(常勤) (40362537)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: pluripotent stem cells / tissue engineering / cardiomyocytes / regenerative medicine / cell maturation / maturation / 心筋梗塞治療 / 成熟心筋 / 自発進行波

Outline of Research at the Start

ヒトiPS細胞由来の心筋を用いた再生医療による治療法の開発が期待されている。しかし、既存の方法で作製した心筋細胞シートは厚さ0.2mmが限界であり、成熟度や収縮力、そして物理的な強度などが不足している。これまでに、我々は組織工学的技術を駆使したiPS細胞由来心筋リングの作製に成功することによって、心筋細胞特異的な進行波の自発を誘発することが実現し、心筋細胞の成熟を促進することを明らかとなった。さらに、十分な強度と良好なハンドリング性を有する。本研究課題においては、この高成熟度組織化心筋リングを心筋梗塞モデル動物の心臓を嵌め込む形で、力学的に心臓の収縮をサポートする新規治療法の開発を目指す。

Outline of Final Research Achievements

Cardiomyocytes derived from human iPSCs are expected to repair the infarcted heart, however, their maturation level could affect the therapeutic effect. Supported by the present project, we prepared the matured self-organized tissue rings and evaluate their therapeutic effect on the rat heart with myocardium infarction. The achivements are as following:　1.The matured tissue sheet paced by the traveling wave have been prepared. The cardiac-specific markers have been verified.　2.The mature tissue group demonstrated an improved therapeutic effect on the rat heart with myocardial infarction compared with the control group. In addition, we find the improved survival rate and improved therapeutic effect of matured tissue could be related to the higher expression of myoglobin, cytochrome C, and other maturation related markers.
3. We published 3 papers and applied for 1 patent, we gave an oral presentation at 2021 American Heart Association conference.

Academic Significance and Societal Importance of the Research Achievements

This technology could be used to produce matured iPSC-derived cardiac tissue for treating infarcted hearts. We expect that this new technology could be of great usefulness and importance for both researchers and clinical users working on developing regenerative therapy for the human heart.

Research Products

• [Int'l Joint Research] Perking University(中国)
• [Journal Article] Therapeutic efficacy of large aligned cardiac tissue derived from induced pluripotent stem cell in a porcine ischemic cardiomyopathy model (2021)
  • Author(s): Suzuki Kota、Miyagawa Shigeru、Liu Li、Kawamura Takuji、Li Junjun、Qu Xiang、Harada Akima、Toda Koichi、Yoshioka Daisuke、Kainuma Satoshi、Kawamura Ai、Sawa Yoshiki
  • Journal Title: The Journal of Heart and Lung Transplantation Volume: 40 Issue: 8 Pages: 767-777
  • DOI: 10.1016/j.healun.2021.04.010
  • Peer Reviewed
• [Journal Article] hiPSC-Derived Cardiac Tissue for Disease Modeling and Drug Discovery (2020)
  • Author(s): Li Junjun、Hua Ying、Miyagawa Shigeru、Zhang Jingbo、Li Lingjun、Liu Li、Sawa Yoshiki
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 23 Pages: 8893-8893
  • DOI: 10.3390/ijms21238893
  • Peer Reviewed / Open Access
• [Journal Article] Circulating re-entrant waves promote maturation of hiPSC-derived cardiomyocytes in self-organized tissue ring (2020)
  • Author(s): Li Junjun、Zhang Lu、Yu Leqian、Minami Itsunari、Miyagawa Shigeru、H?rning Marcel、Dong Ji、Qiao Jing、Qu Xiang、Hua Ying、Fujimoto Nanae、Shiba Yuji、Zhao Yang、Tang Fuchou、Chen Yong、Sawa Yoshiki、Tang Chao、Liu Li
  • Journal Title: Communications Biology Volume: 3 Issue: 1
  • DOI: 10.1038/s42003-020-0853-0
  • Peer Reviewed / Open Access
• [Presentation] Human iPSC derived cardiac tissue matured by spontaneous traveling waves for improved drug assessment (2021)
  • Author(s): 1.Li, J., Liu, L., Miyagawa, S., Kawamura, T., Matsuura, R., Hua, Y., Qu, X., Sougawa, N., Sawa, Y.,
  • Organizer: American Heart Association Scientific Session, (2021)
  • Int'l Joint Research
• [Presentation] Circulating TRAVELING WAVES ENHANCE THE MATURATION OF HIPSC-DERIVED CARDIOMYOCYTES IN SELF-ORGANIZED TISSUE RING (2019)
  • Author(s): Li Junjun
  • Organizer: The 8th Meeting of the International Federation for Artificial Organs
  • Int'l Joint Research
• [Presentation] CIRCULATING TRAVELING WAVES ENHANCE THE MATURATION OF HIPSC-DERIVED CARDIOMYOCYTES IN SELF-ORGANIZED TISSUE RING (2019)
  • Author(s): Li Junjun
  • Organizer: CiRA 2019 International Symposium
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 心筋細胞層の製造方法、心筋細胞層、およびその利用 (2021)
  • Inventor(s): 劉莉、澤芳樹、宮川繁、李俊君、武田真季、三好隼人
  • Industrial Property Rights Holder: 劉莉、澤芳樹、宮川繁、李俊君、武田真季、三好隼人
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021