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Creation of cardiac organoids and bio-artificial hearts using self-organization ability through sympathetic nerve crosstalk

Research Project

Project/Area Number 21H03808
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 90110:Biomedical engineering-related
Research InstitutionOsaka University

Principal Investigator

LEE JONG-KOOK  大阪大学, 大学院医学系研究科, 特任教授(常勤) (60303608)

Co-Investigator(Kenkyū-buntansha) 坂田 泰史  大阪大学, 大学院医学系研究科, 教授 (00397671)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2023: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2022: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2021: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
Keywords三次元心筋組織構築 / 交感神経 / 臓器間クロストーク / iPS細胞 / オルガノイド / 心筋 / 自己組織化 / 成熟化 / iPS細胞由来心筋細胞 / ストレスファイバー / 脱細胞化 / 三次元組織構築 / 3次元心筋組織構築
Outline of Research at the Start

本研究においては、生体臓器に匹敵する機能特性を有する三次元心筋組織構築を目標に、以下の3点を行う.
#1 交感神経-心筋クロストークによる自己組織化・成熟化促進メカニズムの解明と心臓オルガノイド創出.
#2 臓器間クロストークによる生体に匹敵するバイオ人工心臓の構築:分化誘導過程のiPS心筋・神経細胞を心臓脱細胞化マトリックスに共播種し、臓器様三次元心筋組織構築を行う. #3 心臓オルガノイド・バイオ人工心臓の創薬・再生治療への応用:心臓オルガノイドおよびミニバイオ人工心臓を用い、創薬・再生治療研究に利用可能なプラットフォームを創出する.

Outline of Final Research Achievements

In the recellularized 3D cardiac tissue, pharmacological responses to cardiotonic agents comparable to those in vivo were observed. The presence of rat sympathetic nerve cells promoted the self-organization and maturation of human iPS-derived cardiomyocytes, as reconfirmed in an in vitro system. We investigated the relationship between stress fibers (actin) and YAP signaling, related to cell proliferation and migration, in human iPS-derived cardiomyocytes and reported our findings. We established techniques for evaluating the functional characteristics of human iPS-derived atrial and ventricular myocytes, developed foundational technologies for a drug discovery platform, and reported these findings. In the co-culture system of human iPS cardiomyocytes and sympathetic nerves, the increase in spontaneous beating rate after nicotine addition was more pronounced.

Academic Significance and Societal Importance of the Research Achievements

本課題においては、研究代表者らが見出した「交感神経との共培養がiPS 心筋の自己組織化と成熟化を促進する」現象を再確認し、iPS心筋を用いた三次元心筋組織の構築と機能・形態評価を行い、「臓器間クロストーク」の影響を調べた。
本研究は、生体模倣系に基づく創薬プラットフォームを含む社会実装に向けたアプローチに有用な知見をもたらした。1.創薬・再生治療に利用可能な三次元心筋組織を構築するためには、臓器間クロストーク(交感神経-心筋)による心筋の自己組織化と成熟性促進が有用であることを明らかにした。2.交感神経支配を有する三次元心筋組織を構築した。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (15 results)

All 2023 2022 2021

All Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 7 results,  Open Access: 3 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 5 results)

  • [Journal Article] Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for TNNT2 Δ160E-Induced Cardiomyopathy2022

    • Author(s)
      Kondo Takumi、Higo Shuichiro、Shiba Mikio、Kohama Yasuaki、Kameda Satoshi、Tabata Tomoka、Inoue Hiroyuki、Okuno Shota、Ogawa Shou、Nakamura Satoki、Takeda Maki、Ito Emiko、Li Junjun、Liu Li、Kuramoto Yuki、Lee Jong-Kook、Takashima Seiji、Miyagawa Shigeru、Sawa Yoshiki、Hikoso Shungo、Sakata Yasushi
    • Journal Title

      Circulation: Genomic and Precision Medicine

      Volume: 15 Issue: 5 Pages: 429-443

    • DOI

      10.1161/circgen.121.003522

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 巨大陰性T波の発生機序と臨床的意義, HEART's Original [総説]2022

    • Author(s)
      外山淳治, 渡邉英一, 李鍾國, 辻幸臣, 鈴木頼快, 大川育秀, 鈴木孝彦
    • Journal Title

      心臓(日本医学出版)

      Volume: 54 Pages: 1014-1021

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 臨床と基礎の世界を巡るトランスレーショナル研究~日本の基礎研究の現状と不整脈領域の再生医療~2022

    • Author(s)
      李鍾國
    • Journal Title

      心電図(日本不整脈心電学会誌)

      Volume: 42 Pages: 165-169

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Editorial: Induced Pluripotent Stem Cell-Based Disease Modeling and Drug Discovery: Can We Recapitulate Cardiovascular Disease on a Culture Dish?2022

    • Author(s)
      Yuasa Shinsuke、Yazawa Masayuki、Lee Jong-Kook
    • Journal Title

      Frontiers in Cell and Developmental Biology

      Volume: 9 Pages: 831304-831304

    • DOI

      10.3389/fcell.2021.831304

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes2021

    • Author(s)
      Yasutake Hideki、Lee Jong-Kook、Hashimoto Akihito、Masuyama Kiyoshi、Li Jun、Kuramoto Yuki、Higo Shuichiro、Hikoso Shungo、Hidaka Kyoko、Naito Atsuhiko T.、Miyagawa Shigeru、Sawa Yoshiki、Komuro Issei、Sakata Yasushi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 10351-10351

    • DOI

      10.1038/s41598-021-89603-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Homogeneous 2D and 3D alignment of cardiomyocyte in dilated cardiomyopathy revealed by intravital heart imaging2021

    • Author(s)
      Masuyama Kiyoshi、Higo Tomoaki、Lee Jong-Kook、Matsuura Ryohei、Jones Ian、Bakal Chris、Higo Shuichiro、Morimoto Sachio、Miyagawa Shigeru、Sawa Yoshiki、Sakata Yasushi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 14698-14698

    • DOI

      10.1038/s41598-021-94100-z

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protocol for Morphological and Functional Phenotype Analysis of hiPS-Derived Cardiomyocytes2021

    • Author(s)
      Li J, Lee JK
    • Journal Title

      Methods Mol Biol/ Pluripotent Stem-Cell Derived Cardiomyocytes

      Volume: 2320 Pages: 91-100

    • DOI

      10.1007/978-1-0716-1484-6_10

    • ISBN
      9781071614839, 9781071614846
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] High-throughput drug screening system based on human induced pluripotent stem cell-derived atrial myocytes ~ A novel platform to detect cardiac toxicity for atrial arrhythmias2021

    • Author(s)
      Honda Y, Li J, Hino A, Tsujimoto S, Lee JK
    • Journal Title

      Frontiers in Pharmacology

      Volume: 12 Pages: 680618-680618

    • DOI

      10.3389/fphar.2021.680618

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Presentation] 不整脈関連トランスレーショナルリサーチの展望~不整脈医療従事者・研究者にこれだけは知ってほしい心筋再生の基礎とその応用~2023

    • Author(s)
      李鍾國
    • Organizer
      心電学関連春季大会2023,
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] iPS-based platforms for disease modeling with sympathetic innervation in the heart2023

    • Author(s)
      Jong-Kook LEE
    • Organizer
      The 7th Cardiovascular Bioengineering Symposium 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Sympathetic innervation facilitates the maturation of iPS-derived cardiomyocytes: implication for in vitro arrhythmia modeling2023

    • Author(s)
      李俊, 李鍾國, 坂田泰史
    • Organizer
      第69回日本不整脈心電学会学術大会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 内在性酸化ストレス制御ヒトiPS細胞を用いた心筋細胞老化モデルの樹立2023

    • Author(s)
      岡素雅子、李俊、王苑犁、鷹野典子、大野みずき、李鍾國、日高京子
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Developmental change of extracellular matrix composition -Implication for engineering of 3D cardiac tissue-2023

    • Author(s)
      Jieran LYU, Jun LI, Kyoko HIDAKA, Jong-Kook LEE
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 不整脈領域の心筋再生医療:iPS心筋を用いた創薬とバイオペースメーカー2022

    • Author(s)
      李 鍾國
    • Organizer
      第68回日本不整脈心電学会学術大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] ヒトiPS心房筋を用いた創薬プラットフォームの構築2021

    • Author(s)
      李鍾國
    • Organizer
      心電学関連春季大会2021
    • Related Report
      2021 Annual Research Report
    • Invited

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Published: 2021-04-28   Modified: 2025-01-30  

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