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Analysis of novel genes involved in cardiac function using iPSC-derived cardiomyocytes

Research Project

Project/Area Number 17K08551
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General physiology
Research InstitutionOsaka Medical College

Principal Investigator

Wakabayashi Shigeo  大阪医科大学, 医学部, 非常勤講師 (70158583)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsiPS細胞 / Na+/H+交換輸送体 / NHE1 / rhoキナーゼ / 細胞死 / 細胞運動 / ネクロ―シス / 細胞内pH / Rhoキナーゼ / モネンシン / 心筋細胞分化 / ゲノム編集 / 心筋収縮 / 遺伝子発現 / 生体分子 / バイオテクノロジー / 循環器・高血圧 / 生理学 / シグナル伝達
Outline of Final Research Achievements

Induced pluripotent stem cells (iPSCs) are expected in the field of the regenerative medicine from the point of view which can differentiate into cells of all organs. However, after making them differentiate, there is a serious possibility that undifferentiated remaining iPSCs become cancer. In this research, we found that overexpression of the plasma membrane Na+/H+ exchanger (NHE1) induces the cell death of iPSCs. We found that cell death occurs through strong activation of rho kinase ROCK caused by a local intracellular pH rise triggered by NHE1. Analogy to this, we also found that Na+-ionophore monensin which is a small compound with similar function as NHE1, specifically killed iPSCs. This study provides a new simple procedure through which to eliminate the iPSCs that remain after differentiation.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、学術的には大変意義のある研究である。①細胞骨格の維持や細胞の収縮に関与するとして知られるrhoキナーゼ、ROCKが従来考えられていなかった”細胞内pHの上昇”という新しいシグナルによって活性化されること、②また、その現象が未分化なiPSCsでのみ起こり、その細胞死をもたらすことが明らかになった。社会的には、iPSCsを再生医療へ応用する際、分化せずに残ってしまうiPSCsがガン化してしまうという危険性があった。本研究で、NHE1と同様な機能を持つ低分子モネンシンはiPSCs特異的に死滅させることが判明し、簡単な操作でiPSCsを死滅除去できる方法論へと応用可能である。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (14 results)

All 2020 2019 2018 2017

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (8 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Exacerbation of autoimmune myocarditis by an immune checkpoint inhibitor is dependent on its time of administration in mice2020

    • Author(s)
      Tsuruoka Kenjiro、Wakabayashi Shigeo、Morihara Hirofumi、Matsunaga Ninso、Fujisaka Yasuhito、Goto Isao、Imagawa Akihisa、Asahi Michio
    • Journal Title

      International Journal of Cardiology

      Volume: S0167-5273 Pages: 34641-34648

    • DOI

      10.1016/j.ijcard.2020.04.033

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Production of TRPV2-targeting functional antibody ameliorating dilated cardiomyopathy and muscular dystrophy in animal models2020

    • Author(s)
      Yuko Iwata, Shigeo Wakabayashi, Shin Ito, Masafumi Kitakaze
    • Journal Title

      Laboratory Investigation

      Volume: 100 Pages: 324-337

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Overexpression of Na+/H+ exchanger 1 specifically induces cell death in human iPS cells via sustained activation of the Rho kinase ROCK2019

    • Author(s)
      Shigeo Wakabayashi, Hirofumi Morihara, Shunichi Yokoe, Takatoshi Nakagawa, Kazumasa Moriwaki, Kiichiro Tomoda, Michio Asahi
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Pages: 19577-19588

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reduced transient receptor potential vanilloid 2 expression in alveolar macrophages causes COPD in mice through impaired phagocytic activity2019

    • Author(s)
      Masubuchi Hiroaki、Ueno Manabu、Maeno Toshitaka、Yamaguchi Koichi、Hara Kenichiro、Sunaga Hiroaki、Matsui Hiroki、Nagasawa Masahiro、Kojima Itaru、Iwata Yuko、Wakabayashi Shigeo、Kurabayashi Masahiko
    • Journal Title

      BMC Pulmonary Medicine

      Volume: 19 Issue: 1 Pages: 70-70

    • DOI

      10.1186/s12890-019-0821-y

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Emerging roles of neuronal Ca2+ sensor-1 in cardiac and neuronal tissues: a mini review2019

    • Author(s)
      Nakamura TY., Nakao S, Wakabayashi S
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 12 Pages: 56-56

    • DOI

      10.3389/fnmol.2019.00056

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel inhibitor candidates of TRPV2 prevent damage of dystrophic myocytes and ameliorate against dilated cardiomyopathy in a hamster model2018

    • Author(s)
      Yuko Iwata, Yoshimi Katayama, Yasushi Okuno, Shigeo Wakabayashi
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 18 Pages: 14042-14067

    • DOI

      10.18632/oncotarget.24449

    • NAID

      120006892046

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Overexpression of the Na+/H+ exchanger NHE1 induces selective cell death of human iPS cells via sustained activation of rho kinase ROCK.2019

    • Author(s)
      Shigeo Wakabayashi, Kiichiro Tomoda, Shunichi Yokoe, Hirofumi Morihara, Michio Asahi
    • Organizer
      京都大学iPS細胞研究所シンポジウム
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Na+/H+交換輸送体NHE1の過剰発現は、RhoキナーゼROCKの持続的活性化を介してヒトiPS細胞の選択的細胞死を誘導する2019

    • Author(s)
      若林繁夫、友田紀一郎、朝日通雄
    • Organizer
      近畿生理学談話会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Overexpression of the Na+/H+ exchanger NHE1 induces selective cell death of human iPS cells via sustained activation of rho kinase ROCK2019

    • Author(s)
      Shigeo Wakabayashi, Kiichiro Tomoda, Shunichi Yokoe, Hirofumi Morihara, Michio Asahi
    • Organizer
      第92回日本生化学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Overexpression of NHE1 induces a selective cell death of human iPS cells viathesustainedactivationofrhokinase ROCK2019

    • Author(s)
      Shigeo Wakabayashi, Kiichiro Tomoda, Shunichi Yokoe, Hirofumi Morihara, Michio Asahi
    • Organizer
      アジア・オセアニア生理学会連合大会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Function analysis of NHE1 using a strategy of cardiomyocyte differentiation from human iPS cells2019

    • Author(s)
      Shigeo Wakabayashi, Kiichiro Tomoda, Shunichi Yokoe, Hirofumi Morihara, Michio Asahi
    • Organizer
      日本生理学会大会 FAOPS
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ヒトiPS細胞からの心筋分化系を用いた形質膜Na+/H+交換輸送体の機能解析2018

    • Author(s)
      若林繁夫、友田紀一郎、横江俊一、森原啓文、朝日通雄
    • Organizer
      日本生化学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] ヒトiPS細胞からの心筋分化系を用いた遺伝子の機能解析2017

    • Author(s)
      若林繁夫、友田紀一郎、朝日通雄
    • Organizer
      第110回近畿生理学談話会
    • Related Report
      2017 Research-status Report
  • [Presentation] ヒトiPS細胞からの心筋分化系を用いた心筋に高発現するCa2+結合蛋白質CHP3の機能解析2017

    • Author(s)
      若林繁夫、友田紀一郎、金美花、横江俊一、森原啓文、朝日通雄
    • Organizer
      Conbio生命科学系合同年会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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