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Identification of master factors for mesoderm induction from pluripotent stem cells and establishment of a method for selective cardiac induction

Research Project

Project/Area Number 18K08114
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionUniversity of Tsukuba

Principal Investigator

Sadahiro Taketaro  筑波大学, 医学医療系, 講師 (60571130)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords再生 / 多能性幹細胞 / 中胚葉 / 発生 / 心筋再生 / 心臓中胚葉 / ダイレクトリプログラミング / 心筋細胞 / メカノトランスダクション / 細胞増殖 / 骨格筋 / 軟骨細胞 / 心臓
Outline of Final Research Achievements

In order to induce cardiomyocytes from pluripotent stem cells, it is common to use multiple growth factors to induce cardiac mesoderm and then differentiate it into cardiomyocytes. However, this method suffers from the complexity of the induction process and the high cost of growth factors. We have discovered that cardiac mesoderm cells can be induced from pluripotent stem cells, such as mouse ES cells and human iPS cells, without the use of growth factors by overexpression of Tbx6. Furthermore, we found that skeletal muscle and chondrocytes can be induced by adjusting the expression period of Tbx6. We also found that the Tbx6 gene has a proliferative effect on cardiomyocytes, indicating the possibility of a new cardiac regeneration therapy.

Academic Significance and Societal Importance of the Research Achievements

世界総死亡数のなかで、心疾患は約半数を占める。終末分化細胞である心筋細胞には増殖能がなく、一度低下した心臓機能が回復することは困難である。ES細胞、iPS細胞などの幹細胞から、心臓幹細胞である心臓中胚葉を経て分化した誘導心筋は、再生医療のツールとして期待されるが、液性因子による誘導が必須である。この誘導法は、高価な液性因子によるコストの問題以外に、誘導手法が不安定かつ煩雑という課題がある。液性因子に頼らず、単一遺伝子によって多能性幹細胞から選択的な心臓中胚葉・心筋細胞への誘導が可能となる本研究成果により安定かつ簡便、さらに安価に心筋作製が可能となり、心臓再生医療の飛躍的な前進が期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (17 results)

All 2021 2020 2019 2018

All Journal Article (9 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 9 results,  Open Access: 6 results) Presentation (5 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results) Book (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 2 results)

  • [Journal Article] Soft Matrix Promotes Cardiac Reprogramming via Inhibition of YAP/TAZ and Suppression of Fibroblast Signatures2020

    • Author(s)
      Kurotsu Shota、Sadahiro Taketaro、Fujita Ryo、Tani Hidenori、Yamakawa Hiroyuki、Tamura Fumiya、Isomi Mari、Kojima Hidenori、Yamada Yu、Abe Yuto、Murakata Yoshiko、Akiyama Tatsuya、Muraoka Naoto、Harada Ichiro、Suzuki Takeshi、Fukuda Keiichi、Ieda Masaki
    • Journal Title

      Stem Cell Reports

      Volume: 15 Issue: 3 Pages: 612-628

    • DOI

      10.1016/j.stemcr.2020.07.022

    • NAID

      120007165453

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Direct Cardiac Reprogramming for Cardiovascular Regeneration and Differentiation2019

    • Author(s)
      Sadahiro Taketaro、Ieda Masaki
    • Journal Title

      The Keio Journal of Medicine

      Volume: - Issue: 3 Pages: 49-58

    • DOI

      10.2302/kjm.2019-0008-oa

    • NAID

      130007907362

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cardiac regeneration with pluripotent stem cell-derived cardiomyocytes and direct cardiac reprogramming2019

    • Author(s)
      Sadahiro Taketaro
    • Journal Title

      Regenerative Therapy

      Volume: 11 Pages: 95-100

    • DOI

      10.1016/j.reth.2019.06.004

    • NAID

      120007132753

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] 2.Tbx6 induces cardiomyocyte proliferation in postnatal and adult mouse hearts.2019

    • Author(s)
      Haginiwa S, Sadahiro T, Kojima H, Isomi M, Tamura F, Kurotsu S, Tani H, Muraoka N, Miyake N, Miyake K, Fukuda K, Ieda M.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 513 Issue: 4 Pages: 1041-1047

    • DOI

      10.1016/j.bbrc.2019.04.087

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming2019

    • Author(s)
      Muraoka Naoto、Nara Kaori、Tamura Fumiya、Kojima Hidenori、Yamakawa Hiroyuki、Sadahiro Taketaro、Miyamoto Kazutaka、Isomi Mari、Haginiwa Sho、Tani Hidenori、Kurotsu Shota、Osakabe Rina、Torii Satoru、Shimizu Shigeomi、Okano Hideyuki、Sugimoto Yukihiko、Fukuda Keiichi、Ieda Masaki
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 674-674

    • DOI

      10.1038/s41467-019-08626-y

    • NAID

      120007128245

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rapid and high-efficient generation of mutant mice using freeze-thawed embryos of the C57BL/6J strain2019

    • Author(s)
      Darwish Mohamed、Nishizono Hirofumi、Uosaki Hideki、Sawada Hitomi、Sadahiro Taketaro、Ieda Masaki、Takao Keizo
    • Journal Title

      Journal of Neuroscience Methods

      Volume: 317 Pages: 149-156

    • DOI

      10.1016/j.jneumeth.2019.01.010

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Progress and Challenge of Cardiac Regeneration to Treat Heart Failure2019

    • Author(s)
      Isomi Mari、Sadahiro Taketaro、Ieda Masaki
    • Journal Title

      Journal of Cardiology

      Volume: 73 Issue: 2 Pages: 97-101

    • DOI

      10.1016/j.jjcc.2018.10.002

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Direct Cardiac Reprogramming: A Novel Approach for Heart Regeneration2018

    • Author(s)
      Tani Hidenori、Sadahiro Taketaro、Ieda Masaki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 19 Issue: 9 Pages: 2629-2629

    • DOI

      10.3390/ijms19092629

    • NAID

      120007128488

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Tbx6 Induces Nascent Mesoderm from Pluripotent Stem Cells and Temporally Controls Cardiac versus Somite Lineage Diversification.2018

    • Author(s)
      Sadahiro T, Isomi M, Muraoka N, Kojima H, Haginiwa S, Kurotsu S, Tamura F, Tani H, Tohyama S, Fujita J, Miyoshi H, Kawamura Y, Goshima N, Iwasaki YW, Murano K, Saito K, Oda M, Andersen P, Kwon C, Uosaki H, Nishizono H, Fukuda K, Ieda M
    • Journal Title

      Cell stem cell

      Volume: 23(3) Issue: 3 Pages: 382-395

    • DOI

      10.1016/j.stem.2018.07.001

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Soft Matrix Rigidity Improves Direct Cardiac Reprogramming via Inhibition of Rho/ROCK, Actomyosin, and YAP/TAZ Pathway and Silencing Fibroblast Signature2021

    • Author(s)
      Taketaro Sadahiro
    • Organizer
      CVMW2020
    • Related Report
      2020 Annual Research Report
  • [Presentation] Developmental and Regenerative Biology of Cardiac Stem Cells2021

    • Author(s)
      貞廣威太郎
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] iCMの最新事情2020

    • Author(s)
      貞廣威太郎
    • Organizer
      第24回日本心不全学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ダイレクトリプログラミングによる心筋再生2020

    • Author(s)
      貞廣威太郎
    • Organizer
      第19回日本再生医療学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Tbx6 is Critical for Mesoderm Induction and Specification Into Cardiovascular and Somite Lineages2018

    • Author(s)
      Taketaro Sadahiro
    • Organizer
      AHA
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Book] 疾患に挑むメカノバイオロジー2020

    • Author(s)
      貞廣威太郎、家田真樹
    • Total Pages
      220
    • Publisher
      羊土社
    • ISBN
      9784758103862
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] 線維芽細胞からの心臓前駆細胞と心筋細胞の直接製造方法2018

    • Inventor(s)
      家田 真樹、貞廣 威太郎、礒見 まり、五島 直樹
    • Industrial Property Rights Holder
      家田 真樹、貞廣 威太郎、礒見 まり、五島 直樹
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Acquisition Date
      2018
    • Related Report
      2018 Research-status Report
    • Overseas
  • [Patent(Industrial Property Rights)] 多能性幹細胞からの心臓前駆細胞と心筋細胞の製造方法2018

    • Inventor(s)
      家田 真樹、貞廣 威太郎、礒見 まり、五島 直樹
    • Industrial Property Rights Holder
      家田 真樹、貞廣 威太郎、礒見 まり、五島 直樹
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Acquisition Date
      2018
    • Related Report
      2018 Research-status Report
    • Overseas

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Published: 2018-04-23   Modified: 2022-01-27  

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