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Study on the mechanism of HSC aging through quiescence maintaining culture

Research Project

Project/Area Number 19K17847
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionNational Center for Global Health and Medicine

Principal Investigator

Kobayashi Hiroshi  国立研究開発法人国立国際医療研究センター, その他部局等, 研究員 (10749542)

Project Period (FY) 2019-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords造血幹細胞 / 静止期維持培養 / ステムセルエイジング
Outline of Research at the Start

造血幹細胞は全ての血球を作り出すことで生涯にわたって造血恒常性を保つ。加齢に伴って造血幹細胞はその性質を徐々に変えていき、造血再構築能が低下する。こうした造血幹細胞の加齢変化(エイジング)は造血微小環境と造血幹細胞の長期にわたる相互作用の帰結であるが、生体内の複雑性からどの環境因子が加齢に関係するのかは不明であった。本申請課題では、申請者が開発した既知因子のみで構成された造血幹細胞の静止期維持培養系と、若齢から高齢造血幹細胞の単一細胞RNA-シークエンスより得られた加齢特異的遺伝子による評価を組み合わせて、造血幹細胞の加齢因子を特定するとともに、造血幹細胞の老化フリーな長期培養法の開発を行う。

Outline of Final Research Achievements

Hematopoietic stem cells (HSCs) maintain lifelong hematopoiesis by remaining quiescent in the bone marrow niche. I recently developed a culture method to maintain HSCs quiescent in vitro. HSCs cultured in this system, however, exhibited aging-associated phenotype with the high level expression of CD41 and P-selectin. I improved the maintenance culture condition by searching for factors inhibiting and promoting CD41 and P-selectin expression in HSCs. Among various signal molecules, TGF-βand retinoic acid receptor signals promote the aging-associated phenotype, while cholesterol inhibited the aging phenotype. Thrombopoietn was inhibitory against CD41 expression at the range of low concentration, but was promoting at the higher range of concentration. Combining these factors, high TPO culture restored lymphopoiesis in old HSCs and resulted in higher reconstitution capacity than that of freshly isolated old HSCs.

Academic Significance and Societal Importance of the Research Achievements

造血幹細胞は幹細胞モデルとしての基礎科学的な側面と、造血幹細胞移植による血液疾患や先天性疾患の治療という臨床的な側面から重要な細胞である。しかし造血幹細胞の未分化性維持の必要最小限の要素は何か、そしてどのような環境因子が造血幹細胞を加齢させ、その機能喪失にかかわっているかは十分理解されておらず、結果として長期にわたる造血幹細胞の体外維持培養法も未確立であった。本研究により、幹細胞が生体内で一生涯にわたり維持されるメカニズムとは何か、そしてより良い移植医療のための質の高い幹細胞に必要な条件は何かという両面について、幹細胞の機能を維持する方法論を提供することにつながる。

Report

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

    (13 results)

All 2021 2020 2019 Other

All Journal Article (7 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 7 results,  Open Access: 6 results) Presentation (5 results) (of which Int'l Joint Research: 1 results) Remarks (1 results)

  • [Journal Article] OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy2021

    • Author(s)
      Murakami Koichi、 ... 、Takubo Keiyo、Okamoto Shinichiro、Tamura Tomohiko、Nakajima Hideaki
    • Journal Title

      Cell Reports

      Volume: 34 Issue: 1 Pages: 108579-108579

    • DOI

      10.1016/j.celrep.2020.108579

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts2021

    • Author(s)
      Sorimachi Yuriko、Karigane Daiki、Ootomo Yukako、Kobayashi Hiroshi、Morikawa Takayuki、Otsu Kinya、Kubota Yoshiaki、Okamoto Shinichiro、Goda Nobuhito、Takubo Keiyo
    • Journal Title

      Journal of Biological Chemistry

      Volume: 296 Pages: 100563-100563

    • DOI

      10.1016/j.jbc.2021.100563

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] UTX maintains functional integrity of murine hematopoietic system by globally regulating aging-associated genes.2021

    • Author(s)
      Sera Y; Nakata Y; Ueda T; Yamasaki N; Koide S; Kobayashi H; Ikeda KI; Kobatake K; Iwasaki M; Oda H; Wolff L; Kanai A; Nagamachi A; Inaba T; Sotomaru Y; Ichinohe T; Koizumi M; Miyakawa Y; Honda ZI; Iwama A; Suda T; Takubo K; Honda H
    • Journal Title

      Blood.

      Volume: 137 Issue: 7 Pages: 908-922

    • DOI

      10.1182/blood.2019001044

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Detection of residual disease in chronic myeloid leukemia utilizing genomic next generation sequencing reveals persistence of differentiated Ph+ B cells but not bone marrow stem/progenitors2020

    • Author(s)
      Daiki Karigane, Hidenori Kasahara, ... , Keiyo Takubo.
    • Journal Title

      Leukemia & Lymphoma

      Volume: 62 Issue: 3 Pages: 679-687

    • DOI

      10.1080/10428194.2020.1837366

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protocol for the Maintenance of Quiescent Murine Hematopoietic Stem Cells2020

    • Author(s)
      Kobayashi Hiroshi、Takubo Keiyo
    • Journal Title

      STAR Protocols

      Volume: 1 Issue: 2 Pages: 100078-100078

    • DOI

      10.1016/j.xpro.2020.100078

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ATP turnover and glucose dependency in hematopoietic stem/progenitor cells are increased by proliferation and differentiation2019

    • Author(s)
      Watanuki Shintaro、Kobayashi Hiroshi、Sorimachi Yuriko、Yamamoto Masamichi、Okamoto Shinichiro、Takubo Keiyo
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 印刷中 Issue: 1 Pages: 287-294

    • DOI

      10.1016/j.bbrc.2019.04.123

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo.2019

    • Author(s)
      Kobayashi H, Morikawa T, Okinaga A, Hamano F, Hashidate-Yoshida T, Watanuki S, Hishikawa D, Shindou H, Arai F, Kabe Y, Suematsu M, Shimizu T, Takubo K.
    • Journal Title

      Cell Reports

      Volume: 28 Issue: 1 Pages: 145-158

    • DOI

      10.1016/j.celrep.2019.06.008

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 統合的代謝解析による加齢造血幹細胞特異的なエネルギー代謝制御とその意義の解明2020

    • Author(s)
      綿貫 慎太郎, 小林 央, 杉浦 悠毅, 反町 優理子, 山本 正道, 末松 誠, 岡本 真一郎, 田久保 圭誉
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Maintenance of quiescent hematopoietic stem cells ex vivo2019

    • Author(s)
      小林 央
    • Organizer
      第17回幹細胞シンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo2019

    • Author(s)
      Hiroshi Kobayashi, Keiyo Takubo
    • Organizer
      48th Annual Scientific Meeting, International Society of Experimental Hematology
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 造血幹細胞の休眠状態を体外で誘導する2019

    • Author(s)
      小林 央、田久保 圭誉
    • Organizer
      第92回日本生化学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 造血幹細胞の静止期維持培養法2019

    • Author(s)
      小林 央、田久保 圭誉
    • Organizer
      第81回日本血液学会
    • Related Report
      2019 Research-status Report
  • [Remarks] 国立国際医療研究センター研究所 生体恒常性プロジェクト

    • URL

      https://takubolab.com/

    • Related Report
      2019 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2022-01-27  

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