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Epigenetic regulation and cell fate determination of hematopoietic stem cell in stress conditions

Research Project

Project/Area Number 21H02952
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionKumamoto University

Principal Investigator

Sashida Goro  熊本大学, 国際先端医学研究機構, 特別招聘教授 (70349447)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
KeywordsHMGA2 / クロマチン / TNFa / 5-FU / RFX5 / CK2 / 造血幹細胞 / ストレス / HMGA2 / TNF-a / Casein Kinase 2 / 炎症 / 骨髄移植術 / HMGA1 / 炎症応答 / IGF2BP2
Outline of Research at the Start

造血は、造血幹細胞と骨髄ニッチや骨髄細胞が、老化を含めた様々な状況に応じて相互に関連することで精密に維持されている。ただし、定常状態とストレス状態に応じて、造血幹細胞が自己複製と分化を使い分ける制御機構は、骨髄・組織レベルはもとより、幹細胞・内因性因子レベルですら明白ではない。申請者の見出したHMGA2によるストレス造血再生を手掛かりに、クロマチン制御・転写因子ネットワークによる幹細胞制御機構の解明を、新規Hmga2/Hmga1/Hmga1b遺伝子改変マウスを用いて目指す。こうして得られる知見から、「幹細胞の運命制御」の解明と造血再生のための新規治療開発の知見が期待できる。

Outline of Final Research Achievements

Tissue stem cells are self-renewing and multipotent cells that maintain developmental and adult tissue homeostasis and are essential cells that repair stress-induced organ damage. To understand the molecular basis of stem cell self-renewal and differentiation, symmetric and asymmetric division of stem cells, and maintenance and regeneration of hematopoietic tissues under steady-state and stress conditions, we analyzed the stem cell regulatory mechanisms in stress hematopoiesis by HMGA2 chromatin modifier. We found the molecular basis of hematopoietic regulation by the TNFa-CK2-HMGA2 pathway, which specifically acts in hematopoietic stem cell under stress conditions.

Academic Significance and Societal Importance of the Research Achievements

造血は、造血幹細胞と骨髄ニッチや骨髄細胞が、老化を含めた様々な状況に応じて相互に関連することで精密に維持されている。ただし、定常状態とストレス状態に応じて、造血幹細胞が自己複製と分化を使い分ける制御機構は、骨髄・組織レベルはもとより、幹細胞レベルですら明白ではない。本研究によって、幹細胞研究の積年の課題である「幹細胞の運命制御」の解明に貢献できた。また、将来、ストレス暴露後の造血障害を速やかに再生するための標的因子や新規治療開発への貢献も期待できる。

Report

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

    (14 results)

All 2023 2022 2021 Other

All Int'l Joint Research (5 results) Journal Article (6 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (3 results) (of which Int'l Joint Research: 2 results)

  • [Int'l Joint Research] テキサス大学サンアントニオ健康科学センター(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] コンケン大学(タイ)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] テキサス大学サンアントニオ健康科学センター(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] コンケン大学(タイ)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] シンガポール国立大学(シンガポール)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] A gain‐of‐function mutation in microRNA-142 is sufficient to cause the development of T‐cell leukemia in mice.2023

    • Author(s)
      Kawano Shingo、Araki Kimi、Bai Jie、Furukawa Imari、Tateishi Keigo、Yoshinobu Kumiko、Usuki Shingo、Nimmo Rachael A.、Kaname Tadashi、Yoshihara Masaharu、Takahashi Satoru、Sashida Goro、Araki Masatake
    • Journal Title

      Cancer Science

      Volume: - Issue: 7 Pages: 2821-2834

    • DOI

      10.1111/cas.15794

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs2023

    • Author(s)
      Yokomizo-Nakano T, Hamashima A, Kubota S, Bai J, Sorin S, Sun Y, Kikuchi K, Iimori M, Morii M, Kanai A, Iwama A, Huang G, Kurotaki D, Takizawa H, Matsui H, Sashida G.
    • Journal Title

      Journal of Experimental Medicine (JEM)

      Volume: 220 (7) Issue: 7 Pages: 9999-9999

    • DOI

      10.1084/jem.20220962

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The acidic domain of Hmga2 and the domain's linker region are critical for driving self-renewal of hematopoietic stem cell.2022

    • Author(s)
      Sun Y, Kubota S, Iimori M, Hamashima A, Murakami H, Bai J, Morii M, Yokomizo-Nakano T, Osato M, Araki K, Sashida G.
    • Journal Title

      Int J Hematol.

      Volume: 115 Issue: 4 Pages: 553-562

    • DOI

      10.1007/s12185-021-03274-9

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] HMGN3 represses transcription of epithelial regulators to promote migration of cholangiocarcinoma in a SNAI2-dependent manner2022

    • Author(s)
      Supannika Sorin, Sho Kubota, Sofiane Hamidi, Takako Yokomizo-Nakano, Kulthida Vaeteewoottacharn, Sopit Wongkham, Sakda Waraasawapati, Chawalit Pairojkul, Jie Bai, Mariko Morii, Guojun Sheng, Kanlayanee Sawanyawisuth, Goro Sashida
    • Journal Title

      The FASEB Journal

      Volume: 36 Issue: 7

    • DOI

      10.1096/fj.202200386r

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Two faces of RUNX3 in myeloid transformation2021

    • Author(s)
      Yokomizo-Nakano Takako、Sashida Goro
    • Journal Title

      Experimental Hematology

      Volume: 97 Pages: 14-20

    • DOI

      10.1016/j.exphem.2021.02.005

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RUNX1-ETO (RUNX1-RUNX1T1) induces myeloid leukemia in mice in an age-dependent manner2021

    • Author(s)
      Abdallah Mohamed Gaber、Niibori-Nambu Akiko、Morii Mariko、Yokomizo Takako、Yokomizo Tomomasa, at al.
    • Journal Title

      Leukemia

      Volume: 35 Issue: 10 Pages: 2983-2988

    • DOI

      10.1038/s41375-021-01268-4

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Inflammatory stress activates the Hmga2 protein to remodel chromatin and expand hematopoietic stem cell2023

    • Author(s)
      指田吾郎
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Hmga2 activates Igf2bp2 but also represses expression of inflammatory response genes in stress hematopoiesis2022

    • Author(s)
      Sho Kubota, Goro Sashida
    • Organizer
      51st ISEH Annual Scientific Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] HMGA2 maintains hematopoietic stem cell via pleiotropic regulation of the transcription in stress conditions2021

    • Author(s)
      Sho Kubota, Yuqi Sun, Jie Bai, Takako Yokomizo-Nakano, Mariko Morii, Takako Ideue, Motomi Osato, Terumasa Umemoto, Kimi Araki, Goro Sashida
    • Organizer
      63rd ASH Annual Meeting and Exposition
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research

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

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