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Gene regulatory network in cellular niches for hematopoietic stem cells

Research Project

Project/Area Number 19K06688
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 44020:Developmental biology-related
Research InstitutionOsaka University

Principal Investigator

Omatsu Yoshiki  大阪大学, 生命機能研究科, 准教授 (80437277)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords造血幹細胞 / ニッチ / 間葉系細胞 / 転写因子 / 骨髄 / 発生 / CAR細胞 / Foxc1
Outline of Research at the Start

骨髄は全身を循環する血液細胞・免疫細胞を産生する造血臓器である。造血に重要な分泌因子CXCL12を高発現する細網細胞(CAR細胞)は骨髄に存在し,造血幹細胞・前駆細胞を維持するニッチと呼ばれる特殊な微小環境として機能するが,このCAR細胞の発生や機能維持における分子機構は未だに不明である。そこで本研究では,CAR細胞が発生する時期の骨髄細胞のシングルセルレベルでの詳細な解析や,種々の病態モデルマウスを用いたCAR細胞の変容の分子機構の解析を行う。それにより,全身に存在する他の組織幹細胞ニッチの機能およびその発生機構においても共通する分子機構の解明を目指す。

Outline of Final Research Achievements

Previous studies have identified some transcription factors essential for the development and functional maintenance of CAR cells (CXCL12-abundant reticular cells) that construct niches for hematopoietic stem cells in bone marrow. However, the mechanisms how the gene regulatory network of CAR cells is established and maintained has not been fully understood.
In this study, we identified several novel transcriptional regulators that are highly expressed in CAR cells and may have important rolls for niche function, and generated conditional knockout mice. In these mice, Runx1/2 conditional knockout mice displayed severe fibrosis and hematopoietic defects in bone marrow. Thus, HSC cellular niches require Runx1 or Runx2 to prevent their fibrotic conversion and maintain HSCs and hematopoiesis in adults.

Academic Significance and Societal Importance of the Research Achievements

本研究により、CAR細胞に特異的に発現しその線維化を抑制することによって造血幹細胞の維持に必須の役割を果たす転写因子が同定された。この転写因子はそれぞれ造血幹細胞と骨芽細胞の発生に必須の遺伝子(Runx1とRunx2)としてよく知られていたものであったが、CAR細胞における線維芽細胞への変化を抑制するという機能が新たに解明された。また骨髄線維症においてはCAR細胞でRunx1/2の発現が低下することがその進展に関与すると推測されたため、Runx1/2遺伝子が疾患における新たな治療や診断の標的となる可能性がある。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (6 results)

All 2021 2020

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

  • [Journal Article] Cellular Niches for Hematopoietic Stem Cells and Lympho-Hematopoiesis in Bone Marrow During Homeostasis and Blood Cancers2021

    • Author(s)
      Omatsu Yoshiki、Higaki Kei、Nagasawa Takashi
    • Journal Title

      Curr Top Microbiol Immunol.

      Volume: 434 Pages: 33-54

    • DOI

      10.1007/978-3-030-86016-5_2

    • ISBN
      9783030860158, 9783030860165
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A multistate stem cell dynamics maintains homeostasis in mouse spermatogenesis2021

    • Author(s)
      Nakagawa Toshinori、Jorg David J.、Watanabe Hitomi、Mizuno Seiya、Han Seungmin、Ikeda Tatsuro、Omatsu Yoshiki、Nishimura Keiko、Fujita Miyako、Takahashi Satoru、Kondoh Gen、Simons Benjamin D.、Yoshida Shosei、Nagasawa Takashi
    • Journal Title

      Cell Reports

      Volume: 37 Issue: 3 Pages: 109875-109875

    • DOI

      10.1016/j.celrep.2021.109875

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of microenvironmental niches for hematopoietic stem cells and lymphoid progenitors - bone marrow fibroblastic reticular cells with salient features2021

    • Author(s)
      Omatsu Yoshiki、Nagasawa Takashi
    • Journal Title

      International Immunology

      Volume: 33 Issue: 12 Pages: 821-826

    • DOI

      10.1093/intimm/dxab092

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Presentation] Niches for hematopoietic stem cells in bone marrow2021

    • Author(s)
      尾松芳樹
    • Organizer
      Virtual Immunology2021 (American Association of Immunologists)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 骨髄造血幹細胞ニッチを構成する間葉系幹細胞2021

    • Author(s)
      尾松芳樹
    • Organizer
      第42回 日本炎症・再生医学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 造血幹・前駆細胞ニッチを構成するCAR細胞は骨芽細胞と骨髄脂肪細胞を供給する間葉系幹細胞である2020

    • Author(s)
      尾松芳樹
    • Organizer
      第38回日本骨代謝学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited

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Published: 2019-04-18   Modified: 2023-01-30  

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