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Innovation of new methods rejuvenating lymphopoietic activity in aged hematopoietic stem cells

Research Project

Project/Area Number 18K08355
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionOsaka University

Principal Investigator

Yokota Takafumi  大阪大学, 医学系研究科, 准教授 (60403200)

Co-Investigator(Kenkyū-buntansha) 金倉 譲  大阪大学, 医学系研究科, 教授 (20177489)
土居 由貴子  大阪大学, 医学部附属病院, 医員 (60722288)
上田 智朗  大阪大学, 医学部附属病院, 医員 (60747517)
新開 泰宏  大阪大学, 医学部附属病院, 医員 (70791614)
小澤 孝幸  大阪大学, 医学部附属病院, 医員 (90815474)
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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords造血幹細胞 / 老化 / リンパ球分化 / クロマチン構造制御タンパク / クロマチン構造調節蛋白 / リンパ球 / 造血 / 免疫
Outline of Final Research Achievements

We previously identified special AT-rich sequence binding protein 1 (SATB1), a global chromatin organizer, as a lymphoid-inducing molecule in hematopoietic stem cells (HSCs). In this study, we generated SATB1 reporter mice in which SATB1 expression can be precisely monitored in vivo, and examined the early differentiation of HSCs. HSC-enriched fraction consisted of diverse HSCs in terms of SATB1 expression levels. Then, HSCs from SATB1/Tomato-knockin reporter mice were classified based on SATB1/Tomato intensity and were sorted for functional assessments. With single HSC transplantation, we revealed that high self-renewing capability as well as stronger differentiation potential toward the lymphocytic lineage was associated with high SATB1 levels. Furthermore, we observed high susceptibility to malignant tumors in SATB1 reporter mice, in which SATB1 gene was heterozygously deleted.

Academic Significance and Societal Importance of the Research Achievements

申請者らはリンパ球造血の老化とSATB1の発現低下が密接に関係していることを見出し、「免疫老化」のメカニズムとその予防の観点から研究を行なってきた。本研究では、SATB1の生体での機能を解析する上で、信頼性の高い研究材料としてSATB1-tdTomatoレポーターマウスを作製し、造血幹細胞の機能がSATB1によって制御されていることを示した。さらに予想外の知見として、SATB1の半欠損が加齢に伴って悪性腫瘍を誘発することを見出した。この結果は、高齢者の悪性腫瘍にSATB1の異常が関連している可能性を示唆しており、今後従来とは異なる角度から、悪性腫瘍の発症予防研究につながることが期待される。

Report

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

    (20 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (7 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] University of California, San Francisco(米国)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Graft-versus-host disease develops in mice transplanted with lymphocyte-depleted bone marrow cells from signal-transducing adaptor protein-2 transgenic mice2021

    • Author(s)
      Saito H, Ichii M, Toda J, Kitai Y, Muromoto R, Kashiwakura JI, Saitoh K, Tanimura A, Yokota T, Shibayama H, Matsuda T, Oritani K, Kanakura Y, Hosen N.
    • Journal Title

      Biochem Biophys Res Commun .

      Volume: 537 Pages: 118-124

    • DOI

      10.1016/j.bbrc.2020.12.080

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia2021

    • Author(s)
      Yasuhiro Shingai , Takafumi Yokota,et al
    • Journal Title

      Stem cells

      Volume: - Issue: 6 Pages: 723-736

    • DOI

      10.1002/stem.3348

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Group 2 innate lymphoid cells support hematopoietic recovery under stress conditions2021

    • Author(s)
      Sudo Takao、Motomura Yasutaka、Okuzaki Daisuke、Hasegawa Tetsuo、Yokota Takafumi、Kikuta Junichi、Ao Tomoka、Mizuno Hiroki、Matsui Takahiro、Motooka Daisuke、Yoshizawa Ryosuke、Nagasawa Takashi、Kanakura Yuzuru、Moro Kazuyo、Ishii Masaru
    • Journal Title

      Journal of Experimental Medicine

      Volume: 218 Issue: 5 Pages: 20200817-20200817

    • DOI

      10.1084/jem.20200817

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enterococcus: A predictor of ravaged microbiota and poor prognosis after allogeneic hematopoietic stem cell transplantation.2020

    • Author(s)
      Kusakabe S, Fukushima K, Yokota T, Hino A, Fujita J, Motooka D, Nakamura S, Shibayama H, Kanakura Y.
    • Journal Title

      Biol Blood Marrow Transplant

      Volume: 26 Issue: 5 Pages: 1028-1033

    • DOI

      10.1016/j.bbmt.2020.01.019

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function.2020

    • Author(s)
      Yasuhiro Nagate, Sachiko Ezoe, Jiro Fujita, Daisuke Okuzakis, Daisuke Motooka, Tomohiko Ishibashi, Michiko Ichii, Akira Tanimura, Masako Kurashige, Eiichi Morii, Takuya Fukushima, Youko Suehiro, Takafumi Yokota, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
    • Journal Title

      Leukemia

      Volume: - Issue: 1 Pages: 107-118

    • DOI

      10.1038/s41375-020-0788-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Signal-transducing adapter protein-1 is required for maintenance of leukemic stem cells in CML.2020

    • Author(s)
      Toda J, Ichii M, Oritani K, Shibayama H, Tanimura A, Saito H, Yokota T, Motooka D, Okuzaki D, Kitai Y, Muromoto R, Kashiwakura JI, Matsuda T, Hosen N, Kanakura Y.
    • Journal Title

      Oncogene

      Volume: 39 Issue: 34 Pages: 5601-5615

    • DOI

      10.1038/s41388-020-01387-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endothelial Cell-Selective Adhesion Molecule Contributes to the Development of Definitive Hematopoiesis in the Fetal Liver2019

    • Author(s)
      Ueda Tomoaki、Yokota Takafumi、Okuzaki Daisuke、Uno Yoshihiro、Mashimo Tomoji、Kubota Yoshiaki、Sudo Takao、Ishibashi Tomohiko、Shingai Yasuhiro、Doi Yukiko、Ozawa Takayuki、Nakai Ritsuko、Tanimura Akira、Ichii Michiko、Ezoe Sachiko、Shibayama Hirohiko、Oritani Kenji、Kanakura Yuzuru
    • Journal Title

      Stem Cell Reports

      Volume: 13 Issue: 6 Pages: 992-1005

    • DOI

      10.1016/j.stemcr.2019.11.002

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] “Hierarchy” and “Holacracy”; A Paradigm of the Hematopoietic System2019

    • Author(s)
      Yokota Takafumi
    • Journal Title

      Cells

      Volume: 8 Issue: 10 Pages: 1138-1138

    • DOI

      10.3390/cells8101138

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate2018

    • Author(s)
      Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Daisuke Okuzaki, Masahiro Tokunaga, Tomohiko Ishibashi, Takao Sudo, Tomoaki Ueda, Yasuhiro Shingai, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Terumi Kohwi-Shigematsu, Junji Takeda, Kenji Oritani, and Yuzuru Kanakura
    • Journal Title

      Cell Reports

      Volume: 23 Issue: 11 Pages: 3223-3235

    • DOI

      10.1016/j.celrep.2018.05.042

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] リンパ球初期分化2020

    • Author(s)
      横田貴史
    • Organizer
      日本血液学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia.2020

    • Author(s)
      Yasuhiro Shingai, Takafumi Yokota, Daisuke Okuzaki, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi, Tomoaki Ueda, Takayuki Ozawa, Ritsuko Nakai, Akira Tanimura, Michiko Ichii, Hirohiko Shibayama, Yuzuru Kanakura, Naoki Hosen
    • Organizer
      日本血液学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Special AT-Rich Sequence Binding Protein 1 Is Involved in Function of B Cell’s Antigen Presentation2020

    • Author(s)
      Takayuki Ozawa, Takafumi Yokota, Ritsuko Nakai, Yasuhiro Shingai, Tomoaki Ueda, Yukiko Doi, Hirohiko Shibayama, Naoki Hosen
    • Organizer
      日本血液学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] クロマチン構造制御蛋白SATB1はリンパ球分化における造血幹細胞の機能的ゆらぎに関与する2018

    • Author(s)
      土居 由貴子, 横田 貴史, 佐藤 友亮, 石橋 知彦, 数藤 孝雄, 上田 智朗, 新開 泰宏, 小澤 孝幸, 一井 倫子, 谷村 朗, 江副 幸子, 柴山 浩彦, Terumi Kohwi-Shigematsu, 織谷 健司, 金倉 譲
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] B細胞免疫寛容におけるSATB1蛋白の機能的意義について2018

    • Author(s)
      小澤 孝幸, 横田 貴史, 新開 泰宏, 上田 智朗, 土居 由貴子, 柴山 浩彦, 金倉 譲
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] ESAM on the Cells of Endothelial Lineage Plays an Important Role in the Development of Definitive Hematopoiesis2018

    • Author(s)
      Tomoaki Ueda, Takafumi Yokota, Yoshihiro Uno, Tomoji Mashimo, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi1, Yasuhiro Shingai, Akira Tanimura, Michiko Ichii, Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
    • Organizer
      The American Society of Hematology 60th Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Monitoring ESAM Expression Levels Reveals Autonomous Fluctuation of Leukemia Stem Cells By Autocrine/Paracrine Cytokine Signaling2018

    • Author(s)
      Yasuhiro Shingai, Takafumi Yokota, Takayuki Ozawa, Tomoaki Ueda, Yukiko Doi, Tomohiko Ishibashi, Akira Tanimura, Michiko Ichii, Hirohiko Shibayama, Yuzuru Kanakura
    • Organizer
      The American Society of Hematology 60th Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Remarks] 大阪大学大学院医学系研究科・医学部ホームページ

    • URL

      http://resou.osaka-u.ac.jp/ja/research/2018/20180613_1

    • Related Report
      2018 Research-status Report
  • [Remarks] 大阪大学大学院医学系研究科 血液・腫瘍内科学ホームページ

    • URL

      http://www.hematology.pro/index/news/article.html?data_id=131

    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] ミトコンドリアのリンパ器官への移植およびそのための組成物2020

    • Inventor(s)
      横田貴史、菅沼正司、山田勇磨
    • Industrial Property Rights Holder
      菅沼正司
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report

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

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