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

• Project/Area Number: 18K08355
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Osaka 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: ¥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。

Research Products

• [Int'l Joint Research] University of California, San Francisco(米国)
• [Journal Article] Graft-versus-host disease develops in mice transplanted with lymphocyte-depleted bone marrow cells from signal-transducing adaptor protein-2 transgenic mice (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia (2021)
  • Author(s): Yasuhiro Shingai , Takafumi Yokota，et al
  • Journal Title: Stem cells Volume: - Issue: 6 Pages: 723-736
  • DOI: 10.1002/stem.3348
  • Peer Reviewed / Open Access
• [Journal Article] Group 2 innate lymphoid cells support hematopoietic recovery under stress conditions (2021)
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial Cell-Selective Adhesion Molecule Contributes to the Development of Definitive Hematopoiesis in the Fetal Liver (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] “Hierarchy” and “Holacracy”; A Paradigm of the Hematopoietic System (2019)
  • Author(s): Yokota Takafumi
  • Journal Title: Cells Volume: 8 Issue: 10 Pages: 1138-1138
  • DOI: 10.3390/cells8101138
  • Peer Reviewed / Open Access
• [Journal Article] Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate (2018)
  • 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
  • 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
  • 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
• [Presentation] Special AT-Rich Sequence Binding Protein 1 Is Involved in Function of B Cell’s Antigen Presentation (2020)
  • 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
• [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
• [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
• [Presentation] ESAM on the Cells of Endothelial Lineage Plays an Important Role in the Development of Definitive Hematopoiesis (2018)
  • 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
  • Int'l Joint Research
• [Presentation] Monitoring ESAM Expression Levels Reveals Autonomous Fluctuation of Leukemia Stem Cells By Autocrine/Paracrine Cytokine Signaling (2018)
  • 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
  • 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
• [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
• [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