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Research on spleen microenvironment supporting extramedullary hematopoiesis and its application to the expansion of hematopoietic stem cells

Research Project

Project/Area Number 16H05047
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Integrative animal science
Research InstitutionTokyo University of Science

Principal Investigator

GOITSUKA RYO  東京理科大学, 研究推進機構生命医科学研究所, 教授 (50301552)

Co-Investigator(Renkei-kenkyūsha) TAKUBO Keiyo  国立研究開発法人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, プロジェクト長 (50502788)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2016: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords造血 / 微小環境 / 転写因子 / 発生 / 再生 / 脾臓 / 脾腫 / 髄外造血 / 造血ニッチ / 骨髄増殖性疾患 / 応用動物 / 再生医学 / 免疫学 / 血液学 / 幹細胞 / 間葉系細胞 / 移植・再生医療 / 発生・分化 / 細胞・組織 / 生体機能利用
Outline of Final Research Achievements

The spleen is a major site for extramedullary hematopoiesis (EMH); however, the niche for EMH in the spleen remain poorly understood compared to the growing understanding of the BM niche at the steady-state as well as in emergency hematopoiesis. In the present study, we demonstrate that mesenchymal progenitor-like cells expressing Tlx1, an essential transcription factor for spleen organogenesis are a major source of HSPC niche factors. Consistently, overexpression of Tlx1 induces EMH, which is associated with mobilization of HSPC into the circulation and their recruitment into the spleen. The alterations in the splenic microenvironment induced by Tlx1 overexpression phenocopy lipopolysaccharide (LPS)-induced EMH, and the conditional loss of Tlx1 abolished LPS-induced splenic EMH. These findings indicate that activation of Tlx1 expression in the postnatal splenic mesenchymal cells is critical for the development of splenic EMH.

Academic Significance and Societal Importance of the Research Achievements

緊急時造血の起こる骨髄以外の組織における造血の制御機構が明らかになったことによって、緊急時には骨髄での造血因子の産生は抑制されるのに対して、脾臓では逆に上昇するなど、造血に関わる環境の共通性ならびに特殊性を比較することが可能になった。このことは、基礎医学的には、造血幹・前駆細胞の維持や機能に関わる環境構成要素の共通原理の解明に貢献でき、また、応用医学的には硬組織である骨内腔の骨髄間葉系細胞に比較し、容易に採取可能な脾臓間葉系細胞を用いた造血幹細胞培養系の構築への応用も期待できる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (38 results)

All 2018 2017 2016 Other

All Journal Article (7 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (29 results) (of which Int'l Joint Research: 8 results,  Invited: 3 results) Remarks (2 results)

  • [Journal Article] Meis1 Coordinates Cerebellar Granule Cell Development by Regulating Pax6 Transcription, BMP Signaling and Atoh1 Degradation2018

    • Author(s)
      Owa Tomoo、Taya Shinichiro、Miyashita Satoshi、Yamashita Mariko、Adachi Toma、Yamada Koyo、Yokoyama Miwa、Aida Shogo、Nishioka Tomoki、Inoue Yukiko U.、Goitsuka Ryo、Nakamura Takuro、Inoue Takayoshi、Kaibuchi Kozo、Hoshino Mikio
    • Journal Title

      The Journal of Neuroscience

      Volume: 38 Issue: 5 Pages: 1277-1294

    • DOI

      10.1523/jneurosci.1545-17.2017

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Niche-induced extramedullary hematopoiesis in the spleen is regulated by the transcription factor Tlx1.2018

    • Author(s)
      Oda A, Ueno Y, Hosoda S, Amemiya Y, Notsu C, Tezuka T, Kasahara T, Nishiyama C, Goitsuka R
    • Journal Title

      Scientific Reports

      Volume: 29 Issue: 1 Pages: 8308-8308

    • DOI

      10.1038/s41598-018-26693-x

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] High-affinity IgM+ memory B cells are defective in differentiation into IgM antibody-secreting cells by re-stimulation with a T cell-dependent antigen2018

    • Author(s)
      Yasuyuki Tashiro, Akikazu Murakami, Yasuyoshi Hara, Takeyuki Shimizu, Masato Kubo, Ryo Goitsuka, Hidehiro Kishimoto, Takachika Azuma
    • Journal Title

      Sci. Rep.

      Volume: 8 Issue: 1 Pages: 14559-14559

    • DOI

      10.1038/s41598-018-32926-w

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Germ cell-intrinsic requirement for the homeodomain transcription factor PKnox1/Prep1 in adult spermatogenesis.2018

    • Author(s)
      Kawai, Y., Oda, A., Kanai, Y., and Goitsuka, R.
    • Journal Title

      PLosOne

      Volume: 13 Issue: 1 Pages: e0190702-e0190702

    • DOI

      10.1371/journal.pone.0190702

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 成体脾臓における髄外造血ニッチとその構成要素2018

    • Author(s)
      小田朗永、後飯塚僚
    • Journal Title

      医学のあゆみ

      Volume: 264 Pages: 258-259

    • Related Report
      2017 Annual Research Report
  • [Journal Article] MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesis.2016

    • Author(s)
      Yokoyama T, Nakatake M, Kuwata T, Couiznet A, Goitsuka R, Tsutsumi S, Aburatani H, Valk PJ, Delwel R, Nakamura T.
    • Journal Title

      J Clin Invest.

      Volume: 印刷中 Issue: 5 Pages: 1664-1678

    • DOI

      10.1172/jci81516

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 間葉系ストローマ細胞による造血制御とその応用2016

    • Author(s)
      後飯塚僚
    • Journal Title

      家畜感染症学会誌

      Volume: 5 Pages: 69-74

    • NAID

      40021598215

    • Related Report
      2016 Annual Research Report
  • [Presentation] 骨髄増殖性疾患発症における脾臓微小環境の役割2018

    • Author(s)
      小田朗永、雨宮祐輔、後飯塚僚
    • Organizer
      第28回学術集会Kyoto T cell conference (KTCC),京都大学芝蘭会館、京都
    • Related Report
      2018 Annual Research Report
  • [Presentation] Wasteland or Wonderland? : the last unmapped organ in the homeostatic maintenance of the body.2018

    • Author(s)
      Ryo Goitsuka
    • Organizer
      2nd International Innovation Dialogue on Genome Engineering Animal Models and Biomedical Research Symposium, Dalian Medical University, China
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The spleen serves as a specific microenvironment that support development of B-1a cells and LAG-3+ CD138+ natural regulatory plasma cells.2018

    • Author(s)
      Akihisa Oda, Keiko Fujisaki, Yuta Ueno, Chiharu Nishiyama, and Ryo Goitsuka
    • Organizer
      第47回日本免疫学会学術集会,福岡国際会議場, 福岡
    • Related Report
      2018 Annual Research Report
  • [Presentation] Transcription factor Tlx1 regulates a niche for innate-like B cells in the spleen.2018

    • Author(s)
      Shoko Hosoda, Keiko Fujisaki, Yuta Ueno, Chiharu Nishiyama, Kei Haniuda, Akihisa Oda, Daisuke Kitamura, and Ryo Goitsuka
    • Organizer
      第47回日本免疫学会学術集会,福岡国際会議場, 福岡
    • Related Report
      2018 Annual Research Report
  • [Presentation] Transcription factor Tlx1 is involved in the postnatal splenic architectural maintenance in a non-cell autonomous manner.2018

    • Author(s)
      Yuta Ueno, Chiharu Nishiyama, Akihisa Oda, and Ryo Goitsuka
    • Organizer
      第47回日本免疫学会学術集会,福岡国際会議場, 福岡
    • Related Report
      2018 Annual Research Report
  • [Presentation] Abnormality in the splenic microenvironment is involved in the malignant transformation of acute myeloid leukemia.2018

    • Author(s)
      Yusuke Amemiya, Chiharu Nishiyama, Akihisa Oda, Takuro Nakamura and Ryo Goitsuka
    • Organizer
      第47回日本免疫学会学術集会,福岡国際会議場, 福岡
    • Related Report
      2018 Annual Research Report
  • [Presentation] Myeloproliferative diseases triggered by the leukemogenic niche in the spleen2018

    • Author(s)
      Ryo Goitsuka
    • Organizer
      3rd International Biomedical Interface Symposium
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Transcription factor Tlx1 marks hematopoietic stem/ progenitor cell niche in the spleen.2017

    • Author(s)
      Yuta Ueno, Akihisa Oda, Toshiki Tezuka, Chiharu Nishiyama and Ryo Goitsuka:
    • Organizer
      International Symposium on Imaging Frontier 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The mesenchymal cells expressing Tlx1 retain a potential to give rise to various types of mature stromal cells in the adult spleen.2017

    • Author(s)
      Akihisa Oda, and Ryo Goitsuka
    • Organizer
      International Symposium on Imaging Frontier 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The role of transcription factor Tlx1 in converting cell fate of dorsal pancreatic to spleen mesenchymal progenitors.2017

    • Author(s)
      Ryo Goitsuka
    • Organizer
      International Symposium on Imaging Frontier 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 骨髄増殖性疾患発症における脾臓微小環境の役割2017

    • Author(s)
      後飯塚僚
    • Organizer
      第160回日本獣医学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Role of Meis1 in the cerebellar development.2017

    • Author(s)
      Tomoo Owa, Shinichiro Taya, Satoshi Miyashita, Tomoki Nishioka, Ryo Goitsuka, Takuro Nakamura, Kozo Kaibuchi and Mikio Hoshino
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Rho GTPase TC10, implicated in neuritegenesis through vesicle transport, promotes axon regeneration after PNS injury.2017

    • Author(s)
      Shingo Koinuma, Riko Nomura, Takuya Kojima, Ryota Negishi, Kohei Takeuchi, Eri Segi-Nishida, Ryo Goitsuka, Teiichi Fruichi, Yoichiro Iwakura, Naoyuki Wada, Naoki Takahashi, Yoshiki Koriyama, Hiroshi Kiyama and Takeshi Nakamura
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] A novel three-dimensional spheroid culture system that maintains mesenchymal progenitor cell populations of the spleen.2017

    • Author(s)
      Yuta Ueno, Shoko Hosoda, Chiharu Nishiyama, Akihisa Oda and Ryo Goitsuka
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Postnatal deletion of a gene encoding a transcription factor Tlx1 in mesenchymal cells causes defects in the formation of white pulp and marginal sinus structures in the spleen.2017

    • Author(s)
      Toshiki Tezuka, Akihisa Oda and Ryo Goitsuka
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] he spleen is a potential leukemogenic niche accelerating myeloproliferative neoplasms.2017

    • Author(s)
      Akihisa Oda, Yusuke Amemiya, Shoko Hosoda, Chiharu Nishiyama and Ryo Goitsuka
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Defects in splenic architectural organization by postnatal deletion of the gene encoding a transcription factor Tlx1.2017

    • Author(s)
      Toshiki Tezuka, Minoru Nishimoto, Akihisa Oda and Ryo Goitsuka
    • Organizer
      第46回日本免疫学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Two mesenchymal progenitor cell populations in the spleen defined by a novel three-dimensional culture system.2017

    • Author(s)
      Yuta Ueno, Shoko Hosoda, Chiharu Nishiyama, Akihisa Oda and Ryo Goitsuka
    • Organizer
      第46回日本免疫学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Niche-induced myeloproliferative-like disease caused by overexpression of Tlx1 in situ in splenic stromal cells.2017

    • Author(s)
      Akihisa Oda, Yusuke Amemiya, Shoko Hosoda, and Ryo Goitsuka
    • Organizer
      第46回日本免疫学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] The cell components of perifollicular hematopoietic niche in the spleen.2017

    • Author(s)
      Akihisa Oda, and Ryo Goitsuka
    • Organizer
      7th International Workshop of Kyoto T Cell Conference
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 間葉系ストローマ細胞による造血制御とその応用2016

    • Author(s)
      後飯塚僚
    • Organizer
      第6回家畜感染症学会シンポジウム
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 脾臓における髄外造血の間葉系ストローマ細胞とマクロファージによる制御.2016

    • Author(s)
      小田朗永、野津智尋、後飯塚僚
    • Organizer
      第26回学術集会Kyoto T cell conference
    • Related Report
      2016 Annual Research Report
  • [Presentation] Extramedullary hematopoietic niche in the spleen.2016

    • Author(s)
      Ryo Goitsuka
    • Organizer
      International Symposium of the Center for Animal Disease Models 2016
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Mesenchymal cells expressing Tlx1 serve as an extramedullary niche in the spleen2016

    • Author(s)
      Akihisa Oda, Toru Kasahara, and Ryo Goitsuka
    • Organizer
      International Congress of Immunology 2016
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 脾臓間葉系細胞による髄外造血の制御2016

    • Author(s)
      後飯塚僚
    • Organizer
      京都大学ウイルス研究所セミナー・共同利用・共同研究拠点セミナー
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Meis1の小脳顆粒細胞における多段階発生制御.2016

    • Author(s)
      大輪智雄、田谷真一郎、宮下聡、西岡朋生、中村卓郎、後飯塚僚、貝淵弘三、星野幹雄
    • Organizer
      第39回日本分子生物学会年会
    • Related Report
      2016 Annual Research Report
  • [Presentation] Interdependent roles of Tlx1-expressing mesenchymals cells and macrophages in extramedullary hematopoiesis in the spleen.2016

    • Author(s)
      Akihisa Oda, Toshiki Tezuka, Toru Kasahara, Yuta Ueno, Chiharu Nishiyama, and Ryo Goitsuka
    • Organizer
      第45回日本免疫学会学術集会
    • Related Report
      2016 Annual Research Report
  • [Presentation] The splenic marginal sinus consists of two distinct cell populations expressing MAdCAM-1.2016

    • Author(s)
      Toru Kasahara, Akihisa Oda, Toshiki Tezuka and Ryo Goitsuka
    • Organizer
      第45回日本免疫学会学術集会
    • Related Report
      2016 Annual Research Report
  • [Presentation] Transcription factor Tlx1 regulates the ability of spleen mesenchymal stromal cells to support the survival of hematopoietic progenitor cells in vitro.2016

    • Author(s)
      Toshiki Tezuka, Toru Kasahara, Yuta Ueno, Chiharu Nishiyama, Akihisa Oda and Ryo Goitsuka
    • Organizer
      第45回日本免疫学会学術集会
    • Related Report
      2016 Annual Research Report
  • [Remarks] 東京理科大学生命科学研究科時間生物学専攻

    • URL

      http://www.ribs.tus.ac.jp/index.php/course/labforstu/goitsukalab/

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
  • [Remarks] 東京理科大学生命医科学研究所発生及び老化研究部門

    • URL

      http://www.ribs.tus.ac.jp/index.php/institute/labforres/goitsukalab/

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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