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造血幹細胞ニッチを構成する骨髄間葉系前駆細胞の老化とその分子機構の解明

Publicly Offered Research

Project AreaEstablishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging
Project/Area Number 17H05643
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionOsaka University

Principal Investigator

長澤 丘司  大阪大学, 生命機能研究科, 教授 (80281690)

Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords微小環境 / 組織幹細胞 / 発生・分化 / 再生医学 / 免疫学
Outline of Annual Research Achievements

生涯にわたり血液細胞を供給する造血幹細胞は、骨髄のニッチ(niche)と呼ばれる限局した微小環境に接着し維持されている。CAR細胞は、骨髄で造血幹細胞の維持に必須のニッチを構成する中心的な細胞で老化に伴い骨髄を占有する脂肪細胞を産生する脂肪・骨芽細胞前駆細胞である。私たちは、転写因子Ebf3がCAR細胞特異的に発現し、発現が老齢マウスで低下することを見出した。そこで薬剤投与でEbf3発現細胞をラベルできるマウスを作製し、CAR細胞は1年以上自己複製能を持ち骨芽細胞と脂肪細胞を供給する幹細胞であること、老齢マウスで増加する脂肪細胞は、CAR細胞由来であることを明らかにした。次にCAR細胞特異的にEbf3を欠損するマウスを作製し、野生型マウスと比較したところ、26週令での骨髄は、組織学的に著差なく、造血幹細胞・前駆細胞の数が約半分に低下していた。しかし、老齢の遺伝子欠損マウス(90週令)の骨髄では、CAR細胞の骨芽細胞への分化が進み、骨棘が著増して骨髄腔が著しく減少し(重症大理石病様)、骨髄腔あたりの造血幹細胞・前駆細胞の細胞数が著減していた。一方、Ebf3と相同性が高いEbf1とEbf3の両方をCAR細胞で欠損させると若齢より骨棘が著増し骨髄腔が著しく減少した。以上より、老齢個体における骨髄腔の維持、CAR細胞の骨芽細胞への分化の抑制による未分化性維持にEbf3が必須であること、Ebf1は若年ではEbf3の機能を代替できるが老齢ではできず、機能が低下することが示された。本研究によって、CAR細胞が間葉系幹細胞であることが証明され、間葉系幹細胞(CAR細胞)の未分化性維持における老化特異的分子機構が初めて明らかになった。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (12 results)

All 2019 2018 2017

All Journal Article (10 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 10 results,  Open Access: 3 results) Presentation (2 results) (of which Invited: 2 results)

  • [Journal Article] Mesenchymal Niche-Specific Expression of Cxcl12 Controls Quiescence of Treatment-Resistant Leukemia Stem Cells.2019

    • Author(s)
      Agarwal, P., Isringhausen, S., Li, H., Paterson, A.J., He, J., Gomariz, Á., Nagasawa, T., Nombela-Arrieta, C., and Bhatia, R.
    • Journal Title

      Cell Stem Cell

      Volume: 印刷中 Issue: 5 Pages: 769-784

    • DOI

      10.1016/j.stem.2019.02.018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Niches for hematopoietic stem cells and immune cell progenitors.2019

    • Author(s)
      Sugiyama, T., Omatsu, Y., and Nagasawa, T.
    • Journal Title

      Int Immunol.

      Volume: 31 Issue: 1 Pages: 5-11

    • DOI

      10.1093/intimm/dxy058

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Resting zone of the growth plate houses a unique class of skeletal stem cells.2018

    • Author(s)
      Mizuhashi, K., Ono, W., Matsushita, Y., Sakagami, N., Takahashi, A., Saunders, T.L., Nagasawa, T., Kronenberg, H.M., and Ono, N.
    • Journal Title

      Nature

      Volume: 563 Issue: 7730 Pages: 7730-7730

    • DOI

      10.1038/s41586-018-0662-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Neutrophils instruct homeostatic and pathological states in naive tissues.2018

    • Author(s)
      Casanova-Acebes, M., Nicolás-Ávila, J.A., Li, J.L., García-Silva, S., Balachander, A., Rubio-Ponce, A., Weiss, L.A., Adrover, J.M., Burrows, K., A.-González, N., Ballesteros, I., Devi, S., (他5名), Nagasawa, T., Soehnlein, O., Merad, M., Mortha, A., Ng, L.G., Peinado, H., and Hidalgo, A.
    • Journal Title

      J Exp Med.

      Volume: 215 Issue: 11 Pages: 2778-2795

    • DOI

      10.1084/jem.20181468

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy.2018

    • Author(s)
      Gomariz, A., Helbling, P.M., Isringhausen, S., Suessbier, U., Becker, A., Boss, A., Nagasawa, T., Paul, G., Goksel, O., Székely, G., Stoma, S., Nørrelykke, S.F., Manz, M.G., and Nombela-Arrieta, C.
    • Journal Title

      Nat Commun.

      Volume: 9 Issue: 1 Pages: 2532-2532

    • DOI

      10.1038/s41467-018-04770-z

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Peripheral PDGFRα+gp38+ mesenchymal cells support the differentiation of fetal liver-derived ILC2.2018

    • Author(s)
      Koga, S., Hozumi, K., Hirano, K.I., Yazawa, M., Terooatea, T., Minoda, A., Nagasawa, T., Koyasu, S., and Moro, K.
    • Journal Title

      J Exp Med.

      Volume: 215 Issue: 6 Pages: 1609-1626

    • DOI

      10.1084/jem.20172310

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Stem cell nich-specific Ebf3 maintains the bone marrow cavity.2018

    • Author(s)
      Seike, M., Omatsu, Y., Watanabe, H., Kondoh, G., Nagasawa, T.
    • Journal Title

      Genes & Development

      Volume: 32 Issue: 5-6 Pages: 359-372

    • DOI

      10.1101/gad.311068.117

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR42018

    • Author(s)
      Shimba A, Cui G, Tani-Ichi S, Ogawa M, Abe S, Okazaki F, Kitano S, Miyachi H, Yamada H, Hara T, Yoshikai Y, Nagasawa T, Schütz G, Ikuta K.
    • Journal Title

      Immunity

      Volume: 48 Issue: 2 Pages: 286-298

    • DOI

      10.1016/j.immuni.2018.01.004

    • NAID

      120006401712

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Numerous niches for hematopoietic stem cells remain empty during homeostasis.2017

    • Author(s)
      Shimoto, M., Sugiyama, T., Nagasawa, T.
    • Journal Title

      Blood

      Volume: 129 Issue: 15 Pages: 2124-2131

    • DOI

      10.1182/blood-2016-09-740563

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dll4 and Notch signalling couples sprouting angiogenesis and artery formation2017

    • Author(s)
      Pitulescu, M. E., Schmidt, I., Giaimo, B. D., Antoine, T., Berkenfeld, F., Ferrante, F., Park, H., Ehling, M., Biljes, D., Rocha, S.F., Langen, U.H., Stehling, M., Nagasawa, T., Ferrara, N., Borggrefe, T., Adams, R.H..
    • Journal Title

      Nat. Cell Biol.

      Volume: 19 Issue: 8 Pages: 915-927

    • DOI

      10.1038/ncb3555

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 骨髄の造血幹細胞ニッチを構成する脂肪・骨芽細前駆細胞2017

    • Author(s)
      長澤 丘司
    • Organizer
      第90回日本内分泌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 造血幹細胞ニッチを構成する骨髄特異的な脂肪・骨芽細胞前駆細胞2017

    • Author(s)
      長澤 丘司
    • Organizer
      第35回日本骨代謝学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited

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Published: 2017-04-28   Modified: 2019-12-27  

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