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肺線維症モデルを用いた線維化の分子・細胞基盤の研究

Research Project

Project/Area Number 13J05983
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section国内
Research Field Experimental pathology
Research InstitutionThe University of Tokyo

Principal Investigator

津久井 達哉  東京大学, 医学系研究科, 特別研究員(DC1)

Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2015: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2014: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2013: ¥900,000 (Direct Cost: ¥900,000)
Keywords線維症 / 呼吸器疾患 / 創傷治癒 / 肺線維症 / 線維芽細胞 / 筋線維芽細胞 / オステオポンチン
Outline of Annual Research Achievements

私は肺線維症モデルにおける新たな経気道細胞移入系を確立した(Tsukui et al. Am J Pathol 2015)。ブレオマイシン誘導性肺線維症モデルの初期において、上皮細胞が欠落した肺胞腔に活性化線維芽細胞が移動している様子が組織学的解析により観察された。そこで私は肺傷害初期に肺胞腔に移動した線維芽細胞がやがて瘢痕を形成すると仮説を立てた。この仮説を確かめるため、ブレオマイシンを投与して肺傷害を誘導した野生型のマウスに、Col-GFPマウスから単離した常在性線維芽細胞を経気道的に移入する実験を行った。ブレオマシン処理後4日~10日の間に経気道移入を行った時に、ホストの肺においてCol-GFP陽性細胞の生着が見られた。生着したCol-GFP陽性細胞をセルソーターにより純化し、遺伝子発現解析を行ったところ、I型コラーゲンやalpha-smooth muscle actin (a-SMA)等の活性化マーカーを顕著に発現していた。移入した細胞の一部は線維化部位で線維芽細胞巣を形成しており、これらはヒトの特発性線維症でみられる線維芽細胞巣とよく似た特徴を持っていた。これらの結果により、経気道移入実験系は、内因性線維芽細胞の活性化の一部を再現し、そのメカニズムの解析に有用であることが明らかになった。

この経気道細胞移入系を用い、前年度までに同定方法を確立した常在性線維芽細胞、血管周囲平滑筋細胞、血管周囲細胞、さらに上皮細胞の系譜追跡を行った。常在性線維芽細胞が移入後に活性化線維芽細胞様の形態と線維芽細胞巣の形成を示したのに対し、血管周囲平滑筋細胞、血管周囲細胞、上皮細胞では活性化線維芽細胞への分化は見られなかった。これらの結果から、常在性線維芽細胞が肺線維症における活性化線維芽細胞の主要な起源であることが示唆された。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Report

(3 results)
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (13 results)

All 2016 2015 2014 2013 Other

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 1 results) Presentation (7 results) (of which Int'l Joint Research: 2 results) Remarks (1 results)

  • [Journal Article] Heat Shock Protein 27 Plays a Pivotal Role in Myofibroblast Differentiation and in the Development of Bleomycin-Induced Pulmonary Fibrosis2016

    • Author(s)
      Park AM, Kanai K, Itoh T, Sato T, Tsukui T, Inagaki Y, Selman M, Matsushima K, Yoshie O.
    • Journal Title

      Plos One

      Volume: 11 Issue: 2 Pages: e0148998-e0148998

    • DOI

      10.1371/journal.pone.0148998

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis.2015

    • Author(s)
      TatsuyaTsukui, Satoshi Ueha, Shigeyuki Shichino, Yutaka Inagaki, and Kouji Matsushima:
    • Journal Title

      Am J Pathol

      Volume: 185 Issue: 11 Pages: 2939-2948

    • DOI

      10.1016/j.ajpath.2015.07.022

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reduced supply of monocyte-derived macrophages leads to a transition from nodular to diffuse lesions and tissue cell activation in silica-induced pulmonary fibrosis in mice.2015

    • Author(s)
      Shigeyuki Shichino, Jun Abe, Satoshi Ueha, Mikiya Otsuji, Tatsuya Tsukui, Mizuha Kosugi-Kanaya, Francis HW Shand, Shin-ichi Hashimoto, Hiroshi I. Suzuki, Teppei Morikawa, Yutaka Inagaki, and Kouji Matsushima:
    • Journal Title

      Am J Pathol

      Volume: 185 Issue: 11 Pages: 2923-2938

    • DOI

      10.1016/j.ajpath.2015.07.013

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Qualitative Rather than Quantitative Changes Are Hallmarks of Fibroblasts in Bleomycin-Induced Pulmonary Fibrosis2013

    • Author(s)
      Tatsuya Tsukui, Satoshi Ueha, Jun Abe, Shin-ichi Hashimoto, Shigeyuki Shichino, Takeshi Shimaoka, Francis H. W. Shand, Yasuka Arakawa, Kenshiro Oshima, Masahira Hattori, Yutaka
    • Journal Title

      The American Journal of Pathology

      Volume: 3 Issue: 3 Pages: 758-773

    • DOI

      10.1016/j.ajpath.2013.06.005

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 慢性炎症に伴う線維化機構2013

    • Author(s)
      津久井達哉, 上羽悟史, 松島綱治
    • Journal Title

      BIO Clinica

      Volume: 11

    • Related Report
      2013 Annual Research Report
  • [Presentation] Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis2016

    • Author(s)
      Tsukui T, Ueha S, Shichino S, Inagaki Y, Matsushima K
    • Organizer
      Keystone Symposia, Fibrosis: From Basic Mechanisms to Targeted Therapies (Q3)
    • Place of Presentation
      Keystone, CO, USA
    • Year and Date
      2016-02-07
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis2015

    • Author(s)
      Tsukui T, Ueha S, Shichino S, Inagaki Y, Matsushima K
    • Organizer
      第43回日本免疫学会学術集会
    • Place of Presentation
      札幌コンベンションセンター
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
  • [Presentation] Lineage tracing of resident fibroblasts by the intratracheal cell transfer elucidates the cellular origin of activated fibroblasts in pulmonary fibrosis2015

    • Author(s)
      Tsukui T, Ueha S, Shichino S, Inagaki Y, Matsushima K
    • Organizer
      12th World Congress on Inflammation.
    • Place of Presentation
      Boston, MA, USA
    • Year and Date
      2015-08-08
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis2015

    • Author(s)
      Tatsuya Tsukui
    • Organizer
      The 4th NIF winter school
    • Place of Presentation
      シンガポール
    • Year and Date
      2015-01-18 – 2015-01-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] 線維化領域辺縁部に存在する線維芽細胞に特徴的なオステオポンチンの発現2014

    • Author(s)
      津久井達哉
    • Organizer
      日本炎症・再生医学会
    • Place of Presentation
      沖縄 万国津梁館
    • Year and Date
      2014-07-01 – 2014-07-04
    • Related Report
      2014 Annual Research Report
  • [Presentation] Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis2014

    • Author(s)
      Tatsuya Tsukui, Satoshi Ueha, Jun Abe, Shin-ichi Hashimoto, Shigeyuki Shichino, Takeshi Shimaoka, Yutaka Inagaki, Kouji Matsushima
    • Organizer
      Keystone Symposia : Fibrosis
    • Place of Presentation
      Keystone, Colorado, USA
    • Year and Date
      2014-03-24
    • Related Report
      2013 Annual Research Report
  • [Presentation] Osteopontin identifies a novel profibrotic population of fibroblasts2013

    • Author(s)
      ABE Jun, SHICHINO Shigeyuki, HASHIMOTO Shin-ichi, SHIMAOKA Takeshi, TOMURA Michio, INAGAKI Yutaka, MATSUSHIMA Kouji
    • Organizer
      日本免疫学会学術集会
    • Place of Presentation
      幕張メッセ
    • Year and Date
      2013-12-13
    • Related Report
      2013 Annual Research Report
  • [Remarks] 肺線維症をもたらす細胞の起源を新規実験法で解明

    • URL

      http://www.m.u-tokyo.ac.jp/news/admin/release_20151008-2.pdf

    • Related Report
      2015 Annual Research Report

URL: 

Published: 2014-01-29   Modified: 2024-03-26  

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