• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Study on the regulatory mechanisms of macrophage in the fundamental process of liver fibrosis

Research Project

Project/Area Number 18H02801
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionNational Center for Global Health and Medicine

Principal Investigator

Tanaka Minoru  国立研究開発法人国立国際医療研究センター, その他部局等, 細胞療法開発研究室長 (80321909)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2020: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2019: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Keywords線維化 / マクロファージ / 星細胞 / サイトカイン / 細胞間相互作用 / 肝線維化 / 肝星細胞 / 診断マーカー
Outline of Final Research Achievements

In this research, based on the discovery that Oncostatin M (OSM) exhibits a powerful fibrotic activity in liver fibrosis, we shed light on a crucial role of cell-cell interaction between hepatic stellate cells and the other non-parenchymal cells during liver fibrogenesis. Especially, we focused on two hepatic macrophages, Kupffer cells (KC), a resident hepatic macrophage and bone marrow-derived macrophages (BMDM). To find OSM-dependent factors relevant to liver fibrosis, we compared the gene expression profiles of KC and BMDM from wild-type and OSM KO mice, which were subjected to chronic hepatitis by RNA-seq analysis. As a result, we could identify several factors of which expression is upregulated in fibrotic liver. Among them, we found that a few factors could induce liver fibrosis in normal liver by their enforced expression via adeno-associated viral vector. Thus, we succeeded to identifying novel secretory factors from macrophages related to liver fibrogenesis.

Academic Significance and Societal Importance of the Research Achievements

慢性肝障害が長い経過を辿ると肝線維化が進行し、やがては肝硬変・肝発がんに至る。そのため、肝線維化の治療法の開発は喫緊の課題となっているが、未だ有効な治療法は確立されていない。肝線維化は多くの細胞が関わる複雑なプロセスにより進行することが想定されているが、その全容については不明な点が多く残る。本研究では肝星細胞と肝マクロファージ間の細胞間相互作用が肝線維化において重要であることを明らかにするとともに、マクロファージが産生する新規線維化促進因子の同定にも成功しており、今後、新たな治療法の開発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 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (32 results)

All 2020 2019 2018 Other

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 5 results) Presentation (23 results) (of which Int'l Joint Research: 10 results,  Invited: 4 results) Remarks (3 results)

  • [Journal Article] Tubular bile duct structure mimicking bile duct morphogenesis for prospective in vitro liver metabolite recovery2020

    • Author(s)
      Rizki-Safitri Astia、Shinohara Marie、Tanaka Minoru、Sakai Yasuyuki
    • Journal Title

      Journal of Biological Engineering

      Volume: 14 Issue: 1

    • DOI

      10.1186/s13036-020-0230-z

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tubular bile duct structure mimicking bile duct morphogenesis for prospective in vitro liver metabolite recovery.2020

    • Author(s)
      Rizki-Safitri A, Shinohara M, Tanaka M, Sakai Y.
    • Journal Title

      J Biol Eng.

      Volume: 14 Pages: 1-13

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis2019

    • Author(s)
      Tsurusaki Shinya、Tsuchiya Yuichi、Koumura Tomoko、Nakasone Misaki、Sakamoto Taro、Matsuoka Masaki、Imai Hirotaka、Yuet-Yin Kok Cindy、Okochi Hitoshi、Nakano Hiroyasu、Miyajima Atsushi、Tanaka Minoru
    • Journal Title

      Cell Death & Disease

      Volume: 10 Issue: 6 Pages: 449-449

    • DOI

      10.1038/s41419-019-1678-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential expression of Lutheran/BCAM regulates biliary tissue remodeling in ductular reaction during liver regeneration2018

    • Author(s)
      Miura Yasushi、Matsui Satoshi、Miyata Naoko、Harada Kenichi、Kikkawa Yamato、Ohmuraya Masaki、Araki Kimi、Tsurusaki Shinya、Okochi Hitoshi、Goda Nobuhito、Miyajima Atsushi、Tanaka Minoru
    • Journal Title

      eLife

      Volume: 7 Pages: 36572-36572

    • DOI

      10.7554/elife.36572

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization of Peribiliary Gland-Constituting Cells Based on Differential Expression of Trophoblast Cell Surface Protein 2 in Biliary Tract.2018

    • Author(s)
      Matsui S, Harada K, Miyata N, Okochi H, Miyajima A, Tanaka M.
    • Journal Title

      Am J Pathol.

      Volume: 188 Issue: 9 Pages: 2059-2073

    • DOI

      10.1016/j.ajpath.2018.05.016

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Efficient functional cyst formation of biliary epithelial cells using microwells for potential bile duct organisation in vitro.2018

    • Author(s)
      Rizki-Safitri A, Shinohara M, Miura Y, Danoy M, Tanaka M, Miyajima A, Sakai Y.
    • Journal Title

      Sci Rep.

      Volume: 8 Issue: 1 Pages: 11086-11086

    • DOI

      10.1038/s41598-018-29464-w

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Hepatic Ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis.2020

    • Author(s)
      田中稔
    • Organizer
      日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 非アルコール性脂肪性肝炎における計画的細胞死フェロトーシスの関与2020

    • Author(s)
      田中稔
    • Organizer
      肝細胞研究会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 2.Establishment of a Hepatic Organoid Culture System using a Human iPS Cell-derived Hepatoblast Resource2020

    • Author(s)
      王路遥,木戸丈友,宮島篤,田中稔
    • Organizer
      肝細胞研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 肝疾患における多様な細胞死の意義2020

    • Author(s)
      田中稔
    • Organizer
      千里ライフサイエンスセミナーP5
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatoheptitits.2019

    • Author(s)
      Minoru Tanaka
    • Organizer
      Cold Spring Harbor Asia, Liver Biology, Disease & Cancer
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatoheptitits.2019

    • Author(s)
      Shinya Tsurusaki, Hiroyasu Nakano, Hitotaka Imai, Atsushi Miyajima, Minoru Tanaka
    • Organizer
      Cold Spring Harbor Asia, Liver Biology, Disease & Cancer
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] フェロトーシスによる肝細胞死が非アルコール性脂肪性肝炎の初期炎症の起点として重要である2019

    • Author(s)
      鶴崎慎也, 土屋勇一, 今井浩孝, 大河内仁志, 中野裕康, 田中稔
    • Organizer
      第92回 日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] フェロトーシスによる肝細胞死が非アルコール性脂肪性肝炎の初期炎症の起点として重要である2019

    • Author(s)
      鶴崎慎也, 土屋勇一, Cindy Yuet-Yin Kok, 大河内仁志, 中野裕康, 宮島篤, 田中稔
    • Organizer
      第28回 日本Cell Death学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Elucidation of molecular mechanisms underlying the tissue repair and remodeling in liver diseases2019

    • Author(s)
      田中稔
    • Organizer
      IARI Symposium 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 慢性肝疾患における肝リモデリングの制御機構の解明2018

    • Author(s)
      田中稔
    • Organizer
      日本Cell Death学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Cell Death and Regeneration in Liver Diseases2018

    • Author(s)
      田中稔
    • Organizer
      Australia-Japan meeting on cell death
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidation of the type of cell death at the onset of non-alcoholic steatohepatitis (NASH)2018

    • Author(s)
      鶴崎慎也、松田道隆、清水重臣、中野裕廉、宮島敦、田中稔
    • Organizer
      ComBio2018, Australia
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidation of the type of cell death at the onset of non-alcoholic steatohepatitis (NASH)2018

    • Author(s)
      鶴崎慎也、松田道隆、清水重臣、中野裕康、宮島篤、田中稔
    • Organizer
      Australia-Japan meeting on cell death
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidation of the type of cell death at the onset of non-alcoholic steatohepatitis2018

    • Author(s)
      鶴崎慎也、松田道隆、清水重臣、中野裕康、宮島篤、田中稔
    • Organizer
      AASLD 2018
    • Related Report
      2018 Annual Research Report
  • [Presentation] Oncostatin M regulates the role of macrophage during progression and resolution of hepatic fibrosis2018

    • Author(s)
      松田道隆、田中稔
    • Organizer
      EASL The International Liver Congress 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 慢性肝炎原因除去後の線維肝における、オンコスタチンMによる向/抗線維性マクロファージ切り替え機構の解析2018

    • Author(s)
      松田道隆、田中稔
    • Organizer
      JDDW 2018
    • Related Report
      2018 Annual Research Report
  • [Presentation] Kupffer cell with different origin underlies pathogen clearance dysfunction of chronicallu injured liver2018

    • Author(s)
      松田道隆、田中稔
    • Organizer
      AASLD 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] OncostatinM causes liver fibrosis by regulating cooperation between Hepatic stellate cells and macrophages2018

    • Author(s)
      松田道隆、鶴崎慎也、宮島篤、田中 稔
    • Organizer
      Australia-Japan Meeting on Cell Death
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 肝幹/前駆細胞の新規制御因子Tsukushiの機能解明2018

    • Author(s)
      木村拓也、真家進吾、太田訓正、宮島篤、田中稔
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 慢性肝疾患における肝リモデリングを制御する因子Tsukushiの機能解析2018

    • Author(s)
      木村拓也、真家進吾、太田訓正、宮島篤、田中稔
    • Organizer
      第29回日本肝臓医生物研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 非アルコール性脂肪性肝炎の病態形成における多様な細胞死とその意義2018

    • Author(s)
      鶴崎慎也、松田道隆、清水重臣、中野裕康、宮島篤、田中稔
    • Organizer
      第30回 日本肝臓医生物研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 胆管周囲付属線の単離法の確立とその生理的役割の解明2018

    • Author(s)
      松井 理司, 原田 憲一, 宮田 奈保子, 大河内 仁志, 宮島 篤, 田中 稔
    • Organizer
      第25回 肝細胞研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Characterization of peribiliary gland-constituting cells based on localization of Trop2 in biliary tract.2018

    • Author(s)
      Matsui S, Harada K, Miyata N, Okochi H, Miyajima A and Tanaka M
    • Organizer
      FASEB SRC, Fundamental Biology and Pathophysiology of the Liver
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Remarks] https://ncgm-regenerative-medicine.org/index.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] 細胞組織再生医学研究部 肝臓の研究

    • URL

      https://ncgm-regenerative-medicine.org/research/r4.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] https://ncgm-regenerative-medicine.org/

    • Related Report
      2018 Annual Research Report

URL: 

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

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi