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The lineage plasticity fo mature hepatocytes during liver injury and regeneration

Research Project

Project/Area Number 16K08716
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Experimental pathology
Research InstitutionSapporo Medical University

Principal Investigator

Tanimizu Naoki  札幌医科大学, 医学部, 准教授 (00333386)

Research Collaborator Mitaka Toshihiro  札幌医科大学, フロンティア医学研究所組織再生学部門, 教授 (50231618)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords肝臓 / 再生 / 肝細胞 / 分化可塑性 / 脱分化 / 分化転換 / 胆管上皮細胞 / Notch / Grhl2 / 肝前駆細胞 / 組織再生 / 前駆細胞 / 細胞・組織
Outline of Final Research Achievements

We focus on the lineage plasticity of hepatocytes and cholangiocytes during development and regeneration. After acetaminophen administration, SOX9(+) dedifferentiated hepatocytes appeared around the necrotic area, which was suppressed in aged livers. Given that the survival of mice was remarkably decreased, hepatocyte de-differentiation could be correlated with the protection of liver tissue. When hepatocytes were introduced with the intracellular domain of Notch 2 and Grhl2, they transdifferentiated into CK19(+) cholangiocyte-like cells after chronic injury. ON the other hand, Grhl2 null cholangiocytes isolated from chronically injured liver differentiated into hepatocytes in vitro. Furthermore, we found that part of hepatocyte express SOX9 during formation of hepatocellular carcinoma induced by diethylnitrosamine. Since SOX9 expression was observed before foci formation, de-differentiation could be involved in the early stage of tumorigenesis.

Academic Significance and Societal Importance of the Research Achievements

肝疾患形成過程において肝細胞の脱分化が組織保護に寄与している可能性を見出した。また、NotchシグナルとGrhl2が協調して、肝上皮細胞の分化可塑性を制御することが明らかになった。NotchシグナルやGrhl2の活性を制御することで、障害時に出現する内在性の肝前駆細胞から肝細胞への分化をコントロールし、肝組織再生の促進に活用できる可能性がある。また、腫瘍形成初期に現れるSOX9(+)肝細胞を解析することで、肝細胞が癌化する際の初期に現れる変化を明らかにできる可能性を示すことができた。

Report

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

    (25 results)

All 2019 2018 2017 2016 Other

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 4 results,  Acknowledgement Compliant: 2 results) Presentation (12 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Book (1 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Isolation of Bipotential Liver Progenitor Cells from Neonatal Mouse Liver.2019

    • Author(s)
      Naoki Tanimizu
    • Journal Title

      Methods in Molecular BIology

      Volume: 1905 Pages: 9-17

    • DOI

      10.1007/978-1-4939-8961-4_2

    • ISBN
      9781493989607, 9781493989614
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification and In Vitro Expansion of Adult Hepatocyte Progenitors from Chronically Injured Livers.2019

    • Author(s)
      Naoki Tanimizu
    • Journal Title

      Methods in Molecular Biology

      Volume: 1940 Pages: 267-273

    • DOI

      10.1007/978-1-4939-9086-3_19

    • ISBN
      9781493990856, 9781493990863
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Intrahepatic bile ducts guide establishment of the intrahepatic nerve network in developing and regenerating mouse liver.2018

    • Author(s)
      Tanimizu N, Ichinohe N,Mitaka T.
    • Journal Title

      Development

      Volume: 印刷中

    • DOI

      10.1242/dev.159095

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hepatocytic parental progenitor cells of rat small hepatocytes maintain a self-renewal capability after long-term culture.2017

    • Author(s)
      Ishii M, Kino J, Ichinohe N, Tanimizu N, Ninomiya T, Suzuki H, Mizuguchi T, Hirata K, Mitaka T.
    • Journal Title

      Scientific Reports,

      Volume: 7 Issue: 1 Pages: 46177-46177

    • DOI

      10.1038/srep46177

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Transplantation of Thy1+ cells accelerates liver regeneration by enhancing the growth of small hepatocyte-like progenitor cells via IL17RB signaling.2017

    • Author(s)
      Ichinohe N, Ishii M, Tanimizu N, Kon J, Mizuguchi T, Hirata K, Mitaka T.
    • Journal Title

      Stem Cells

      Volume: 35(4) Issue: 4 Pages: 920-931

    • DOI

      10.1002/stem.2548

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Epithelial Morphogenesis during Liver Development.2017

    • Author(s)
      Tanimizu N, Mitaka T.
    • Journal Title

      Cold Spring Harb Perspect Biol.

      Volume: Feb 17 Issue: 8 Pages: 1-10

    • DOI

      10.1101/cshperspect.a027862

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Which is better source for functional hepatocytes?2017

    • Author(s)
      Tanimizu N, Mitaka T.
    • Journal Title

      Stem Cell Investigation

      Volume: 4 Pages: 12-12

    • DOI

      10.21037/sci.2017.02.08

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Morphogenesis of Liver Epithelial Cells2016

    • Author(s)
      Tanimizu N, Mitaka T
    • Journal Title

      Hepatology Research

      Volume: in press Issue: 10 Pages: 964-976

    • DOI

      10.1111/hepr.12654

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Intrahepatic bile ducts are developed through formation of homogeneous continuous liminal network and its dynamic rearrangement.2016

    • Author(s)
      Tanimizu N, Kaneko K, Itoh T, Ichinohe N, Ishii M, Mizuguchi T, Hirata K, Miyajima A, Mitaka T.
    • Journal Title

      Hepatology

      Volume: in press Issue: 1 Pages: 175-188

    • DOI

      10.1002/hep.28521

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Liver progenitors isolated from adult healthy mouse liver efficiently differentiate to functional hepatocytes in vitro and repopulate liver tissue.2016

    • Author(s)
      Tanimizu N, Ichinohe N, Ishii M, Kino J, Mizuguchi T, Hirata K, Mitaka T.
    • Journal Title

      Stem Cells

      Volume: 34(12) Issue: 12 Pages: 2889-2901

    • DOI

      10.1002/stem.2457

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Presentation] Ex vivoにおける肝臓の上皮組織構造の再構築2019

    • Author(s)
      谷水 直樹
    • Organizer
      第18回日本再生医療学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Ex vivoにおける肝臓の3次元組織構造の再構築とその応用2019

    • Author(s)
      谷水 直樹
    • Organizer
      日本農芸化学会2019年度大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Interactions between intrahepatic bile ducts and autonomic nerves in developing and regenerating liver2018

    • Author(s)
      Naoki Tanimizu and Toshihiro Mitaka
    • Organizer
      FASEB SRC
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] NGFを介した肝内胆管と自律神経ネットワークの相互作用2018

    • Author(s)
      谷水 直樹、三高 俊広
    • Organizer
      第25回肝細胞研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 障害肝臓における肝前駆細胞の誘導機構の解明2018

    • Author(s)
      谷水 直樹
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 肝臓の発生と再生における肝内胆管と自律神経ネットワークの相互作用2018

    • Author(s)
      谷水 直樹
    • Organizer
      第51回北海道病理談話会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 肝機能向上を目指した肝前駆細胞の培養条件の検討2018

    • Author(s)
      谷水 直樹、三高 俊広
    • Organizer
      第17回日本再生医療学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 肝細胞のHeterogeneityと分化可塑性の制御機構2017

    • Author(s)
      谷水 直樹、三高 俊広
    • Organizer
      第24回肝細胞研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 肝臓の上皮細胞の分化可塑性の制御機構2017

    • Author(s)
      谷水 直樹、三高 俊広
    • Organizer
      Conbio2017
    • Related Report
      2017 Research-status Report
  • [Presentation] 肝傷害・再生過程において成熟肝細胞が示す分化可塑性の制御機構の解明2016

    • Author(s)
      谷水 直樹
    • Organizer
      JDDW2016
    • Place of Presentation
      神戸コンベンションセンター(兵庫県神戸市)
    • Year and Date
      2016-11-03
    • Related Report
      2016 Research-status Report
  • [Presentation] 肝細胞の分化可塑性に依存した肝組織再生機構2016

    • Author(s)
      谷水 直樹
    • Organizer
      生化学会
    • Place of Presentation
      仙台国際センター(宮城県仙台市)
    • Year and Date
      2016-09-25
    • Related Report
      2016 Research-status Report
  • [Presentation] 肝再生過程における肝細胞の分化可塑性の制御機構2016

    • Author(s)
      谷水 直樹
    • Organizer
      肝細胞研究会
    • Place of Presentation
      大阪国際会議場(大阪市北区)
    • Year and Date
      2016-07-07
    • Related Report
      2016 Research-status Report
  • [Book] Advances in Medicine and Biology2018

    • Author(s)
      Tanimizu N.
    • Publisher
      Nova Publisher
    • Related Report
      2017 Research-status Report
  • [Remarks] 札幌医科大学フロンティア医学研究所組織再生学部門ホームページ

    • URL

      https://www.smu-tisdevreg.jp/

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 肝細胞と胆管上皮細胞との接続部構造を有する肝上皮様組織の培養方法2019

    • Inventor(s)
      谷水 直樹、三高 俊広
    • Industrial Property Rights Holder
      谷水 直樹、三高 俊広
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Annual Research Report

URL: 

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

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