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Establishment of hepatobiliary connection ex vivo

Research Project

Project/Area Number 20K05843
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 38030:Applied biochemistry-related
Research InstitutionThe University of Tokyo (2021-2022)
Sapporo Medical University (2020)

Principal Investigator

Tanimizu Naoki  東京大学, 医科学研究所, 准教授 (00333386)

Co-Investigator(Kenkyū-buntansha) 三高 俊広  札幌医科大学, 医学部, 教授 (50231618)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords上皮組織 / オルガノイド / 肝臓 / 胆管 / 代謝産物 / 組織構造 / 薬物動態
Outline of Research at the Start

体外と体内の物質交換や輸送を担う上皮系の臓器では、機能発現や維持のために、隣接する「管腔」を持つ上皮組織が正しく接続する必要がある。肝臓の肝細胞と胆管の接続部構造はヘリング管(CoH)と呼ばれている。胆汁が胆管に輸送されずに組織内に滞留すると、肝細胞死が誘導されて重篤な疾患の原因となることからも、CoHは肝機能発現と組織恒常性維持にとって非常に重要な接続部構造である。本研究では、我々が独自に開発した肝細胞と胆管の接続を再現する培養系を用いて、CoHの形成のメカニズム解明と、薬物動態アッセイや肝病態モデル構築などにつながる研究成果をあげることを目的に研究を行う。

Outline of Final Research Achievements

Inside the liver, hepatocytes and biliary epithelial cells (BECs) form bile canaliculi and bile ducts, respectively, which are interconnected to establish the bile excretion system for transporting the bile produced by hepatocytes into the duodenum. We applied an organoid culture technique on hepatocyte progenitors and BECs, we established a novel hepato-biliary tubular organoid (HBTO) in which bile acid and bilirubin up-taken by hepatocytes are secreted into bile ducts within the organoid.
We targeted two types of liver injury, steatosis and cholestasis, to generate hepatic injury models with HBTO. By incubating HBTOs with free fatty acids, lipid droplets were accumulated inside hepatocytes. When troglitazone that inhibits bile salt export pump (BSEP) was added to culture medium, bile acids were accumulated in hepatocytes instead of secreted into bile canaliculi and bile ducts.

Academic Significance and Societal Importance of the Research Achievements

我々は肝臓の上皮組織である肝細胞の毛細胆管と胆管の接続をin vitroで再現することに初めて成功した。臓器再生において、隣接する組織の空間配置を制御することは非常に重要であり、上皮組織形成の理解および応用のいずれの面からも本研究成果は学術的・社会的意義が高いものである。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (22 results)

All 2023 2022 2021 2020 Other

All Journal Article (6 results) (of which Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (15 results) (of which Int'l Joint Research: 2 results,  Invited: 8 results) Remarks (1 results)

  • [Journal Article] Preparation of Functional Human Hepatocytes Ex Vivo.2022

    • Author(s)
      Okumura A and Tanimizu N
    • Journal Title

      Methods in Molecular Biology

      Volume: 2544 Pages: 269-278

    • DOI

      10.1007/978-1-0716-2557-6_20

    • ISBN
      9781071625569, 9781071625576
    • Related Report
      2022 Annual Research Report
  • [Journal Article] Generation of functional liver organoids on combining hepatocytes and cholangiocytes with hepatobiliary connections ex vivo2021

    • Author(s)
      Tanimizu Naoki、Ichinohe Norihisa、Sasaki Yasushi、Itoh Tohru、Sudo Ryo、Yamaguchi Tomoko、Katsuda Takeshi、Ninomiya Takafumi、Tokino Takashi、Ochiya Takahiro、Miyajima Atsushi、Mitaka Toshihiro
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 3390-3401

    • DOI

      10.1038/s41467-021-23575-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of human iPSC-derived quiescent hepatic stellate cell-like cells for drug discovery and in vitro disease modeling2021

    • Author(s)
      Koui Yuta、Himeno Misao、Mori Yusuke、Nakano Yasuhiro、Saijou Eiko、Tanimizu Naoki、Kamiya Yoshiko、Anzai Hiroko、Maeda Natsuki、Wang Luyao、Yamada Tadanori、Sakai Yasuyuki、Nakato Ryuichiro、Miyajima Atsushi、Kido Taketomo
    • Journal Title

      Stem Cell Reports

      Volume: 16 Issue: 12 Pages: 3050-3063

    • DOI

      10.1016/j.stemcr.2021.11.002

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extracellular vesicles containing miR-146a-5p secreted by bone marrow mesenchymal cells activate hepatocytic progenitors in regenerating rat livers2021

    • Author(s)
      Ichinohe Norihisa、Ishii Masayuki、Tanimizu Naoki、Mizuguchi Toru、Yoshioka Yusuke、Ochiya Takahiro、Suzuki Hiromu、Mitaka Toshihiro
    • Journal Title

      Stem Cell Research & Therapy

      Volume: 12 Issue: 1 Pages: 312-331

    • DOI

      10.1186/s13287-021-02387-6

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The neonatal liver: Normal development and response to injury and disease2021

    • Author(s)
      Tanimizu Naoki
    • Journal Title

      Seminars in Fetal and Neonatal Medicine

      Volume: 印刷中 Issue: 1 Pages: 101229-101229

    • DOI

      10.1016/j.siny.2021.101229

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Prolonged oxidative stress and delayed tissue repair exacerbate acetaminophen-induced liver injury in aged mice2020

    • Author(s)
      Tanimizu Naoki、Ichinohe Norihisa、Suzuki Hiromu、Mitaka Toshihiro
    • Journal Title

      Aging

      Volume: 12 Issue: 19 Pages: 18907-18927

    • DOI

      10.18632/aging.103973

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] "Liver Regeneration in response to acute and chronic liver injury”2023

    • Author(s)
      Naoki Tanimizu
    • Organizer
      APASL 2023 annual meeting (Asian Pacific Association for the study of the liver) ,Taipei, Taiwan Symposium session “Liver injury and regeneration
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 肝臓発生過程の理解に基づくEx vivo組織構造の試み」2022

    • Author(s)
      谷水 直樹
    • Organizer
      iMeC-WISEセミナー
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 「胆管を接続した肝臓オルガノイドを用いた肝疾患モデルの構築」2022

    • Author(s)
      谷水 直樹
    • Organizer
      第29回肝細胞研究会 シンポジウム:創薬のための生理学的培養肝組織モデルの開発
    • Related Report
      2022 Annual Research Report
  • [Presentation] 「肝臓オルガノイドを用いた肝疾患モデルの構築」2022

    • Author(s)
      谷水 直樹
    • Organizer
      第6回東海肝臓病研究会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 肝臓の3次元構造解析に基づく肝臓オルガノイドの構築2022

    • Author(s)
      谷水 直樹、三高 俊広
    • Organizer
      第28回肝細胞研究会
    • Related Report
      2021 Research-status Report
  • [Presentation] 胆管接続型肝臓オルガノイドを用いた肝疾患モデルの構築2022

    • Author(s)
      谷水 直樹
    • Organizer
      薬物動態談話会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 胆汁排泄型肝臓オルガノイドを用いた応用研究の展開2022

    • Author(s)
      谷水 直樹
    • Organizer
      第21回日本再生医療学会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 3D analyses of liver tissue structures and reconstitution of the hepatobiliary connection ex vivo2021

    • Author(s)
      谷水 直樹
    • Organizer
      FACS SRC
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 肝オルガノイドを用いた肝疾患モデルの構築2021

    • Author(s)
      谷水 直樹、三高 俊広
    • Organizer
      第57回 日本肝臓学会
    • Related Report
      2021 Research-status Report
  • [Presentation] 胆汁輸送路を備えた肝臓オルガノイドの開発2021

    • Author(s)
      谷水 直樹
    • Organizer
      創薬フォーラム第7回シンポジウム
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 胆汁排泄型肝臓オルガノイドを用いた肝疾患モデル構築2021

    • Author(s)
      谷水 直樹
    • Organizer
      CBI学会2021年大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Modeling of liver tissue structures ex vivo2021

    • Author(s)
      谷水 直樹
    • Organizer
      East Asia Symposium
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] 胆汁排泄路を備えた肝オルガノイドの構築とその応用2021

    • Author(s)
      谷水 直樹
    • Organizer
      日本再生医療学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 肝臓創出のためのEx vivo組織構築2021

    • Author(s)
      谷水 直樹
    • Organizer
      第6回デザイン生命工学研究会
    • Related Report
      2020 Research-status Report
  • [Presentation] Ex vivoにおける肝組織の再構築2020

    • Author(s)
      谷水 直樹
    • Organizer
      肝細胞研究会
    • Related Report
      2020 Research-status Report
  • [Remarks] 札幌医科大学附属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
      2020 Research-status Report

URL: 

Published: 2020-04-28   Modified: 2024-01-30  

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