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

Generation of zone-specific hepatocyte for study of liver injury and diseases

Research Project

Project/Area Number 17K19657
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field General internal medicine and related fields
Research InstitutionOsaka University

Principal Investigator

Takayama Kazuo  大阪大学, 薬学研究科, 助教 (10759509)

Research Collaborator Mizuguchi Hiroyuki  
Imagawa Kazuo  
Mitani Seiji  
Project Period (FY) 2017-06-30 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords肝細胞 / 毒性 / 薬物代謝 / zonation / ヒトiPS細胞 / ヒトES細胞 / 肝障害 / 胆管上皮細胞 / 創薬 / 異物代謝 / 分化誘導 / 肝臓 / ヒトES/iPS細胞
Outline of Final Research Achievements

The function of hepatocytes largely depends on their position in the liver lobule. Although the method of differentiating hepatocytes from human pluripotent stem cells has been largely improved over the past decade, there remains no technique for generating hepatocyte-like cells (HLCs) with zone-specific hepatic properties. In this study, we searched for the factors that promote acquisition of zone-specific properties of HLCs. Here, we identified that WNT7B and WNT8B play important roles in achieving perivenous zone-specific characteristics, such as the enhancement of glutamine secretion, citric acid cycle, cytochrome P450 (CYP) 1A2 metabolism, and CYP1A2 induction capacities. We also found that WNT inhibitory factor (WIF-1) was necessary for achieving periportal zone-specific characteristics, such as the enhancement of urea secretion and gluconeogenesis capacities. Therefore, WNT signal modulators conferred zone-specific hepatic properties onto HLCs.

Academic Significance and Societal Importance of the Research Achievements

医薬品の毒性判明による市場撤退・開発中止のうち、多くの事例で肝障害が認められることから、肝障害の高精度な予測技術は不可欠である。しかし、多くの肝障害にzone特異性が見られるものの、既存の創薬ではzone特異的なヒト肝細胞モデルが存在しないため、zonation情報を考慮した毒性予測試験が実施できなかった。本研究成果を応用することにより、肝臓を構成する肝細胞の不均一性を加味した医薬品の安全性試験を初めて実施できる可能性があり、従来の創薬プロセスを大きく進歩させる潜在性を有する。

Report

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

    (10 results)

All 2019 2018 2017

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 1 results) Presentation (3 results) (of which Invited: 2 results)

  • [Journal Article] Pharmaceutical Research for Inherited Metabolic Disorders of the Liver Using Human Induced Pluripotent Stem Cell and Genome Editing Technologies2019

    • Author(s)
      Yamashita T, Takayama K, Hori M, Harada-Shiba M, Mizuguchi H.
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 3 Pages: 312-318

    • DOI

      10.1248/bpb.b18-00544

    • NAID

      130007607360

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-03-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] FGF signal is not required for hepatoblast differentiation of human iPS cells.2019

    • Author(s)
      Toba Y, Kiso A, Nakamae S, Sakurai F, Takayama K, Mizuguchi H.
    • Journal Title

      Sci Rep.

      Volume: 9 Issue: 1 Pages: 3713-3713

    • DOI

      10.1038/s41598-019-40305-2

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Optimal human iPS cell culture method for efficient hepatic differentiation.2018

    • Author(s)
      Matoba N, Yamashita T, Takayama K, Sakurai F, Mizuguchi H.
    • Journal Title

      Differentiation

      Volume: 104 Pages: 13-21

    • DOI

      10.1016/j.diff.2018.09.005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enrichment of high-functioning human iPS cell-derived hepatocyte-like cells for pharmaceutical research.2018

    • Author(s)
      Takayama K, Hagihara Y, Toba Y, Sekiguchi K, Sakurai F, Mizuguchi H.
    • Journal Title

      Biomaterials.

      Volume: 161 Pages: 24-32

    • DOI

      10.1016/j.biomaterials.2018.01.019

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nanaomycin A Treatment Promotes Hepatoblast Differentiation from Human iPS Cells.2018

    • Author(s)
      Nakamae S, Toba Y, Takayama K, Sakurai F, Mizuguchi H.
    • Journal Title

      Stem Cells Dev.

      Volume: 未定 Issue: 6 Pages: 405-414

    • DOI

      10.1089/scd.2017.0251

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Billion-scale production of hepatocyte-like cells from human induced pluripotent stem cells.2018

    • Author(s)
      Yamashita T, Takayama K, Sakurai F, Mizuguchi H.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 496 Issue: 4 Pages: 1269-1275

    • DOI

      10.1016/j.bbrc.2018.01.186

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Human ESC/iPSC-Derived Hepatocyte-like Cells Achieve Zone-Specific Hepatic Properties by Modulation of WNT Signaling.2017

    • Author(s)
      Mitani S, Takayama K, Nagamoto Y, Imagawa K, Sakurai F, Tachibana M, Sumazaki R, Mizuguchi H.
    • Journal Title

      Mol Ther.

      Volume: 25 Issue: 6 Pages: 1420-1433

    • DOI

      10.1016/j.ymthe.2017.04.006

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] ヒトES/iPS細胞のゲノム編集と創薬研究への応用2018

    • Author(s)
      高山和雄、水口裕之
    • Organizer
      第17回日本再生医療学会総会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Generation of hepatocytes from human ES/iPS cells for medicinal sciences2018

    • Author(s)
      Takayama K., Mizuguchi H.
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] WNTシグナル制御による門脈域及び中心静脈域肝細胞の性質を有するヒトiPS細胞由来肝細胞作製法の開発2017

    • Author(s)
      三谷成二、高山和雄、櫻井文教、水口裕之
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report

URL: 

Published: 2017-07-21   Modified: 2020-03-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi