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

In vivo reconstruction of human iPS cell-derived human three dimensional hepatic tissue with neurovascular network

Research Project

Project/Area Number 21H02991
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 55010:General surgery and pediatric surgery-related
Research InstitutionYokohama City University

Principal Investigator

Koike Naoto  横浜市立大学, 医学研究科, 客員教授 (50301081)

Co-Investigator(Kenkyū-buntansha) 田所 友美  横浜市立大学, 医学部, 助教 (20507644)
小林 達哉  横浜市立大学, 医学研究科, 共同研究員 (60837839)
谷口 英樹  東京大学, 医科学研究所, 教授 (70292555)
村田 聡一郎  横浜市立大学, 医学研究科, 客員准教授 (40436275)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2022: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2021: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Keywords高次肝組織 / 神経 / 血管 / 門脈域 / ヒトiPS細胞 / 肝細胞索 / 微小血管 / iPS細胞
Outline of Research at the Start

これまでの研究で肝細胞、血管内皮細胞、間葉系細胞に分化させたhiPS細胞を用いて、体外で肝芽を再生し、それを移植する事により、血管ネットワークを有し障害肝の機能を代償できる高次肝組織を生体内で再構築することに成功した。しかし、胆管、動静脈、神経から成る門脈域を構築し、長期安定な胆汁分泌を再現することができなかった。本研究の概要は、これまでの研究では欠落していた神経の幹細胞を肝芽作成に加えて、ヒト型高次肝組織を生体内において再構築し、組織再構築過程をライブ観察で解析するとともに、組織的に門脈域を有し、胆汁分泌などの高次機能を発揮可能な移植用肝組織の開発への基礎を築くことを目的とする研究である。

Outline of Final Research Achievements

The liver buds prepared from human iPS cell (hiPSC)-derived hepatic progenitor cells, vascular endothelial cells, and mesenchymal stem cell, were cultured on nerve fibers obtained from hiPSC derived neural stem cells in order to regenerate a micro-hepatic tissue having a portal area consisting of bile ducts, vessels and nerves.  In the result, protrusions accompanied by nerve fibers reminiscent of bile canaliculi in the portal area appeared in the liver bud. However, confirmation of bile canaliculus using fluorescent bile acid analogs and labeling of cholangiocyte and hepatocyte markers suggested that these protrusions were human-type hepatic cords accompanying nerve fibers. This construct generated microscopic hepatic tissue with blood flow from host after transplant into the mouse cranial window, and this tissue survived for a long time. In conclusion, nerve fibers suspected to be play important roles for the morphogenesis of human-type liver parenchyma and its maintenance.

Academic Significance and Societal Importance of the Research Achievements

肝内の自律神経は糖代謝、サーカジアンリズム等に関与する他、肝血流や肝再生に関与しているとも言われている。しかし、神経系の肝発生に関する意義ははっきりしていない。今回の研究で神経線維が肝細胞索などの肝実質の形態、及び生体内でその維持に関与している可能性を示唆する新たな知見を得ることができた。今回の方法でできた神経線維を有するヒト型高次肝組織は、創薬における極めて有用なプラットフォームとなる可能性がある。更にこのモデルが生体内で成熟し長期安定化できれば、肝疾患に対する再生医療に利用可能であり、本研究の究極の目的である絶対的に不足している移植臓器に取って代わる革新的な医療技術となりうると思われる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (17 results)

All 2024 2023 2022 2021

All Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Open Access: 9 results,  Peer Reviewed: 8 results) Presentation (8 results) (of which Invited: 2 results)

  • [Journal Article] 移植医療の未来 ―ヒト iPS 細胞を駆使した再生医療の展望2023

    • Author(s)
      谷口英樹
    • Journal Title

      小児内科

      Volume: 55 Pages: 857-862

    • Related Report
      2023 Annual Research Report
    • Open Access
  • [Journal Article] PDGF Receptors and Signaling Are Required for 3D-Structure Formation and Differentiation of Human iPSC-Derived Hepatic Spheroids.2023

    • Author(s)
      3.Syusaku Tsuzuki Tomoyuki Yamaguchi Takashi Okumura Toshiharu Kasai  and Hideki Taniguchi
    • Journal Title

      Int.J.Mol.Sci.

      Volume: 24(8) Issue: 8 Pages: 7075-7075

    • DOI

      10.3390/ijms24087075

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Incorporation of human iPSC-derived stromal cells creates a pancreatic cancer organoid with heterogeneous cancer-associated fibroblasts2023

    • Author(s)
      Takeuchi Kenta、Tabe Shunsuke、Takahashi Kenta、Aoshima Kenji、Matsuo Megumi、Ueno Yasuharu、Furukawa Yoichi、Yamaguchi Kiyoshi、Ohtsuka Masayuki、Morinaga Soichiro、Miyagi Yohei、Yamaguchi Tomoyuki、Tanimizu Naoki、Taniguchi Hideki
    • Journal Title

      Cell Reports

      Volume: 42 Issue: 11 Pages: 113420-113420

    • DOI

      10.1016/j.celrep.2023.113420

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stabilized generation of human iPSC-derived liver organoids using a modified coating approach2022

    • Author(s)
      Kamishibahara Yu、Okamoto Satoshi、Ohkuma Takuya、Taniguchi Hideki
    • Journal Title

      Biology Methods and Protocols

      Volume: 8 Issue: 1

    • DOI

      10.1093/biomethods/bpac034

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] In vitro elastic cartilage reconstruction using human auricular perichondrial chondroprogenitor cell?derived micro 3D spheroids2022

    • Author(s)
      Oba Takayoshi、Okamoto Satoshi、Ueno Yasuharu、Matsuo Megumi、Tadokoro Tomomi、Kobayashi Shinji、Yasumura Kazunori、Kagimoto Shintaro、Inaba Yutaka、Taniguchi Hideki
    • Journal Title

      Journal of Tissue Engineering

      Volume: 13 Pages: 1-13

    • DOI

      10.1177/20417314221143484

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transhiatal bilateral thoracic duct ligation for duplicated thoracic duct injury after esophagectomy: a case report2022

    • Author(s)
      Komatsuzaki Shuhei、Hisakura Katsuji、Ogawa Koichi、Akashi Yoshimasa、Kim Jaejeong、Moue Shoko、Miyazaki Yoshihiro、Furuya Kinji、Doi Manami、Owada Yohei、Shimomura Osamu、Ohara Yusuke、Takahashi Kazuhiro、Hashimoto Shinji、Enomoto Tsuyoshi、Koike Naoto、Oda Tatsuya
    • Journal Title

      Surgical Case Reports

      Volume: 8 Issue: 1

    • DOI

      10.1186/s40792-022-01567-7

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mechanical guidance of self-condensation patterns of differentiating progeny2022

    • Author(s)
      Matsuzaki Takahisa、Shimokawa Yuko、Koike Hiroyuki、Kimura Masaki、Kawano Yuma、Okuma Nao、Kawamura Ryuzo、Yoneyama Yosuke、Furuichi Yasuro、Hakuno Fumihiko、Takahashi Shin-Ichiro、Nakabayashi Seiichiro、Okamoto Satoshi、Nakauchi Hiromitsu、Taniguchi Hideki、Takebe Takanori、Yoshikawa Hiroshi Y.
    • Journal Title

      iScience

      Volume: 25 Issue: 10 Pages: 105109-105109

    • DOI

      10.1016/j.isci.2022.105109

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Development of the nervous system in mouse liver.2022

    • Author(s)
      Koike N, Tadokoro T, Ueno Y, Okamoto S, Kobayashi T, Murata S, Taniguchi H
    • Journal Title

      World Journal of Hepatology

      Volume: 14 Issue: 2 Pages: 386-399

    • DOI

      10.4254/wjh.v14.i2.386

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dorso-ventral heterogeneity in tracheal basal stem cells.2021

    • Author(s)
      Tadokoro T, Tanaka K, Osakabe S, Kato M, Kobayashi H, Hogan BLM, Taniguchi H.
    • Journal Title

      Biology Open

      Volume: 10 Issue: 9

    • DOI

      10.1242/bio.058676

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 固形臓器の再構成には何が必要か?2024

    • Author(s)
      谷口英樹
    • Organizer
      第23回日本再生医療学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 血管-上皮の相互作用に基づく組織再構成2024

    • Author(s)
      谷水 直樹、Carolina Erica、奥村 歩、青嶋 研治、露木 泰地、谷口 英樹
    • Organizer
      第23回日本再生医療学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Integration of Kupffer cells to hiPSC-derived liver organoids for modeling septic liver dysfunction2024

    • Author(s)
      聶 運中、李 楊、谷口 英樹
    • Organizer
      第23回日本再生医療学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 臓器形成メカニズム解析に向けた発生プロセスの3次元的理解2024

    • Author(s)
      久世 祥己、谷口 英樹
    • Organizer
      第23回日本再生医療学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 体外灌流を用いたヒト臓器創出への挑戦―ヒト iPS 細胞オルガノ イドの新展開―2023

    • Author(s)
      谷口英樹
    • Organizer
      第49回日本臓器保存生物医学会学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 孤立性再発胆道癌に対する放射線療法の経験2023

    • Author(s)
      小池直人、大島祐二、川上浩幸
    • Organizer
      第59回日本胆道学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 当科における消化管GISTに対する手術加療例の検討2023

    • Author(s)
      小池直人、大島祐二、武内俊章、岡田晃一郎、池口文香、有田誠司、笹井大督
    • Organizer
      第85回臨床外科学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] ヒトiPS細胞オルガノイドを用いた新規肝疾患治療法の開発2021

    • Author(s)
      谷口英樹
    • Organizer
      第115回日本消化器病学会四国支部例会
    • Related Report
      2021 Annual Research Report
    • Invited

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi