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Regenerative capacity of intrinsic stem cells subjected to disease-causing gene mutations

Research Project

Project/Area Number 20K21526
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 49:Pathology, infection/immunology, and related fields
Research InstitutionKobe University

Principal Investigator

Enomoto Hideki  神戸大学, 医学研究科, 教授 (00360511)

Project Period (FY) 2020-07-30 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2021: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords先天性疾患 / 組織欠損 / 内在性幹細胞 / 遺伝子変異 / ヒルシュスプルング病 / 幹細胞 / 自己組織化 / シュワン細胞 / RET / Sox10 / 組織再生 / 自己組織能 / 神経幹細胞 / 腸管神経系
Outline of Research at the Start

病的な幹細胞は原因遺伝子の修復により自律的組織形成能を再獲得できるかという命題解明のため、先天性の腸管神経幹細胞の異常により広範に神経欠損を起こす難治性ヒルシュスプルング病(HSCR)のマウスモデルを遺伝子異常が修復可能な形で作製し、一部の神経幹細胞の正常化を行い、修復神経幹細胞により腸管神経系が正常に形成されるかを解明する。この研究遂行により、内在性の幹細胞を治療して組織再生を誘導する新しい治療法創出のための基盤情報を得る。

Outline of Final Research Achievements

In this study, we evaluated the tissue regeneration capacity of intrinsic stem cells in congenital diseases. As a model system, we chose to examine Hirschsprung disease (HSCR). HSCR is characterized by the congenital absence of the enteric ganglia in the distal gut and caused by dysfunction of enteric neural stem cells. We generated a HSCR mouse model in which a disease causing mutation can be removed in a conditional fashion. We found that, after removal of the mutation, enteric neural stem cells participated in neurogenesis, which led to regeneration of the enteric nervous system. These findings demonstrate that, once the disease causing mutation is eliminated, intrinsic stem cells can contribute to the regeneration of tissues and prevent tissue loss.

Academic Significance and Societal Importance of the Research Achievements

難治性HSCRの克服を目指し、ES細胞やiPS細胞由来から誘導された腸管神経前駆細胞を腸管に移植する細胞補充療法の開発が始まっている。しかし、難治性HSCRでは、細胞を移植すべき腸管が極めて長いことに加え、移植した細胞が生後の腸に生着しにくいという大きな問題を抱えている。本研究では、内在性の腸管神経幹細胞を治療すれば組織再生が誘導されることが明らかとなり、HSCRの新規治療法として内在性幹細胞の応用が有用な戦略になり得ることが示された。また、この結果は、他の先天性疾患でも同様のことが起こり得る可能性を示唆しており、先天性疾患の治療法に新たな可能性を提示する。

Report

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

    (11 results)

All 2023 2022 2021 2020

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

  • [Journal Article] Uts2b is a microbiota-regulated gene expressed in vagal afferent neurons connected to enteroendocrine cells producing cholecystokinin.2022

    • Author(s)
      Yuta Yoshioka, Yoshihisa Tachibana, Toshihiro Uesaka, Hiroyuki Hioki, Yuya Sato, Takumi Fukumoto, Hideki Enomoto.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 608 Pages: 66-72

    • DOI

      10.1016/j.bbrc.2022.03.117

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Single RET Mutation in Hirschsprung Disease Induces Intestinal Aganglionosis Via a Dominant-Negative Mechanism2022

    • Author(s)
      Sunardi Mukhamad、Ito Keisuke、Sato Yuya、Uesaka Toshihiro、Iwasaki Mitsuhiro、Enomoto Hideki
    • Journal Title

      Cellular and Molecular Gastroenterology and Hepatology

      Volume: 14 Issue: 6 Pages: 1505-1524

    • DOI

      10.1016/j.jcmgh.2022.12.003

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased RET Activity Coupled with a Reduction in the <i>RET</i> Gene Dosage Causes Intestinal Aganglionosis in Mice2021

    • Author(s)
      Okamoto Mitsumasa、Uesaka Toshihiro、Ito Keisuke、Enomoto Hideki
    • Journal Title

      eneuro

      Volume: 8 Issue: 3 Pages: 1-12

    • DOI

      10.1523/eneuro.0534-20.2021

    • NAID

      120007177532

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhanced enteric neurogenesis by Schwann cell precursors in mouse models of Hirschsprung disease2021

    • Author(s)
      Uesaka Toshihiro、Okamoto Mitsumasa、Nagashimada Mayumi、Tsuda Yoshihiro、Kihara Miho、Kiyonari Hiroshi、Enomoto Hideki
    • Journal Title

      Glia

      Volume: 69 Issue: 11 Pages: 2575-2590

    • DOI

      10.1002/glia.24059

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Point mutagenesis in mouse reveals contrasting pathogenetic effects between MEN2B‐ and Hirschsprung disease‐associated missense mutations of the RET gene2020

    • Author(s)
      Nakatani Taichi、Iwasaki Mitsuhiro、Yamamichi Atsuhiro、Yoshioka Yuta、Uesaka Toshihiro、Bitoh Yuko、Maeda Kosaku、Fukumoto Takumi、Takemoto Tatsuya、Enomoto Hideki
    • Journal Title

      Development, Growth & Differentiation

      Volume: 62 Issue: 4 Pages: 214-222

    • DOI

      10.1111/dgd.12664

    • NAID

      120006863591

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Schwann Cell Precursor-Derived Neurogenesis in Development and Pathology of the Autonomic Nervous System2023

    • Author(s)
      Hideki Enomoto
    • Organizer
      Gordon Research Conference: Neural Crest and Cranial Placodes
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] New understanding of ENS development2022

    • Author(s)
      Hideki Enomoto
    • Organizer
      6th INTERNATIONAL SYMPOSIUM ON DEVELOPMENT OF THE ENS
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] シュワン細胞前駆細胞による神経形成:その制御・分布・病態への関与について2022

    • Author(s)
      榎本秀樹
    • Organizer
      第33回日本末梢神経学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 腸管神経の発生・病理・再生2021

    • Author(s)
      榎本秀樹
    • Organizer
      第58回日本小児外科学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Function of Schwann cell precursors as autonomic neural stem cells2021

    • Author(s)
      榎本秀樹
    • Organizer
      The International Society for Stem Cell Research (ISSCR)
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] 組織幹細胞としてのシュワン細胞の機能 発生・病理・再生医療の観点から2021

    • Author(s)
      榎本秀樹
    • Organizer
      日本再生医療学会総会
    • Related Report
      2020 Research-status Report

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Published: 2020-08-03   Modified: 2024-01-30  

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