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Elucidation of regulatory mechanism of intestinal stem cell proliferation and differentiation via non-neuronal acetylcholine receptors

Research Project

Project/Area Number 20K06751
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 44050:Animal physiological chemistry, physiology and behavioral biology-related
Research InstitutionSuntory Foundation for Life Sciences

Principal Investigator

Toshio Takahashi  公益財団法人サントリー生命科学財団, 生物有機科学研究所・統合生体分子機能研究部, 主幹研究員 (20390792)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords非神経性アセチルコリン / オルガノイド / 腸幹細胞 / シグナル伝達経路 / 分化 / 増殖 / 組織形成 / 生体分子 / 細胞・組織 / シグナル伝達 / 生理学 / 発生・分化
Outline of Research at the Start

本研究では、遺伝子改変マウスを用いた分子生物学的アプローチによってAChが非神経細胞型ACh受容体を介して幹細胞制御に関与するという仮説をin vivoで検証する。具体的には、2つに大別されるACh受容体の欠損マウスを用いて、腸幹細胞における代謝型mAChRsとチャネル型nAChRsの機能及びシグナル伝達経路の違いを明らかにする。また、生物学的シグナル伝達系にはポジティブループとネガティブループの双方が存在するという一般原則を考慮すると、代謝型mAChRsとチャネル型nAChRsによる腸幹細胞制御の拮抗的二重支配という受容体間の機能的相互作用の存在が想定され、その存在の有無を明らかにする。

Outline of Final Research Achievements

Recent studies show that various mammalian non-neuronal cells synthesize acetylcholine (ACh) and operate cholinergic signaling via nicotinic and muscarinic ACh receptors (n- and mAChRs) in response to internal or external stimuli. Experiments using intestinal organoids that lack nerve and immune cells in culture show that endogenous ACh is synthesized in the intestinal epithelium to drive organoid growth and differentiation through activation of nAChRs and mAChRs. We found that ACh binds to α2β4 nicotinic ACh receptor, and induced Wnt signaling, and eventually proliferation and differentiation of intestinal stem cells (ISCs) are enhanced. Furthermore, Genetic ablation of M3 muscarinic ACh receptor showed to enhance proliferation and differentiation of ISCs through activation of EphB/ephrin-B signaling pathway. Collectively, signaling through the M3 and α2β4 appears to work together to maintain the homeostasis of intestinal epithelial cell growth and differentiation.

Academic Significance and Societal Importance of the Research Achievements

本研究では、幹細胞やそのニッチを容易に同定することができる腸幹細胞システムをモデル系とすることにより、いまだ不明な点が多く残存する腸幹細胞と微小環境の相互作用によるホメオスタシスの維持機構の一端を明らかにすることができた。このことは、様々な組織幹細胞の基礎生物学的特性の理解にも繋がると考える。また、本研究により、腸上皮に存在するAChが腸幹細胞を制御する局所のシグナル分子であり、腸幹細胞制御の直接的及び間接的なACh作動性シグナリングが解明され、組織幹細胞による組織形成プログラムの解明に大きく貢献できると期待している。

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 Int'l Joint Research (1 results) Journal Article (15 results) (of which Peer Reviewed: 15 results,  Open Access: 11 results) Presentation (2 results) (of which Invited: 1 results) Book (2 results) Remarks (2 results)

  • [Int'l Joint Research] NIDDK(米国)

    • Related Report
      2020 Research-status Report
  • [Journal Article] The 3D Culturing of Organoids from Murine Intestinal Crypts and a Single Stem Cell for Organoid Research2023

    • Author(s)
      Takase Yuta、Fujishima Kazuto、Takahashi Toshio
    • Journal Title

      Journal of Visualized Experiments

      Volume: - Issue: 194 Pages: 1-10

    • DOI

      10.3791/65219

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Muscarinic receptor M3 contributes to intestinal stem cell maintenance via EphB/ephrin-B signaling2021

    • Author(s)
      Takahashi Toshio、Shiraishi Akira、Murata Jun、Matsubara Shin、Nakaoka Satsuki、Kirimoto Shinji、Osawa Masatake
    • Journal Title

      Life Science Alliance

      Volume: 4 Issue: 9 Pages: 1-17

    • DOI

      10.26508/lsa.202000962

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Modeling intestinal stem cell function with organoids2021

    • Author(s)
      Toshio Takahashi, Kazuo Fujishima, and Mineko Kengaku
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 22 Issue: 20 Pages: 1-14

    • DOI

      10.3390/ijms222010912

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multiple roles for cholinergic signaling from the perspective of stem cell function2021

    • Author(s)
      Toshio Takahashi
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 22 Issue: 2 Pages: 1-16

    • DOI

      10.3390/ijms22020666

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 非神経細胞型アセチルコリン受容体を介した腸幹細胞の維持機構の解明2021

    • Author(s)
      高橋俊雄
    • Journal Title

      BIO Clinica

      Volume: 36 Pages: 94-97

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Distribution and physiological effect of enterin neuropeptides in the olfactory centers of the terrestrial slug Limax.2020

    • Author(s)
      *Matsuo R, Kobayashi S, Furuta A, Osugi T, Takahashi T, Satake H, and Matsuo Y
    • Journal Title

      J Comp Physiol A

      Volume: in press Issue: 3 Pages: 401-418

    • DOI

      10.1007/s00359-020-01400-2

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mechanism of gamete shedding in starfish: Involvement of acetylcholine in extracellular Ca2+-dependent contraction of gonadal walls2020

    • Author(s)
      Mita Masatoshi、Osugi Tomohiro、Takahashi Toshio、Watanabe Takehiro、Satake Honoo
    • Journal Title

      General and Comparative Endocrinology

      Volume: 290 Pages: 113401-113401

    • DOI

      10.1016/j.ygcen.2020.113401

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Roles of nAChR and Wnt signaling in intestinal stem cell function and inflammation2020

    • Author(s)
      Takahashi T.
    • Journal Title

      Int. Immunopharmacol.

      Volume: 81 Pages: 1-5

    • DOI

      10.1016/j.intimp.2020.106260

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stem cell signaling pathways in the small intestine2020

    • Author(s)
      Takahashi T. and Shiraishi A.
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 21 Issue: 6 Pages: 1-18

    • DOI

      10.3390/ijms21062032

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of neuropeptides in gastropod mollusks. Classical and brand-new approaches2020

    • Author(s)
      F Morishita, T Takahashi, T Watanabe, T Uto, K Ukena, M Furumitsu and T Horiguchi
    • Journal Title

      IOP Conf. Ser.: Earth and Environ. Sci.

      Volume: 456 Issue: 1 Pages: 012001-012001

    • DOI

      10.1088/1755-1315/456/1/012001

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comparative Aspects of Structure and Function of Cnidarian Neuropeptides2020

    • Author(s)
      Toshio Takahashi
    • Journal Title

      Front. Endocrinol.

      Volume: 11 Pages: 339-339

    • DOI

      10.3389/fendo.2020.00339

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 非神経細胞型アセチルコリン受容体を介した腸幹細胞の分化・増殖制御機構の解明2020

    • Author(s)
      高橋俊雄
    • Journal Title

      Precision Medicine

      Volume: 3 Pages: 88-91

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] ヒトデの配偶子放出のメカニズム:ヒトデの放卵・放精はアセチルコリンによるCa2+-influxにより誘起される2020

    • Author(s)
      三田雅敏、大杉知宏、高橋俊雄、渡辺健宏、佐竹炎
    • Journal Title

      Comparative Endocrinology

      Volume: 46 Issue: 170 Pages: 79-81

    • DOI

      10.5983/nl2008jsce.46.79

    • NAID

      130007854007

    • ISSN
      1882-6636, 1882-6644
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection2020

    • Author(s)
      Tsugawa Hitoshi、Kabe Yasuaki、Kanai Ayaka、Sugiura Yuki、Hida Shigeaki、Taniguchi Shun’ichiro、Takahashi Toshio、Matsui Hidenori、Yasukawa Zenta、Itou Hiroyuki、Takubo Keiyo、Suzuki Hidekazu、Honda Kenya、Handa Hiroshi、Suematsu Makoto
    • Journal Title

      PLOS Biology

      Volume: 18 Issue: 9 Pages: 3000813-3000813

    • DOI

      10.1371/journal.pbio.3000813

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Upregulated nicotinic ACh receptor signaling contributes to intestinal stem cell function through activation of Hippo and Notch signaling pathways2020

    • Author(s)
      Takahashi Toshio、Shiraishi Akira、Osawa Masatake
    • Journal Title

      International Immunopharmacology

      Volume: 88 Pages: 106984-106984

    • DOI

      10.1016/j.intimp.2020.106984

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 代謝型ムスカリン性ACh受容体M3は、EphB/ephrin-Bシグナリングを介して腸上皮幹細胞の維持に貢献する2022

    • Author(s)
      高橋俊雄
    • Organizer
      日本発生生物学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 腸の活発な再生・分化を支える非神経性アセチルコリンシグナリング2022

    • Author(s)
      高橋俊雄
    • Organizer
      日本比較内分泌学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Book] BIO Clinica2021

    • Author(s)
      高橋俊雄
    • Total Pages
      4
    • Publisher
      北隆館
    • Related Report
      2021 Research-status Report
  • [Book] Advances Invertebrate (Neuro)Endocrinology2020

    • Author(s)
      Toshio Takahashi
    • Total Pages
      406
    • Publisher
      Apple Academic Press, USA
    • ISBN
      9781771888936
    • Related Report
      2020 Research-status Report
  • [Remarks] 公益財団法人サントリー生命科学財団

    • URL

      http://www.sunbor.or.jp

    • Related Report
      2022 Annual Research Report
  • [Remarks] 公益財団法人サントリー生命科学財団

    • URL

      http://www.sunbor.or.jp/

    • Related Report
      2021 Research-status Report 2020 Research-status Report

URL: 

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

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