Elucidation of regulatory mechanism of non-neuronal acetylcholine as an endogenous regulator of proliferation, differentiation, and maintenance of intestinal stem cells

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07495
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Animal physiology/Animal behavior
• Research Institution: Suntory Foundation for Life Sciences
• Principal Investigator: Takahashi Toshio 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, 主席研究員 (20390792)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 細胞・組織 / シグナル伝達 / 生理学 / 発生・分化 / 非神経性アセチルコリン / オルガノイド / 腸幹細胞

Outline of Final Research Achievements

Non-neuronal ACh is predicted to function as a local cell signaling molecule. However, the physiological significance of non-neuronal ACh in the intestine remains unclear. Here, experiments using cultured crypt-villus organoids that lack nerve cell led us to suggest that endogenous ACh is synthesized in the intestinal epithelium to evoke growth and differentiation of the organoids through activation of muscarinic and nicotinic ACh receptors. Genetic ablation of M3 muscarinic receptors (M3R) showed enhanced proliferation and differentiation of Lgr5-positive stem cells (ISCs) through activation of Ephrin-b/EphB signaling pathway. Furthermore, we found that endogenous ACh binds to the α2β4 nicotinic ACh receptor subtype, and induces Wnt signaling, and eventually proliferation and differentiation of Lgr5-positive ISCs are enhanced. The characterization of these pathways may clarify the mechanisms underlying developmental processes in the crypt-villus unit.

Free Research Field

動物生理学

Academic Significance and Societal Importance of the Research Achievements

神経伝達物質としてのAChが“非神経系では正常な腸幹細胞の分化・増殖、維持に関与する新規シグナル分子である”という新たなパラダイムの提唱に繋がる。そして、AChは生物進化の初期段階から存在し、細胞間の情報伝達は低分子の化合物によって行われていたと考えられる。翻って、AChによる細胞の基本的性質（分化・増殖、維持）の制御メカニズムは、今でも様々な生物種に保存されている可能性が考えられる。