Elucidation of regulatory mechanism of non-neuronal acetylcholine as an endogenous regulator of proliferation, differentiation, and maintenance of intestinal stem cells
Description: 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.
Amount: ¥4,940,000
Funding type: research
Funder scheme: Grant-in-Aid for Scientific Research (C)
Start date: 2017-04-01
End date: 2020-03-31
Investigator: Toshio Takahashi
Institution: Suntory Foundation for Life Sciences
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 12
Funder award ID: 17K07495
OpenAlex ID: G1933144283