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Non‐neuronal acetylcholine as an endogenous regulator of proliferation and differentiation of Lgr5‐positive stem cells in mice
Author(s) -
Takahashi Toshio,
Ohnishi Hiroe,
Sugiura Yuki,
Honda Kurara,
Suematsu Makoto,
Kawasaki Takashi,
Deguchi Tomonori,
Fujii Takeshi,
Orihashi Kaoru,
Hippo Yoshitaka,
Watanabe Takehiro,
Yamagaki Tohru,
Yuba Shunsuke
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12974
Subject(s) - regulator , lgr5 , endogeny , microbiology and biotechnology , acetylcholine , stem cell , biology , neuroscience , endocrinology , genetics , cancer stem cell , gene
Non‐neuronal acetylcholine ( AC h) is predicted to function as a local cell signaling molecule. However, the physiological significance of the synthesis of non‐neuronal AC h in the intestine remains unclear. Here, experiments using crypt–villus organoids that lack nerve and immune cells in culture led us to suggest that endogenous AC h is synthesized in the intestinal epithelium to evoke growth and differentiation of the organoids through activation of muscarinic AC h receptors (m AC hRs). The extracts of the cultured organoids showed a noticeable capacity for AC h synthesis that was sensitive to a potent inhibitor of choline acetyltransferase. Imaging MS revealed endogenous AC h localized in the epithelial layer in mouse small intestinal epithelium in vivo , suggesting that there are non‐neuronal resources of AC h. Treatment of organoids with carbachol downregulated the growth of organoids and the expression of marker genes for epithelial cells. On the other hand, antagonists for m AC hRs enhanced the growth and differentiation of organoids, indicating the involvement of m AChR s in regulating the proliferation and differentiation of Lgr5‐positive stem cells. Collectively, our data provide evidence that endogenous AC h released from intestinal epithelium maintains homeostasis of intestinal epithelial cell growth and differentiation via m AC hRs in mice.