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Stimulation of the M1 muscarinic acetylcholine receptor induces mucosal growth in the murine small intestine
*Chasen J Greig, *Lucy Zhang, Robert A Cowles
Yale School of Medicine, New Haven, CT

Objective: The role of muscarinic acetylcholine signaling in small intestinal mucosal homeostasis is under active investigation. Using both in-vitro and in-vivo approaches, data suggest a role for cholinergic signaling in mucosal homeostasis and proliferation. We have demonstrated the presence of the muscarinic acetylcholine receptor subtype M1 (M1-mAChR) within the intestinal crypt base in the intestinal stem cell niche. We therefore hypothesized that in-vivo stimulation of this receptor using a specific M1-mAChR agonist would result in intestinal mucosal growth.
Design: With institutional approval, wild-type C57Bl/6 mice were treated with the M1-mAChR-specific agonist McN-A-343. Intestinal segments were then procured and used to make H&E-stained histologic sections. Villus height (VH), crypt depth (CD), villus width (VW) and crypt width (CW) were measured and used to calculate mucosal surface area (MSA). Studentĺs t-test with p<0.05 was considered significant.
Interventions: McN-A-343 was delivered via subcutaneous mini-osmotic pump for seven days. Control mice received saline-filled pumps.
Main Outcome Measures: Morphometric parameters VH, CD, VW and CW were measured and used to determine MSA per mm2 serosa using a previously described mathematical model.
Results: McN-A-343 treatment resulted in significant increases in morphometric parameters and MSA. Values for wild-type vs. McN-A-343-treated mice were as follows: VH - 205▒4Ám vs. 248▒3Ám*, CD - 46▒1Ám vs. 79▒2Ám*, VW - 60▒2Ám vs. 65▒2Ám, CW - 33▒1Ám vs. 36▒1Ám*, and MSA - 39▒2mm2 vs. 48▒2mm2 *. Asterisk = p<0.05.
Conclusions: Stimulation of the M1-mAChR results in intestinal epithelial growth with a corresponding increase in mucosal surface area in the murine intestine. Given the presence of the M1-mAChR in the intestinal stem cell niche, this pathway may mediate proliferative signals between enteric nerves and intestinal stem cells.


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