Abstract
Acetylcholine (ACh) signaling through activation of nicotinic and muscarinic ACh receptors regulates expression of specific genes that mediate and sustain proliferation, differentiation, and homeostasis in the intestinal crypts. This signaling plays a pivotal role in the regulation of intestinal stem cell function, but the details have not been clarified. Here, we performed experiments using type 3 muscarinic acetylcholine receptor (M3) knockout mice and their intestinal organoids and report that endogenous ACh affects the size of the intestinal stem niche via M3 signaling. RNA sequencing of crypts identified up-regulation of the EphB/ephrin-B signaling pathway. Furthermore, using an MEK inhibitor (U0126), we found that mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, which is downstream of EphB/ephrin-B signaling, is activated in M3-deficient crypts. Collectively, M3, EphB/ephrin-B, and the MAPK/ERK signaling cascade work together to maintain the homeostasis of intestinal epithelial cell growth and differentiation following modifications of the cholinergic intestinal niche.
Highlights
The ability of intestinal stem cells (ISCs) to divide and differentiate is necessary for tissue repair and homeostasis
We have reported that endogenous ACh released from the intestinal epithelium maintains homeostasis of intestinal epithelial cell growth and differentiation via M3 (Takahashi et al, 2014)
We found that a deficiency in M3 caused an intestinal phenotype, which was an increase in crypt size and ISC proliferation and differentiation, without differences in the size of the small intestine despite the reduction in somatic growth of M3−/− mice
Summary
The ability of intestinal stem cells (ISCs) to divide and differentiate is necessary for tissue repair and homeostasis. The ISC niche in the small intestine is composed of stem cells and Paneth cells, and is surrounded by mesenchymal cells at the crypt bottom (Sato et al, 2011; Tian et al, 2011). Marked leucine-rich repeatcontaining G-protein coupled receptor 5 (Lgr5)–expressing ISCs temporarily produce undifferentiated cells that divide rapidly while moving toward the intestinal lumen (Batlle et al, 2002). During migration, these cells differentiate into mature cells such as goblet cells, tuft cells, enteroendocrine cells, and absorptive cells (enterocytes) (Potten & Loeffler, 1990; Stappenbeck et al, 1998; McKinley et al, 2017). These special mechanisms are important for life-long steady-state maintenance of the epithelium (Sangiorgi & Capecchi, 2008; Voog & Jones, 2010; Takeda et al, 2011; Tian et al, 2011)
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