Abstract
Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle cells may have. Here, we show that smooth muscle cells may be the dominant suppliers of BMP antagonists, which are niche factors essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the membrane-bound matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle cells, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we propose that MMP17 affects intestinal epithelial reprogramming after damage indirectly by cleaving diffusible factor(s) such as the matricellular protein PERIOSTIN. Together, we identify an important signaling axis that establishes a role for smooth muscle cells as modulators of intestinal epithelial regeneration and the intestinal stem cell niche.
Highlights
Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements
We found little evidence that intestinal smooth muscle expressed niche factors such as WNTs and RSPOs, or growth factors such as epidermal growth factor (EGF), we did find that smooth muscle expresses high levels of factors associated with Bone morphogenic proteins (BMPs) signaling including Grem[1], Grem[2], and Chrdnl[1] (Figs. 1b, S1b)
Fluorescent in situ hybridization (FISH) confirmed high levels of these factors in a muscle-specific manner, in particular, we found enrichment of these factors in the muscularis mucosa that resides in close proximity to the bottom of epithelial crypts (Fig. 1c)
Summary
Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. Adult intestinal epithelial (stem cell) maintenance relies on a variety of niche factors such as WNTs, R-spondins (RSPOs), Bone morphogenic proteins (BMPs), and prostaglandins, all of which are expressed by mesenchymal cell subtypes[8,9,10,11,12,13]. These mesenchymal cells reside in the intestinal lamina propria between the epithelium and the muscularis mucosae. We show that MMP17, a membrane-bound MMP which is expressed in smooth muscle, is important to maintain optimal ISC stemness during homeostasis, and preserve the regenerative capacity of intestinal epithelium
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