Abstract
Organs are anatomically compartmentalised to cater for specialised functions. In the small intestine (SI), regionalisation enables sequential processing of food and nutrient absorption. While several studies indicate the critical importance of non-epithelial cells during development and homeostasis, the extent to which these cells contribute to regionalisation during morphogenesis remains unexplored. Here, we identify a mesenchymal-epithelial crosstalk that shapes the developing SI during late morphogenesis. We find that subepithelial mesenchymal cells are characterised by gradients of factors supporting Wnt signalling and stimulate epithelial growth in vitro. Such a gradient impacts epithelial gene expression and regional villus formation along the anterior-posterior axis of the SI. Notably, we further provide evidence that Wnt signalling directly regulates epithelial expression of Sonic Hedgehog (SHH), which, in turn, acts on mesenchymal cells to drive villi formation. Taken together our results uncover a mechanistic link between Wnt and Hedgehog signalling across different cellular compartments that is central for anterior-posterior regionalisation and correct formation of the SI.
Highlights
Organs are anatomically compartmentalised to cater for specialised functions
We focused our further studies on the PDGFRahigh population, due to its immediate vicinity to the developing epithelium, and the PDGFRamed population that represents a “bulk” mesenchymal signature
RNA-sequencing showed elevated expression of genes associated with muscle function such as Acta[2], Myl[4], and Des (CD29high vs PDGFRamed (log2(fold change) > 0.5 and FDR < 0.05)) and gene ontology (GO) analysis displayed enrichment for genes involved in muscle system process and muscle contraction (Supplementary Fig. 1b, c and Supplementary Data 1 and 2)
Summary
Organs are anatomically compartmentalised to cater for specialised functions. In the small intestine (SI), regionalisation enables sequential processing of food and nutrient absorption. We find that subepithelial mesenchymal cells are characterised by gradients of factors supporting Wnt signalling and stimulate epithelial growth in vitro Such a gradient impacts epithelial gene expression and regional villus formation along the anterior-posterior axis of the SI. The SI sub-regions - duodenum, jejunum and ileum - have characteristic cell types and tissue architecture that reflect their specialised functions in digestion and nutrient absorption. These regional traits emerge during late morphogenesis when a simple intestinal tube morphs into a more complex system with undulating structures. We show that a functionally distinct PDGFRahigh mesenchymal cell population supports gradient activation of canonical Wnt signalling in the epithelium and uncover region-specific roles for the Wnt pathway in SI development. Taken together our results reveal a new level of mesenchymal-epithelial crosstalk which promotes villus formation and shapes SI development
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