Intestinal stromal cell types in health and inflammatory bowel disease uncovered by single-cell transcriptomics
<p>Colonic stromal cells provide critical structural support but also regulate immunity, tolerance and inflammatory responses in the mucosa. Substantial variability and plasticity of mucosal stromal cells has been reported but a paucity of distinct marker genes exist to identify distinct cell...
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| Format: | Thesis |
| Language: | English |
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2017
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| Summary: | <p>Colonic stromal cells provide critical structural support but also regulate immunity, tolerance and inflammatory responses in the mucosa. Substantial variability and plasticity of mucosal stromal cells has been reported but a paucity of distinct marker genes exist to identify distinct cell states. Here single-cell RNA-sequencing is used to document heterogeneity and subtype specific markers of individual colonic stromal cells in human and mouse.</p> <p>Marker-free transcriptional clustering of fibroblast-like cells derived from healthy human tissue reveals distinct populations corresponding to myofibroblasts and three transcriptionally and functionally dissimilar populations of fibroblasts. A <em>SOX6</em> high fibroblast subset occupies a position adjacent to the epithelial basement membrane and expresses multiple epithelial morphogens including WNT5A and BMP2. Additional fibroblast subtypes show specific enrichment for chemokine signalling and prostaglandin E<sub>2</sub> synthesis respectively.</p> <p>In ulcerative colitis, substantial remodelling occurs with depletion of the SOX6 high population and emergence of an immune enriched population expressing genes associated with fibroblastic reticular cells including <em>CCL19, CCL21</em> and <em>IL33</em>.</p> <p>A large murine dataset comprising over 7,000 colonic mesenchymal cells from an acute colitis model and matched healthy controls reveals strong preservation of the <em>SOX6</em> high and myofibroblast transcriptional signatures. Unsupervised pseudotemporal ordering is used to relate fibroblast subsets to one another producing a branched developmental hierarchy that includes a potential progenitor population with mesothelial characteristics at its origin. This work provides a molecular basis for re-classification of colonic stromal cells and identifies pathological changes in these cells underpinning inflammation in UC.</p> |
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