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Title: Intestinal stromal cell types in health and inflammatory bowel disease uncovered by single-cell transcriptomics
Author: Kinchen, James
ISNI:       0000 0004 7234 2245
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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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. 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 SOX6 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 E2 synthesis respectively. 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 CCL19, CCL21 and IL33. 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 SOX6 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.
Supervisor: Simmons, Alison Sponsor: Lee Placito Memorial Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Inflammatory bowel diseases ; Mesenchymal stem cells--Differentiation ; single cell RNA sequencing ; ulcerative colitis