Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease

Abstract

SummaryIntestinal mesenchymal cells play essential roles in epithelial homeostasis, matrix remodeling, immunity, and inflammation. But the extent of heterogeneity within the colonic mesenchyme in these processes remains unknown. Using unbiased single-cell profiling of over 16,500 colonic mesenchymal cells, we reveal four subsets of fibroblasts expressing divergent transcriptional regulators and functional pathways, in addition to pericytes and myofibroblasts. We identified a niche population located in proximity to epithelial crypts expressing SOX6, F3 (CD142), and WNT genes essential for colonic epithelial stem cell function. In colitis, we observed dysregulation of this niche and emergence of an activated mesenchymal population. This subset expressed TNF superfamily member 14 (TNFSF14), fibroblastic reticular cell-associated genes, IL-33, and Lysyl oxidases. Further, it induced factors that impaired epithelial proliferation and maturation and contributed to oxidative stress and disease severity in vivo. Our work defines how the colonic mesenchyme remodels to fuel inflammation and barrier dysfunction in IBD.

Gut-Liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids

“…However, monolayers of UC, but not healthy gut MPSs, showed enlargement of hyperchromatic nuclei and irregular actin fragmentation, indicators of IBD dysplasia ( Fig.1E) (32). These morphological findings are consistent with observation that differentially-expressed genes ( Fig.1B,C) include those associated with regulation of actin, focal adhesions and cell junction, which are indicative of IBD-associated remodeling (33).…”

Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease

“…Using the previously described CellPhoneDB algorithm (Efremova et al, unpublished Vento-Tormo et al, 2018), we found that the three mesenchymal populations displaying the highest number of cell-type specific interactions with epithelial cell types were FOXL1+ and WNT4+ fibroblasts and UPK3B+ serosal cells ( Figure 4A). In our dataset, FOXL1+ fibroblasts expressed developmentally related genes such as DLL1 (Notch signaling ligand) and platelet derived growth factor receptor (PDGFR) (Karlsson et al, 2000;Kurahashi et al, 2008) as well as adult colonic mucosal S1 fibroblast markers including F3 and ADAMDEC1 (Kinchen et al, 2018). At 6 PCW, FOXL1 expressing fibroblasts were located in close proximity to the intestinal epithelium, as confirmed in situ using RNAscope ( Figure 4B).…”

Lgr5+ telocytes are a signaling hub at the intestinal villus tip

“…A second mechanism could be a zonated response to spatial gradients of nutrients and bacteria at the luminal sides of the tissue. Yet a third mechanism could entail zonated molecular cues that originate in the lamina propria, the underlying stroma at the basal sides of the epithelial layer [7][8][9][10] . Here, we use spatially-resolved transcriptomics to characterize the zonated stromal gene expression signatures along the crypt-villus axis.…”