Abstract
Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11–producing inflammatory fibroblasts. We further identify a transcriptional program associated with trans-differentiation of mucosa-associated fibroblasts and define a functional gene signature associated with matrix deposition and remodeling in the inflamed colon. Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing.
Highlights
Fibroblasts are essential components of parenchymal tissues, providing the framework that is necessary for tissue structure
A cellular census of stromal cells in healthy and inflamed mucosal tissues To better understand the cellular and molecular circuitries operating during inflammation, extracellular matrix (ECM) remodeling, and wound healing in the intestine, we implemented a murine model of colonic inflammation based on oral administration of multiple cycles of low-dose dextran sulfate sodium (DSS) to induce epithelial injury and ECM deposition [22,23]
The frequency of the mucosaassociated fibroblasts (MAFs) 3 population, which expressed a potent inflammatory signature (S2 Table), increased dramatically in response to DSS treatment (P value = 0.04, Methods) (Fig 4E), suggesting that this subcluster may be analogous to the inflammation-associated fibroblasts (IAFs) we recently described in ulcerative colitis patients [21]
Summary
Fibroblasts are essential components of parenchymal tissues, providing the framework that is necessary for tissue structure. Fibroblastic responses controlling mucosal matrix remodeling and healing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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