Title: Colon stroma mediates an inflammation-driven fibroblastic response controlling matrix remodeling and healing

Manuscript 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. We identify a transcriptional program associated with trans-differentiation of mucosal-associated fibroblasts to myofibroblasts, 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.

Contributed by: Guadalupe J. Jasso*, Alok Jaiswal*, Mukund Varma, Tyler Laszewski, Angelo Grauel, Abdifatah Omar, Nilsa Silva, Glenn Dranoff, Jeffrey A. Porter, Keith Mansfield, Viviana Cremasco, Aviv Regev, Ramnik J. Xavier, Daniel B. Graham

Tissue Type(s): Mouse colon stroma

Original Publication: Not published as of Jan 2, 2022.