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

PLoS Biol
Authors
Keywords
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.

Year of Publication
2022
Journal
PLoS Biol
Volume
20
Issue
1
Pages
e3001532
Date Published
2022 01
ISSN
1545-7885
DOI
10.1371/journal.pbio.3001532
PubMed ID
35085231
PubMed Central ID
PMC8824371
Links
Grant list
P30 DK043351 / DK / NIDDK NIH HHS / United States
RC2 DK114784 / DK / NIDDK NIH HHS / United States
T32 DK007191 / DK / NIDDK NIH HHS / United States