Open AccessColon stroma mediates an inflammation-driven fibroblastic response controlling matrix remodeling and healing
Author(s) -
Guadalupe J. Jasso,
Alok Jaiswal,
Mukund Varma,
Tyler Laszewski,
Angelo L. Grauel,
Abdifatah Omar,
Nilsa Silva,
Glenn Dranoff,
Jeffrey A. Porter,
Keith G. Mansfield,
Viviana Cremasco,
Aviv Regev,
Ramnik J. Xavier,
Daniel B. Graham
Publication year - 2022
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001532
Subject(s) - fibrosis , inflammation , biology , extracellular matrix , stromal cell , wound healing , mesenchymal stem cell , matrix metalloproteinase , microbiology and biotechnology , pathology , cancer research , immunology , medicine , genetics
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.