Journal Article

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

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

2022

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ADAM Proteins - deficiency / ADAM Proteins - genetics / ADAM Proteins - immunology / Angiogenesis / Animals / Biology and Life Sciences / Cell Differentiation / Colitis / Colitis - chemically induced / Colitis - genetics / Colitis - immunology / Colitis - pathology / Collagen / Colon / Colon - immunology / Colon - pathology / Crohn's disease / Crohns disease / Deposition / Extracellular matrix / Extracellular Matrix - immunology / Extracellular Matrix - metabolism / Fibroblasts / Fibroblasts - immunology / Fibroblasts - pathology / Fibrosis / Gene Expression Regulation / Gene sequencing / Genes / Healing / Health aspects / Heterogeneity / Homeostasis / Humans / Inflammation / Inflammatory bowel disease / Interleukin 11 / Interleukin-11 - genetics / Interleukin-11 - immunology / Interleukins / Intestinal Mucosa - immunology / Intestinal Mucosa - pathology / Male / Medicine and Health Sciences / Mesenchymal Stem Cells - immunology / Mesenchymal Stem Cells - pathology / Mesenchyme / Metalloproteinase / Mice / Mice, Inbred C57BL / Roles / Sequence Analysis, RNA / Single-Cell Analysis / Sodium Dodecyl Sulfate - administration & dosage / Stromal cells / Transcription, Genetic / Transcriptome / Wound healing / Wound Healing - genetics / Wound Healing - immunology