Colon stroma mediates an inflammation-driven fibroblastic response controlling matrix remodeling and healing.
ADAM Proteins
/ deficiency
Animals
Cell Differentiation
Colitis
/ chemically induced
Colon
/ immunology
Extracellular Matrix
/ immunology
Fibroblasts
/ immunology
Fibrosis
Gene Expression Regulation
Humans
Inflammation
Interleukin-11
/ genetics
Intestinal Mucosa
/ immunology
Male
Mesenchymal Stem Cells
/ immunology
Mice
Mice, Inbred C57BL
Sequence Analysis, RNA
Single-Cell Analysis
Sodium Dodecyl Sulfate
/ administration & dosage
Transcription, Genetic
Transcriptome
Wound Healing
/ genetics
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
28
07
2021
accepted:
07
01
2022
revised:
08
02
2022
pubmed:
28
1
2022
medline:
3
3
2022
entrez:
27
1
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35085231
doi: 10.1371/journal.pbio.3001532
pii: PBIOLOGY-D-21-02023
pmc: PMC8824371
doi:
Substances chimiques
Interleukin-11
0
Sodium Dodecyl Sulfate
368GB5141J
ADAM Proteins
EC 3.4.24.-
Adamdec1 protein, mouse
EC 3.4.24.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3001532Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK043351
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK114784
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007191
Pays : United States
Déclaration de conflit d'intérêts
I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.J.X. is a cofounder of Celsius Therapeutics and Jnana Therapeutics.
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