(C) PLOS One [1]. This unaltered content originally appeared in journals.plosone.org.
Licensed under Creative Commons Attribution (CC BY) license.
url:https://journals.plos.org/plosone/s/licenses-and-copyright

------------



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

['Guadalupe J. Jasso', 'Broad Institute Of Mit', 'Harvard', 'Cambridge', 'Massachusetts', 'United States Of America', 'Harvard Medical School', 'Boston', 'Alok Jaiswal', 'Mukund Varma']

Date: 2022-02 

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.

Funding: This study was supported by NIH grant (RC2 DK114784 to R.J.X., D.B.G., and A.R; DK043351 to R.J.X.) and the Klarman Cell Observatory. G.J.J. was supported by the Ford Foundation Fellowship and an NIH T32 grant (2T32DK007191-42). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2022 Jasso et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Here, we employed orthogonal technologies, including next generation sequencing of mucosa-associated stroma to survey cellular heterogeneity in the colon. We identified phenotypic and functionally divergent fibroblast populations in mucosal tissues of the gastrointestinal tract and uncovered molecular circuitries governing inflammation and ECM remodeling during colitis, identifying a key role for Adamdec1 in mucosal matrix remodeling and healing.

The coexistence of distinct subsets of fibroblasts is thought to account for their pleiotropic properties in supporting gut homeostasis and disease pathogenesis. Uncovering the heterogeneity of fibroblasts, however, has been hindered by a dearth of molecular tools available for experimental assessment, including molecular markers and transgenic mouse models. Recent advances in technologies such as single-cell RNA-sequencing (scRNA-seq) now permit the survey of stromal cell heterogeneity across organs [ 16 – 21 ].

The gastrointestinal tract represents a potential vantage point to study fibroblast-imposed immunoregulation, as it constitutes the largest reservoir of immune cells within the human body, ensuring protection from pathogenic infections while promoting mucosal tolerance against commensal microbes. Recent studies have provided foundational insights into how fibroblasts mediate immune activation and inflammation, thus expanding their roles in tissue homeostasis [ 10 , 11 ]. Intestinal stromal cells secrete the CCL19, CCL21, and CXCL13 chemokines to promote isolated lymphoid follicle formation and B cell recruitment [ 12 , 13 ]. Additionally, fibroblasts secrete proinflammatory cytokines within colon tissues from Crohn’s disease patients, establishing that these cells are important contributors of inflammation in the gut [ 14 ]. However, how these diverse functions are regulated by intestinal fibroblasts is incompletely understood. In particular, it remains unclear how mesenchymal cells in the gut may imprint on the ensuing inflammatory response, while also driving excessive production of ECM components that ultimately lead to fibrosis, a hallmark of chronic inflammation in mucosal tissue and a prominent cause of morbidity in diseases like inflammatory bowel disease (IBD) [ 15 ]. It is thus not known how inflammation in pathologies like IBD results in the progressive accumulation of ECM that compromises normal intestinal functions [ 15 ].

This concept is exemplified in the gut, where fibroblasts have been shown to support mucosal crypt architecture, extracellular matrix (ECM) remodeling, and immune fitness [ 4 – 6 ]. By secreting factors like Wnt ligands and bone morphogenetic protein (BMP) antagonists, fibroblasts are critical in supporting colon crypt architecture, creating discrete anatomical zones that maintain the epithelial stem cell niche in defined areas, while supporting epithelial cell differentiation and inhibition of cell proliferation in others [ 2 , 6 , 7 ]. This functional compartmentalization is also reinforced through matrix-dependent signaling cues to neighboring cells that collectively contribute to crypt architecture [ 8 , 9 ].

Fibroblasts are essential components of parenchymal tissues, providing the framework that is necessary for tissue structure. However, emerging evidence has revealed critical functions for fibroblast cells that extend beyond their traditional roles as structural scaffolds, including roles in regulating cell survival, differentiation, and migration [ 1 – 3 ].

Results

[END]

[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001532

(C) Plos One. "Accelerating the publication of peer-reviewed science."
Licensed under Creative Commons Attribution (CC BY 4.0)
URL: https://creativecommons.org/licenses/by/4.0/


via Magical.Fish Gopher News Feeds:
gopher://magical.fish/1/feeds/news/plosone/