Intestinal stromal cells secrete the CCL19, CCL21, and CXCL13 chemokines to promote isolated lymphoid follicle formation and B cell recruitment. Recent studies have provided foundational insights into how fibroblasts mediate immune activation and inflammation, thus expanding their roles in tissue homeostasis. 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. This functional compartmentalization is also reinforced through matrix-dependent signaling cues to neighboring cells that collectively contribute to crypt architecture. 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. This concept is exemplified in the gut, where fibroblasts have been shown to support mucosal crypt architecture, extracellular matrix (ECM) remodeling, and immune fitness. 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. Uniform manifold approximation and projection UMI,įibroblasts are essential components of parenchymal tissues, providing the framework that is necessary for tissue structure. Insulin growth factor binding protein ISH, is a cofounder of Celsius Therapeutics and Jnana Therapeutics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.J.X. was supported by the Ford Foundation Fellowship and an NIH T32 grant (2T32DK007191-42). Source code for the analyses is deposited in GitHub ( ).įunding: 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. Raw data is available at GEO (Accession Number: GSE172261). 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.ĭata Availability: Processed and raw data will be available on the Single Cell Portal. Received: JAccepted: JanuPublished: January 27, 2022Ĭopyright: © 2022 Jasso et al. PLoS Biol 20(1):Īcademic Editor: Connie J. (2022) Colon stroma mediates an inflammation-driven fibroblastic response controlling matrix remodeling and healing. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing.Ĭitation: Jasso GJ, Jaiswal A, Varma M, Laszewski T, Grauel A, Omar A, et al. 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. 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. 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. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. 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.
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