Dataset Information

IL17-producing gamma T cells modulate murine tissue fibrosis through stromal cell interactions

ABSTRACT: Tissue injury responses are governed by dynamic immune-stromal crosstalk that can promote productive tissue repair or drive dysregulated extracellular matrix (ECM) production and aberrant vascular remodeling, culminating in fibrosis. Here, we investigate how gamma T cells interact with stromal cells to shape tissue fibrosis using a preclinical model of the biomaterial foreign body response that induces a reproducible, dense fibrotic encapsulation. A mixed population of tissue-resident and migratory gamma delta T cells, consisting of type-1 (gamma delta IFN gamma) and multiple type-17 (gamma delta 17) effector subsets, accumulated at the biomaterial implantation site during the early inflammatory phase of wound healing. While the gamma delta IFN gamma later contracted as tissue fibrosis progressed, the activated gamma delta 17 persisted and served as a dominant source of interleukin (IL)-17. Aging and exposure to a high-fat diet, both factors associated with chronic inflammation and pathological fibrosis, further heightened the gamma delta 17 response. The gamma delta 17 secreted bioactive factors that stimulated fibroblast expression of pro-inflammatory and collagen genes in a Transwell co-culture assay. Computational inference of intercellular communication further linked cytokines and growth factors expressed by gamma delta T cells to the activation of fibroblast and endothelial cell transcription factors involved in ECM remodeling and vascular development, respectively. The elimination of gamma delta T cells with a TCR delta knockout strain resulted in differential expression of ECM and skeletal muscle components as well as altered blood vessel structure within the fibrotic matrix. Altogether, our results propose that signaling from gamma delta T cells can affect stromal cell phenotypes, ultimately influencing the composition and vascularity of fibrotic tissue.

INSTRUMENT(S): timsTOF HT

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Birgit Schilling

PROVIDER: MSV000098194 | MassIVE | Fri Jun 13 14:58:00 BST 2025

SECONDARY ACCESSION(S): PXD065015

REPOSITORIES: MassIVE

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: Fibrosis is a pathological scarring process characterized by persistent myofibroblasts activation with excessive accumulation of extracellular matrix (ECM). Fibrotic disorders represent an increasing burden of disease-associated morbidity and mortality worldwide for which there are limited therapeutic options. Reversing fibrosis requires the elimination of myofibroblasts, remodeling of the ECM, and regeneration of functional tissue. Multipotent mesenchymal stromal cells (MSC) have antifibrotic properties mediated by secreted factors present in their conditioned medium (MSC-CM). However, there are no standardized in vitro assays to predict the antifibrotic effects of human MSC, and, as a consequence, we lack evidence on the effect of cytokine priming on MSC’s antifibrotic effects. We hypothesize that the MSC-CM promotes fibrosis resolution in vitro and that this effect is enhanced following MSC cytokine priming. Methods: We tested the antifibrotic effects of resting and interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) primed MSC-CM in three in vitro assays: prevention of fibroblast activation, myofibroblasts deactivation and ECM degradation. Furthermore, we performed transcriptomic analysis of myofibroblasts treated or not with resting- or primed-MSC-CM and proteomic characterization of resting- and primed-MSC-CM. Results: We report that MSC-CM treatment prevented TGF-β induced fibroblast activation and reduced fibrogenic myofibroblasts (i.e. transcriptomic upregulation of apoptosis, senescence, and inflammatory pathways). These effects were higher when primed rather than resting MSC-CM was used. Priming increased the ability of MSC-CM to remodel the extracellular matrix reducing its content of collagen I and fibronectin. Priming increased the following antifibrotic proteins in MSC-CM: DKK1, MMP-1, MMP-3, follistatin and cathepsin S. DKK1 inhibition reduced the anti-fibrotic effects of MSC-CM. Thus, cytokine priming increases antifibrotic factors in the MSC-CM which in turn amplify the anti-fibrotic effects of MSC-CM. Conclusions: In a pro-fibrotic in vitro environment MSC-CM promote fibrosis resolution, an effect enhanced following MSC cytokine priming. Specifically, MSC-CM reduces fibrogenic myofibroblasts through apoptosis, senescence, and inflammatory signals, as well as by enhancing ECM degradation. Future studies will establish the in vivo relevance of MSC priming to fibrosis resolution

Project description:Dupuytren's disease (DD) is a classic example of pathological fibrosis which results in a debilitating disorder affecting a large sector of the human population. It is characterized by excessive local proliferation of fibroblasts and over-production of collagen and other components of the extracellular matrix (ECM) in the palmar fascia. The fibrosis progressively results in contracture of elements between the palmar fascia and skin causing flexion deformity or clawing of the fingers and a severe reduction in hand function. While much is known about the pathogenesis and surgical treatment of DD, little is known about the factors that cause its onset and progression, despite many years of research. Gene expression patterns in DD patients now offers the potential to identify genes that direct the pathogenesis of DD. In this study, we used primary cultures of fibroblasts derived from excisional biopsies of fibrotic tissue from DD patients to compare the gene expression profiles on a genome-wide basis with normal control fibroblasts. Our investigations have identified genes that may be involved with DD pathogenesis including some which are directly relevant to fibrosis. In particular, these include significantly reduced expression levels of three matrix metallopeptidases (MMP1, MMP3, MMP16), follistatin, and STAT1, and significantly increased expression levels of fibroblast growth factors (FGF9, FGF11), a number of collagen genes and other ECM genes in DD patient samples. Many of these gene products are known to be involved in fibrosis, tumour formation and in the normal processes of tissue remodelling. In addition, alternative splicing was identified in some DD-associated genes. These highly sensitive genomic investigations provide new insight into the molecular mechanisms that may underpin the development and progression of DD. Four exon arrays of DD primary fibroblasts derived from fibrotic tissue were compared to fibroblasts derived from skin punch biopsies from individuals who did not show DD symptoms.

Dataset Information

IL17-producing gamma T cells modulate murine tissue fibrosis through stromal cell interactions

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets