Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing.
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ABSTRACT:
SUBMITTER: Margadant C
PROVIDER: S-EPMC2828749 | biostudies-other | 2010 Feb
REPOSITORIES: biostudies-other
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Project description:Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a devastating skin blistering disease caused by mutations in the gene encoding type VII collagen (C7), leading to epidermal fragility, trauma-induced blistering, and long term, hard-to-heal wounds. Fibrosis develops rapidly in RDEB skin and contributes to both chronic wounds, which emerge after cycles of repetitive wound and scar formation, and squamous cell carcinoma-the single biggest cause of death in this patient group. The molecular pathways disrupted in a broad spectrum of fibrotic disease are also disrupted in RDEB, and squamous cell carcinomas arising in RDEB are thus far molecularly indistinct from other sub-types of aggressive squamous cell carcinoma (SCC). Collectively these data demonstrate RDEB is a model for understanding the molecular basis of both fibrosis and rapidly developing aggressive cancer. A number of studies have shown that RDEB pathogenesis is driven by a radical change in extracellular matrix (ECM) composition and increased transforming growth factor-beta (TGFβ) signaling that is a direct result of C7 loss-of-function in dermal fibroblasts. However, the exact mechanism of how C7 loss results in extensive fibrosis is unclear, particularly how TGFβ signaling is activated and then sustained through complex networks of cell-cell interaction not limited to the traditional fibrotic protagonist, the dermal fibroblast. Continued study of this rare disease will likely yield paradigms relevant to more common pathologies.
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Project description:Our objective was to identify genes upregulated by TGF-beta in control and Ezh2 cKO decidual stromal cells (DSCs), and to compare this set of genes with a previously identified gene set of H3K27me3-marked decidual genes that are putatively silenced by EZH2/PRC2 (Nancy et al. JCI. 2018). We also wanted to assess baseline (BL) gene expression in control and Ezh2 cKO DSCs, and compare it to an RNA-seq analysis of differential gene expression in whole tissue Ezh2 cKO and control decidua. RNA was isolated from untreated and TGF-beta treated decidual stromal cells from control and Ezh2 cKO mice. Sequencing provided was 706 million total reads with an average of 82.2% of these reads aligning uniquely to the mouse genome. Reads uniquely mapped to known mRNAs were used to identify gene expression changes between housing conditions using DESeq2. TGF-beta induced 638 protein-coding genes in EZH2-deficient DSCs versus 480 in control DSCs (with a 295 gene overlap), demonstrating that EZH2-deficient DSCs are transcriptionally more responsive to TGF- (P=0.0025, Fisher’s exact test). Within the 638 genes, activated fibroblast signature genes were highly over-represented. TGF-target genes were 2.7-fold over-represented within the set of genes with higher expression in EZH2-deficient DSCs at baseline (BL; i.e., when neither EZH2-deficient nor control DSCs were treated with TGF-beta; P<1x10-20) . 741 genes were overexpressed in Ezh2 cKO DSCs compared to control DSCs, and 904 genes were underexpressed. Moreover, by comparing to our laboratory's previous CHIP-Seq analysis (Nancy et al. JCI 2018), we noted that genes overexpressed in cKO mice were enriched in previously identified H3K27me3-marked genes (P<1x10-26).
2022-01-11 | GSE171724 | GEO
Project description:AIMS:To evaluate the expression of transforming growth factor beta1 (TGF-beta1) and fibroblast growth factor 2 (FGF-2) mRNA in stromal cells in response to injury in the presence of either TGF-beta1 or FGF-2. It has been shown previously that heparan sulfate proteoglycans and FGF-2 are present transiently during wound repair in vivo and that an increase in TGF-beta1 mRNA is detected rapidly after injury. METHODS:Primary corneal fibroblasts were cultured to confluency, serum starved, and linear wound(s) were made in medium containing TGF-beta1 or FGF-2. TGF-beta1 and FGF-2 mRNA expression were evaluated using both northern blot analysis and in situ hybridisation. Both dose dependent and time course experiments were performed. Whole eye organ culture experiments were also carried out and growth factor expression was assessed. RESULTS:Injury and exogenous TGF-beta1 increased TGF-beta1 mRNA values. The increase in expression of FGF-2 mRNA was not detected until wound closure. In contrast, FGF-2 inhibited the expression of TGF-beta1. TGF-beta1 increased TGF-beta1 mRNA stability but did not alter that of FGF-2. Migration assay data demonstrated that unstimulated stromal cells could be activated to migrate to specific growth factors. CONCLUSIONS:TGF-beta1 specifically enhances cellular responsiveness, as shown by increased stability after injury and the acquisition of a migratory phenotype. These data suggest that there is an integral relation during wound repair between TGF-beta1 and FGF-2.
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