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PROVIDER: PRJNA1061800 | ENA |
REPOSITORIES: ENA
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Project description:Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)
| PRJNA1060624 | ENA
Project description:Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)
| PRJNA1057863 | ENA
Project description:Fibrotic diseases impose a major socioeconomic challenge on modern societies with limited treatment options. Adropin, a peptide hormone encoded by the energy-homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize Adropin/ENHO as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent downregulation of Adropin/ENHO in SSc skin across different SSc cohorts. The prototypical profibrotic cytokine TGFβ reduced Adropin/ENHO expression in a JNK-dependent manner. Restoration of Adropin signaling by therapeutic application of bioactive Adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, the mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices (PCSS). Knockdown of GPR19, receptor of Adropin, abrogated the antifibrotic effects of Adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of Adropin34-76 were functionally linked to deactivation of GLI1 dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo and ex vivo. ChIP-seq confirmed Adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study thus characterizes the TGFβ-induced downregulation of Adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling. We also provide evidence in multiple preclinical models that Adropin34-76 might offer potential for the treatment of fibrosis.
2024-04-29 | GSE252139 | GEO
Project description:Fibrotic diseases impose a major socioeconomic challenge on modern societies with limited treatment options. Adropin, a peptide hormone encoded by the energy-homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize Adropin/ENHO as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent downregulation of Adropin/ENHO in SSc skin across different SSc cohorts. The prototypical profibrotic cytokine TGFβ reduced Adropin/ENHO expression in a JNK-dependent manner. Restoration of Adropin signaling by therapeutic application of bioactive Adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, the mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices (PCSS). Knockdown of GPR19, receptor of Adropin, abrogated the antifibrotic effects of Adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of Adropin34-76 were functionally linked to deactivation of GLI1 dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo and ex vivo. ChIP-seq confirmed Adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study thus characterizes the TGFβ-induced downregulation of Adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling. We also provide evidence in multiple preclinical models that Adropin34-76 might offer potential for the treatment of fibrosis.
2024-04-29 | GSE252425 | GEO
Project description:The activation of Runt-related transcription factor 1 (RUNX1) in fibroblasts has been implicated in wound healing and fibrosis; however, the role of RUNX1 in the fibrotic progression of the autoimmune disease systemic sclerosis (SSc) is not known. Leveraging gene expression, genome-wide DNA methylation, and single-cell resolution data of SSc skin and fibroblast, we analyzed the impact of RUNX1 dysregulation in SSc dermal fibrosis. RUNX1 function was subsequently assessed using siRNA, pharmacologic inhibition, and CRISPR knockout in 2D and 3D fibroblasts cultures. Analysis of gene expression in multiple cohorts demonstrated an association between the severity of dermal fibrosis and the expression levels of RUNX1 in the skin of patients with SSc. Epigenomic analyses of methylation identified hypomethylated CpG sites proximal to the RUNX1 gene, implicating their potential role in the increased expression of RUNX1. Analysis of single-cell RNA-seq data from skin biopsies of individuals with SSc revealed that RUNX1 is higher in subpopulations of fibroblasts enriched in SSc, which are believed to contribute to fibrosis. RUNX1 CRISPR KO resulted in reduced alpha smooth muscle actin (α-SMA) expression. Inhibition of RUNX1 activity caused a reduction in fibroblast activation, contraction, extracellular matrix components, and proliferation rates including a reduction in SFRP4, LUM and COL1A1. This study is the first to demonstrate a potential role for RUNX1 in the pathogenesis of systemic sclerosis dermal fibrosis. RUNX1 is associated with more severe SSc fibrosis and is associated with a subpopulation of dermal fibroblasts implicated in fibrosis.
2026-01-01 | GSE312591 | GEO
Project description:The activation of Runt-related transcription factor 1 (RUNX1) in fibroblasts has been implicated in wound healing and fibrosis; however, the role of RUNX1 in the fibrotic progression of the autoimmune disease systemic sclerosis (SSc) is not known. Leveraging gene expression, genome-wide DNA methylation, and single-cell resolution data of SSc skin and fibroblast, we analyzed the impact of RUNX1 dysregulation in SSc dermal fibrosis. RUNX1 function was subsequently assessed using siRNA, pharmacologic inhibition, and CRISPR knockout in 2D and 3D fibroblasts cultures. Analysis of gene expression in multiple cohorts demonstrated an association between the severity of dermal fibrosis and the expression levels of RUNX1 in the skin of patients with SSc. Epigenomic analyses of methylation identified hypomethylated CpG sites proximal to the RUNX1 gene, implicating their potential role in the increased expression of RUNX1. Analysis of single-cell RNA-seq data from skin biopsies of individuals with SSc revealed that RUNX1 is higher in subpopulations of fibroblasts enriched in SSc, which are believed to contribute to fibrosis. RUNX1 CRISPR KO resulted in reduced alpha smooth muscle actin (α-SMA) expression. Inhibition of RUNX1 activity caused a reduction in fibroblast activation, contraction, extracellular matrix components, and proliferation rates including a reduction in SFRP4, LUM and COL1A1. This study is the first to demonstrate a potential role for RUNX1 in the pathogenesis of systemic sclerosis dermal fibrosis. RUNX1 is associated with more severe SSc fibrosis and is associated with a subpopulation of dermal fibroblasts implicated in fibrosis.
2026-01-01 | GSE311858 | GEO
Project description:Myofibroblasts are key effector cells in the extracellular matrix remodeling of systemic sclerosis-associated interstitial lung disease (SSc-ILD), however the diversity of fibroblast populations present in the healthy and SSc-ILD lung is unknown, and has prevented the specific study of the myofibroblast transcriptome. We sought to identify and define the transcriptomes of myofibroblasts and other mesenchymal cell populations in human healthy and SSc-ILD lungs to understand how alterations in fibroblast phenotypes lead to SSc-ILD fibrosis.
2019-08-14 | GSE128169 | GEO
Project description:Systemic sclerosis (SSc) is an autoimmune, connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. Trends in efficacy outcome measures favored tofacitnib. Baseline gene expression in fibroblast and keratinocyte subpopulations indicates interferon (IFN) activated gene expression.
2022-07-26 | GSE209635 | GEO
Project description:Autoantibodies (Aab) are frequent in systemic sclerosis (SSc). While recognized as potent biomarkers, their pathogenic role is much debated. This study explored the effect of purified IgG from SSc patients on the phenotype and function of healthy dermal fibroblast (FB) using an innovative multi-omics approach.
2022-06-29 | PXD025885 | Pride
Project description:Objectives: The transcription factor TFAM is controlling the transcription of core proteins required for mitochondrial homeostasis. The aim of the current study was to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function and to evaluate the consequences for fibroblast activation. Methods: The expression of TFAM was analyzed by immunofluorescence and Western blot. The effects of TFAM knockout were investigated in cultured fibroblasts and in bleomycin-induced skin and lung fibrosis and in TβRIact-induced skin fibrosis. Results: The expression of TFAM was downregulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The downregulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mtDNA, accumulation of deletions in mtDNA, metabolic alterations with impaired OXPHOS and release of the mitokine GDF15. Chronic, but not acute exposure of normal fibroblasts to TGFβ mimicked the finding in SSc fibroblasts with downregulation of TFAM and accumulation of mitochondrial damage. Downregulation of TFAM promotes fibroblast activation with upregulation of fibrosis-relevant GO-terms in RNASeq. Mice with fibroblast-specific knockout of TFAM are prone to fibrotic tissue remodeling with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and TβRIact-overexpression. TFAM knockout fosters SMAD3 signaling to promote fibroblast activation. Conclusions: Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.
2021-12-21 | GSE184356 | GEO