Spatial transcriptomic data for skin tissue of systemic sclerosis or localized scleroderma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE334710 | GEO | 2026/06/08
REPOSITORIES: GEO
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Project description:Scleroderma refers to a group of chronic fibrotic immune-mediated diseases of unknown etiology. Characterizing epigenetic changes in childhood-onset scleroderma, systemic sclerosis or localized scleroderma, has not been previously performed. The aim of this study was to assess DNA methylation differences and similarities between juvenile systemic sclerosis (jSSc) and juvenile localized scleroderma (jLS) compared to matched healthy controls. Genome-wide DNA methylation changes in peripheral blood mononuclear cell samples were assessed using the MethylationEPIC array followed by bioinformatic analysis and limited functional assessment. We identified a total of 105 and 144 differentially methylated sites compared to healthy controls in jSSc and jLS, respectively. The majority of differentially methylated sites and genes represented were unique to either jSSc or jLS suggesting a different underlying epigenetic pattern in both diseases. Among shared differentially methylated genes, methylation levels in a CpG site in FGFR2 can distinguish between LS and healthy PBMCs with a high accuracy. Canonical pathway analysis revealed that inflammatory pathways were enriched in genes differentially methylated in jSSc, including STAT3, NF-κB, and IL-15 pathways. In contrast, the HIPPO signaling pathway was enriched in jLS. Our data also suggest a potential role for NOTCH3 in both jSSc and jLS, and revealed a number of transcription factors unique to each of the two diseases. In summary, our data revealed important insights into jSSc and jLS and suggest a potentially novel epigenetic diagnostic biomarker for LS.
2021-05-24 | GSE175379 | GEO
Project description:Using transcriptomic profiling at single-cell resolution, we investigate cell-intrinsic and cell-extrinsic signatures associated with pathogenesis and inflammation-driven fibrosis in both adult and pediatric localized Scleroderma (LS) patients. We perform scRNA-seq on adult and pediatric LS patients and healthy controls. We then analyze the scRNA-seq data using an interpretable factor-analysis machine learning framework, SLIDE, that moves beyond predictive biomarkers to try and infer latent factors underlying LS pathophysiology. SLIDE is a novel latent factor regression-based framework that comes with rigorous statistical guarantees regarding identifiability of the latent factors, corresponding inference, and FDR control. We find distinct differences in the characteristics and complexity in the molecular signatures between adult and pediatric LS. SLIDE identified cell type-specific determinants of LS associated with age and severity and revealed insights into signaling mechanisms shared between LS and Systemic Sclerosis (SSc), as well as differences in onset of the disease in the pediatric compared with adult population. Our analyses recapitulate known drivers of LS pathology and find previously unidentified cellular signaling modules that stratify LS subtypes and define a shared signaling axis with SSc.In this study we compared 17 healthy and 27 LS samples evaluated by 10X Genomics single cell sequencing. Samples were processed and clustered for DEG analysis.
2025-02-28 | GSE288490 | GEO
Project description:Objectives: Scleroderma (systemic sclerosis, SSc), as a prototypic inflammation-driven fibrotic disease, possesses connective tissue lesions populated with persistently activated myofibroblasts maintained by an mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol has recently been identified as a YAP1 inhibitor: however, if celastrol can alleviate SSc fibrosis is unknown. Methods: Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor b1 (TGFb1) in the presence or absence of celastrol. C57BL6J mice were subjected to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol. RNA expression was assessed using RNAseq, real-time polymerase chain reaction and spatial transcriptomic analyses. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining, and indirect immunofluorescence analysis. Results: In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of SSc dermatopathology, celastrol inhibited fibrosis and blocked nuclear localization of YAP in myofibroblasts. Conclusion: Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway may be potential treatments for SSc skin fibrosis.
2023-11-01 | GSE226760 | GEO
Project description:Objectives: Scleroderma (systemic sclerosis, SSc), as a prototypic inflammation-driven fibrotic disease, possesses connective tissue lesions populated with persistently activated myofibroblasts maintained by an mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol has recently been identified as a YAP1 inhibitor: however, if celastrol can alleviate SSc fibrosis is unknown. Methods: Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor b1 (TGFb1) in the presence or absence of celastrol. C57BL6J mice were subjected to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol. RNA expression was assessed using RNAseq, real-time polymerase chain reaction and spatial transcriptomic analyses. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining, and indirect immunofluorescence analysis. Results: In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of SSc dermatopathology, celastrol inhibited fibrosis and blocked nuclear localization of YAP in myofibroblasts. Conclusion: Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway may be potential treatments for SSc skin fibrosis.
2023-11-01 | GSE226375 | GEO
Project description:Objectives: Scleroderma (systemic sclerosis, SSc), as a prototypic inflammation-driven fibrotic disease, possesses connective tissue lesions populated with persistently activated myofibroblasts maintained by an mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol has recently been identified as a YAP1 inhibitor: however, if celastrol can alleviate SSc fibrosis is unknown. Methods: Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor b1 (TGFb1) in the presence or absence of celastrol. C57BL6J mice were subjected to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol. RNA expression was assessed using RNAseq, real-time polymerase chain reaction and spatial transcriptomic analyses. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining, and indirect immunofluorescence analysis. Results: In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of SSc dermatopathology, celastrol inhibited fibrosis and blocked nuclear localization of YAP in myofibroblasts. Conclusion: Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway may be potential treatments for SSc skin fibrosis.
2023-11-01 | GSE226374 | GEO
Project description:In this study we compared 14 healthy and 14 LS samples evaluated by 10X Genomics single cell sequencing. Samples were processed and clustered for DEG analysis. LS = Localized Scleroderma, also called Morphea
2024-10-23 | GSE264508 | GEO
Project description:Uncovering the early interactions and spatial distribution of dermal fibroblasts and immune cells in treatment-naïve diffuse cutaneous systemic sclerosis (dcSSc) patients is critical to understanding the initiating events skin fibrosis. We generated an integrated multiomic dataset of early, treatment naïve dcSSc skin. Skin biopsies were analyzed by single-nuclei multiome sequencing (snRNA-seq and snATAC-seq) and two different paired spatial transcriptomic platforms to comprehensively describe the molecular changes in these individuals. We identified a proinflammatory niche within papillary, hypodermis, and vascular niches, that are enriched for activated myeloid cells and proinflammatory fibroblasts characterized by expression of proinflammatory cytokines. Pathway analyses showed significant enrichment of PI3K-AKT-mTOR signaling pathway expression in these cellular niches, driven by profibrotic growth factor signaling networks. Macrophage subclustering showed SSc-specific macrophage activation of IL6-JAK-STAT signaling and the enrichment of oxidative phosphorylation pathways. Ligand-receptor analysis revealed that SSc macrophages secrete PDGF and TGFB to activate the inflammatory SSc-dominant fibroblast subclusters. Spatial transcriptomic analyses showed infiltrating macrophages secreted PDGF and TGFB, modulating fibroblast activation in these niches. Multiomic data integration and spatial transcriptomic neighborhood analysis showed co-localization of fibroblasts, macrophages, and T cells around the vasculature. These data suggest that interactions between activated immune cells and proinflammatory fibroblasts around vascular niches are an early event in scleroderma pathogenesis.
2025-12-12 | GSE312129 | GEO
Project description:Uncovering the early interactions and spatial distribution of dermal fibroblasts and immune cells in treatment-naïve diffuse cutaneous systemic sclerosis (dcSSc) patients is critical to understanding the initiating events skin fibrosis. We generated an integrated multiomic dataset of early, treatment naïve dcSSc skin. Skin biopsies were analyzed by single-nuclei multiome sequencing (snRNA-seq and snATAC-seq) and two different paired spatial transcriptomic platforms to comprehensively describe the molecular changes in these individuals. We identified a proinflammatory niche within papillary, hypodermis, and vascular niches, that are enriched for activated myeloid cells and proinflammatory fibroblasts characterized by expression of proinflammatory cytokines. Pathway analyses showed significant enrichment of PI3K-AKT-mTOR signaling pathway expression in these cellular niches, driven by profibrotic growth factor signaling networks. Macrophage subclustering showed SSc-specific macrophage activation of IL6-JAK-STAT signaling and the enrichment of oxidative phosphorylation pathways. Ligand-receptor analysis revealed that SSc macrophages secrete PDGF and TGFB to activate the inflammatory SSc-dominant fibroblast subclusters. Spatial transcriptomic analyses showed infiltrating macrophages secreted PDGF and TGFB, modulating fibroblast activation in these niches. Multiomic data integration and spatial transcriptomic neighborhood analysis showed co-localization of fibroblasts, macrophages, and T cells around the vasculature. These data suggest that interactions between activated immune cells and proinflammatory fibroblasts around vascular niches are an early event in scleroderma pathogenesis.
2025-12-12 | GSE312932 | GEO
Project description:Juvenile systemic scleroderma (SSc) is a rare autoimmune disease characterized by excessive fibrosis and vascular involvement. Adult-onset SSc and inflammatory-driven multi-organ fibrosis are similar; interstitial lung disease was recently found in 40% of SSc patients in an international cohort. While recent single-cell studies have explored different types of fibroblasts that are involved in juvenile systemic scleroderma, less is known about the specific immune interactions with fibroblasts that maintain their activation. This study aims to address that gap by mapping macrophage-fibroblast signaling using interaction analyses. The current abstract describes the single-cell RNA sequencing (scRNA-seq) profile of 9 SSc patients’ skin compared to 9 healthy subjects. ScRNA-seq was performed on the skin of 9 SSc patients and 9 healthy age-matched subjects. Samples were dissociated into single-cell suspensions and processed using the 10x Genomics® Chromium platform for single-cell RNA sequencing. Data preprocessing and clustering were performed in R using Seurat and Harmony for normalization and batch correction, followed by visualization with UMAP. Cell-to-cell communication was investigated using NicheNet and CellChat to predict ligand–receptor interactions between macrophage and fibroblast populations, including associated signaling pathways and target gene networks. Analysis of scRNA-sequenced data revealed specific fibroblast and macrophage populations driving fibrosis in systemic scleroderma (SSc). Clustering led to 11 unique groups of fibroblasts. Clusters COL11A1+/POSTN+ and STC1+/FZD9+ were markedly expanded in SSc skin and showed activation of TGFβ, WNT, and FGF pathways associated with extracellular matrix (ECM) production. The STC1+/FZD9 cluster was a novel finding, with pathway involvement in pulmonary and hepatic fibrosis signaling and TGFβ pathway activation. Macrophage subsets MMP19+/CTSL+ and MERTK+ emerged as important profibrotic sender cells, expressing ligands such as TGFB1, AREG, and COL6A2 that signal to fibroblast receptors TGFBR1, TGFBR2, FGFR1, FGFR2, and FZD9. NicheNet and CellChat analyses identified a coordinated macrophage–fibroblast signaling network integrating TGFβ, FGF, WNT, IGF, NOTCH, and TNF pathways. Notably, TGFβ signaling persisted through accessory activators (ITGAV, THBS1, and SDC2), suggesting a self-sustaining loop of fibroblast activation independent of accessory inflammatory input. Analysis of scRNA-sequenced data revealed specific fibroblast and macrophage populations driving fibrosis in systemic scleroderma (SSc). Clustering led to 11 unique groups of fibroblasts. Clusters COL11A1+/POSTN+ and STC1+/FZD9+ were markedly expanded in SSc skin and showed activation of TGFβ, WNT, and FGF pathways associated with extracellular matrix (ECM) production. The STC1+/FZD9 cluster was a novel finding, with pathway involvement in pulmonary and hepatic fibrosis signaling and TGFβ pathway activation. Macrophage subsets MMP19+/CTSL+ and MERTK+ emerged as important profibrotic sender cells, expressing ligands such as TGFB1, AREG, and COL6A2 that signal to fibroblast receptors TGFBR1, TGFBR2, FGFR1, FGFR2, and FZD9. NicheNet and CellChat analyses identified a coordinated macrophage–fibroblast signaling network integrating TGFβ, FGF, WNT, IGF, NOTCH, and TNF pathways. Notably, TGFβ signaling persisted through accessory activators (ITGAV, THBS1, and SDC2), suggesting a self-sustaining loop of fibroblast activation independent of accessory inflammatory input. These findings define a macrophage-driven signaling circuit that reinforces chronic fibrosis and identify novel molecular targets that may disrupt this feedback loop. Consistent with adult SSc, fibroblast–macrophage interactions likely sustain fibrosis in SSc, yet the specific fibroblast populations involved are different. TGFβ, FGF, and WNT pathways form an interconnected network that drives fibroblast persistence and ECM accumulation, while NOTCH and TNF signaling amplify immune–fibrotic crosstalk. Targeting key ligand–receptor interactions or accessory activators such as ITGAV, THBS1, and SDC2 may provide novel therapeutic strategies to disrupt chronic fibrotic signaling in SSc. By characterizing these ligand–receptor interactions, our study provides a detailed picture of macrophage–fibroblast communication in juvenile systemic scleroderma.
2026-04-09 | GSE320020 | GEO
Project description:Human scleroderma skin derived fibroblast were treated with LiCL. This is a study of differential gene expression between LiCl treated SSc group and untreated SSc group.
2024-02-03 | GSE254716 | GEO