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Increased dermal collagen bundle alignment in Systemic Sclerosis is associated with a cell migration signature and role of Arhgdib in directed fibroblast migration on aligned ECMs [bleomycin]

ABSTRACT: Systemic sclerosis (SSc) is a devastating disease affecting the skin and internal organs. Dermal fibrosis manifests early and Modified Rodnan Skin Scores (MRSS) correlate with disease progression. Transcriptomics of SSc skin biopsies suggest the role of the in vivo microenvironment in maintaining the pathological myofibroblasts. Therefore, defining the structural changes in dermal collagen in SSc patients could inform our understanding of fibrosis pathogenesis. Here, we report a method for quantitative whole-slide image analysis of dermal collagen from SSc patients, and our findings of more aligned dermal collagen bundles in diffuse cutaneous SSc (dcSSc) patients. Using the bleomycin-induced mouse model of SSc, we identified a distinct high dermal collagen bundle alignment gene signature, characterized by a concerted upregulation in cell migration, adhesion, and guidance pathways, and downregulation of spindle, replication, and cytokinesis pathways. Furthermore, increased bundle alignment induced a cell migration gene signature in fibroblasts in vitro, and these cells demonstrated increased directed migration on aligned ECM fibers that is dependent on expression of Arhgdib (Rho GDP-dissociation inhibitor 2). Our results indicate that increased cell migration is a cellular response to the increased collagen bundle alignment featured in fibrotic skin. Moreover, many of the cell migration genes identified in our study are shared with human SSc skin and may be new targets for therapeutic intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE100212 | GEO | 2017/08/11

SECONDARY ACCESSION(S): PRJNA390999

REPOSITORIES: GEO

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Increased dermal collagen bundle alignment in Systemic Sclerosis is associated with a cell migration signature and role of Arhgdib in directed fibroblast migration on aligned ECMs [ECMs]

Project description:Systemic sclerosis (SSc) is a devastating disease affecting the skin and internal organs. Dermal fibrosis manifests early and Modified Rodnan Skin Scores (MRSS) correlate with disease progression. Transcriptomics of SSc skin biopsies suggest the role of the in vivo microenvironment in maintaining the pathological myofibroblasts. Therefore, defining the structural changes in dermal collagen in SSc patients could inform our understanding of fibrosis pathogenesis. Here, we report a method for quantitative whole-slide image analysis of dermal collagen from SSc patients, and our findings of more aligned dermal collagen bundles in diffuse cutaneous SSc (dcSSc) patients. Using the bleomycin-induced mouse model of SSc, we identified a distinct high dermal collagen bundle alignment gene signature, characterized by a concerted upregulation in cell migration, adhesion, and guidance pathways, and downregulation of spindle, replication, and cytokinesis pathways. Furthermore, increased bundle alignment induced a cell migration gene signature in fibroblasts in vitro, and these cells demonstrated increased directed migration on aligned ECM fibers that is dependent on expression of Arhgdib (Rho GDP-dissociation inhibitor 2). Our results indicate that increased cell migration is a cellular response to the increased collagen bundle alignment featured in fibrotic skin. Moreover, many of the cell migration genes identified in our study are shared with human SSc skin and may be new targets for therapeutic intervention.

2017-08-11 | GSE99999 | GEO

Increased dermal collagen bundle alignment in Systemic Sclerosis is associated with a cell migration signature and role of Arhgdib in directed fibroblast migration on aligned ECMs

Project description:Increased dermal collagen bundle alignment in Systemic Sclerosis is associated with a cell migration signature and role of Arhgdib in directed fibroblast migration on aligned ECMs

| PRJNA391154 | ENA

Homo sapiens

| PRJNA390302 | ENA

Mus musculus

| PRJNA390999 | ENA

Expression data from untreated and rottlerin-treated normal and systemic sclerosis-derived human fibroblasts

Project description:PKC-δ inhibition with the selective inhibitor, rottlerin, resulted in potent downregulation of type I collagen expression and production in normal human dermal fibroblasts and abrogated the exaggerated type I collagen production and expression in fibroblasts cultured from affected skin from patients with the fibrosing disorder, systemic sclerosis (SSc). To elucidate the mechanisms involved in the ability of PKC-δ to regulate collagen production in fibroblasts, we examined the effects of PKC-δ inhibition on the transcriptome of normal and SSc-derived human dermal fibroblasts. We used microarrays to detail the effects of PKC-δ inhibition with rottlerin on the transcriptome of normal and SSc-derived human dermal fibroblasts and to identify gene networks that might be involved in the regulation of extracellular matrix by PKC-δ.

2010-08-22 | GSE23741 | GEO

Topical Application of Nitrate Ameliorates Skin Fibrosis by Regulating ST2+CD4+ T Cells in Systemic Sclerosis Mouse Model

Project description:Systemic sclerosis (SSc) is characterized by intractable multiorgan fibrosis caused by vascular and immune dysfunction. Currently, effective therapeutic options for patients with SSc are limited. Nitrate, an abundant nutrient in the diet, has been demonstrated to be preventative and therapeutic for several diseases. To determine whether nitrate can slow or reverse SSc progression, topical application of nitrate delivered by dissolving microneedles was used to treat a bleomycin (BLM)-induced dermal fibrosis mouse model. In this study, nitrate considerably attenuated dermal thickness, stiffness, and collagen deposition.To examine the nitrate regulation of gene expression at the genome-wide level, bulk RNA sequencing of skin was performed. Bulk RNA sequencing of skin revealed that Cd4 was a key hub gene in SSc nitrate therapy. Additionally, BLM-induced cytokines and chemokines were inhibited by nitrate, and CD4+ T cells infiltration markedly declined. Il4, Il6, Il13, and Tgfb expression in CD4+ T cells isolated from skin biopsies also significantly decreased. Mechanistically, Il1rl1, a type2 immune response inducer, was markedly repressed in isolated CD4+ T cells and dermal tissues after nitrate treatment. Remarkably, compared with wild type mice, mice lacking Il1rl1 showed impaired transcriptional profiles after intradermal BLM injection. Adoptive transfer of ST2+CD4+ T cells promoted bleomycin-induced Rag2-/- mice dermal fibrosis. Collectively, these findings demonstrate that nitrate targeting ST2+CD4+ T cells is an effective therapeutic option for SSc.

2024-06-04 | GSE264187 | GEO

EphB2 Receptor Promotes Dermal Fibrosis in Systemic Sclerosis

Project description:Objectives: Eph/Ephrin cell-cell signaling is emerging as a key player in tissue fibrogenesis. The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc). Methods: We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting EphB2-knockout mice to both bleomycin-induced and tight skin (Tsk1/+) genetic mouse models. EphB2 kinase-dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin-induced dermal fibrosis. In vitro studies were performed on dermal fibroblasts from SSc patients and healthy controls, which was followed by in vivo analysis of fibroblast-specific EphB2 deficient mice. Results: Expression of EphB2 is upregulated in SSc skin tissue and explanted SSc dermal fibroblasts compared to healthy controls. EphB2 expression is elevated in two animal models of dermal fibrosis. In mice, EphB2 drives dermal fibrosis in both the bleomycin and the Tsk1/+ models of skin fibrosis. EphB2 forward signaling is a critical mediator of dermal fibrosis. Transforming growth factor-β (TGFβ) cytokines upregulate EphB2 in dermal fibroblasts via non-canonical TGFβ/SMAD signaling and silencing EphB2 in dermal fibroblasts is sufficient to dampen TGFβ-induced fibroblast-to-myofibroblast differentiation. Moreover, mice with fibroblast-specific deletion of EphB2 showed impaired fibroblast-to-myofibroblast differentiation and reduced skin fibrosis upon bleomycin challenge. Conclusion: Our data implicate EphB2 overexpression and kinase-mediated forward signaling in the development of dermal fibrosis in SSc. EphB2 thus represents a potential new therapeutic target for SSc.

2024-04-10 | GSE253089 | GEO

Eicosanoid profiles of dermal fibroblasts (part-II)

Project description:The sphingolipid, ceramide-1-phosphate (C1P), directly binds and activates Group IVA cytosolic phospholipase A2 (cPLA2) to generate eicosanoids. Due to the role of eicosanoids in wound healing, we choose to use our novel genetic mouse model expressing cPLA2 with an ablated C1P interaction site (KI) to examine the cPLA2/C1P interaction in wound healing. Wound closure rate was not affected, but wound maturation was enhanced by loss of the C1P/cPLA2α interaction based on the following findings. Wounds in KI mice displayed: i) increased infiltration of dermal fibroblasts into the wound environment; ii) increased wound tensile strength; and iii) higher Type I/Type III collagen ratios. These findings were recapitulated in vitro as primary dermal fibroblasts (pDFs) from KI mice showed significantly increased collagen deposition and migration velocity compared to WT and KO pDFs. Additionally, the KI showed an altered eicosanoid profile of reduced pro-inflammatory prostaglandins (PGE2) and increased levels of specific HETE species (5-HETE). Elevated 5-HETE levels promoted increased dermal fibroblast migration and collagen deposition. This “gain of function” role for the mutant cPLA2 was also linked to differential cellular localization of cPLA2α and 5-HETE biosynthetic factors. These studies demonstrate regulation of key biological mechanisms by a defined protein:lipid interaction in vivo and provide new insights into cPLA2 function.

2019-09-24 | ST001254 | MetabolomicsWorkbench

Eicosanoid profiles of dermal fibroblasts (part-I)

2019-09-22 | ST001252 | MetabolomicsWorkbench

The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [Spatial Transcriptomics]

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

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