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Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease

ABSTRACT: Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease

PROVIDER: PRJNA526667 | ENA |

REPOSITORIES: ENA

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Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease

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

Myofibroblast transcriptome indicates SFRP2+ fibroblast progenitors in systemic sclerosis skin

Project description:Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin (SMA) expressing cells that produce matrix as well as increase tension on surrounding tissues. Myofibroblast progenitors have been described to arise from a variety of cell types in murine fibrosis models, but relatively modest insight is available as to their source and differentiation in fibrotic human diseases. We utilize single cell RNA-sequencing to examine the transcriptome changes that occur in fibroblasts in SSc skin and during myofibroblast differentiation. We show that dermal myofibroblasts arise from an SFRP2/DPP4-expressing progenitor fibroblast population. In SSc skin, fibroblasts undergo global changes in gene expression, including SFRP2-expressing fibroblasts, which globally upregulate expression of markers, such as PRSS23 and THBS1. However, only a fraction of SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, such as SFRP4 and FNDC1. These results indicate that myofibroblasts derive from a specific fibroblast subpopulation in SSc skin, that their differentiation proceeds in two stages and that other fibroblast populations also shift transcriptomes in SSc skin, suggesting a cytokine driven process. The myofibroblast transcriptome implicates upstream transcription factors that should help further unravel the drivers of myofibroblast differentiation.

2021-05-20 | GSE138669 | GEO

Epigenetic regulation of profibrotic macrophages in systemic sclerosis- associated interstitial lung disease

Project description:Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of death in patients with systemic sclerosis (SSc) with unclear pathogenesis and limited treatment options. Evidence strongly supports an important role for profibrotic, SPP1-expressing macrophages in SSc-ILD. We sought to define the transcriptome and chromatin structural changes of SPP1 SSc-ILD macrophages, so as to better understand their role in promoting fibrosis and to identify transcription factors associated with open chromatin driving their altered phenotype.

2022-09-02 | GSE212109 | GEO

Skin gene expression correlates of severity of interstitial lung disease in systemic sclerosis

Project description:We identified eighty two skin transcripts significantly correlated with the severity of interstitial lung disease (ILD) in systemic sclerosis. These genes separated patients with more sever ILD in unsupervised hierarchical clustering. Pathway analysis revealed pathways involved in extravasation and adhesion of inflammatory cells to endothelium. Skin biopsy samples from 59 patients enrolled in the GENISOS cohort or an open label imatinib study were examined by global gene expression studies.

2013-07-12 | E-GEOD-47162 | biostudies-arrayexpress

Skin gene expression correlates of severity of interstitial lung disease in systemic sclerosis

2013-07-12 | GSE47162 | GEO

Myofibroblast transcriptome indicates SFRP2+ fibroblast progenitors in systemic sclerosis skin

Project description:Myofibroblast transcriptome indicates SFRP2+ fibroblast progenitors in systemic sclerosis skin

| PRJNA576702 | ENA

Epigenetic regulation of profibrotic macrophages in systemic sclerosis- associated interstitial lung disease

Project description:Epigenetic regulation of profibrotic macrophages in systemic sclerosis- associated interstitial lung disease

| PRJNA874032 | ENA

Peripheral blood gene expression profiling predicts response to mycophenolate in systemic sclerosis related interstitial lung disease

Project description:PBC RNA samples from 134 baseline and 98 month-12 visits, corresponding to the active treatment period of both arms in Scleroderma Lung Study II, along with 45 healthy controls were investigated by global RNA sequencing. The objective was to examine the peripheral blood cell (PBC) gene expression changes ensuing from mycophenolate mofetil (MMF) or cyclophosphamide (CYC) treatment and to determine the predictive significance of baseline PBC transcript scores for response to immunosuppression in systemic sclerosis (SSc) related interstitial lung disease (ILD).

2022-02-01 | GSE181228 | GEO

IgG from systemic sclerosis patients induce a profibrosing and serotype-dependent phenotype in normal dermal fibroblast: a multi-omics study

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

Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease.

Project description:OBJECTIVES:Myofibroblasts are key effector cells in the extracellular matrix remodelling 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. METHODS:We performed droplet-based, single-cell RNA-sequencing with integrated canonical correlation analysis of 13 explanted lung tissue specimens (56 196 cells) from four healthy control and four patients with SSc-ILD, with findings confirmed by cellular indexing of transcriptomes and epitopes by sequencing in additional samples. RESULTS:Examination of gene expression in mesenchymal cells identified two major, SPINT2hi and MFAP5hi, and one minor, WIF1hi, fibroblast populations in the healthy control lung. Combined analysis of control and SSc-ILD mesenchymal cells identified SPINT2hi, MFAP5hi, few WIF1hi fibroblasts and a new large myofibroblast population with evidence of actively proliferating myofibroblasts. We compared differential gene expression between all SSc-ILD and control mesenchymal cell populations, as well as among the fibroblast subpopulations, showing that myofibroblasts undergo the greatest phenotypic changes in SSc-ILD and strongly upregulate expression of collagens and other profibrotic genes. CONCLUSIONS:Our results demonstrate previously unrecognised fibroblast heterogeneity in SSc-ILD and healthy lungs, and define multimodal transcriptome-phenotypes associated with these populations. Our data indicate that myofibroblast differentiation and proliferation are key pathological mechanisms driving fibrosis in SSc-ILD.

| S-EPMC7255436 | biostudies-literature

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