MiRNA expression data in unstimulated and TGF-β1-stimulated lung fibroblasts
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ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE86185 | GEO | 2017/11/01
SECONDARY ACCESSION(S): PRJNA340781
REPOSITORIES: GEO
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Project description:To identify the target gene repertoire of miRNAs (i.e. the miRNA-targetome) of unstimulated and TGF-β1-stimulated primary parenchymal lung fibroblasts, Ago2-IP was performed followed by mRNA expression profiling.
2017-11-01 | GSE86183 | GEO
Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while gene expression was profiled in the adjacent sample from the same region using the Affymetrix Human Exon 1.0 ST GeneChip. Human fibroblast cell lines (HLF-1) were treated with GHK or TGF-Beta1 for 48 hours and profiled using the Affymetrix Human Gene 1.0 ST GeneChip.
2012-09-11 | E-GEOD-27597 | biostudies-arrayexpress
Project description:Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease of the lungs that is currently the fourth leading cause of death worldwide. Genetic factors account for only a small amount of COPD risk, but epigenetic mechanisms including DNA methylation, have the potential to mediate the interactions between an individual?s genetics and environmental exposure. DNA methylation is highly cell type specific and individual cell type studies of DNA methylation in COPD are sparse. Fibroblasts are present within the airway and parenchyma of the lung and contribute to the aberrant deposition of extracellular matrix in COPD. No assessment or comparison of genome-wide DNA methylation profiles in airway and parenchymal fibroblasts from individuals with and without COPD has been undertaken. These data provide valuable insight into the molecular mechanisms contributing to COPD and the differing pathologies of small airways disease and emphysema in COPD. Methods: Genome-wide DNA methylation was evaluated at over 485,000 CpG sites using the Illumina Infinium HumanMethylation450 BeadChip array in airway (non-COPD n=8, COPD n=7) and parenchymal fibroblasts (non-COPD n=18, COPD n=28) isolated from individuals with and without COPD. Targeted gene expression was assessed by qPCR in matched RNA samples. Results: Differentially methylated DNA regions were identified between cells isolated from individuals with and without COPD in both airway and parenchymal fibroblasts. Only in parenchymal fibroblasts was differential DNA methylation associated with differential gene expression. A second analysis of differential DNA methylation variability identified 359 individual differentially variable CpG sites in parenchymal fibroblasts. No differentially variable CpG sites were identified in airway fibroblasts. Five differentially variable methylated CpG sites, associated with three genes were subsequently assessed for gene expression differences. Two genes (OAT and GRIK2) displayed significantly increased gene expression in cells isolated from individuals with COPD. Conclusions: Differential and variable DNA methylation was associated with COPD status in parenchymal fibroblasts but not airway fibroblasts. Aberrant DNA methylation was associated with altered gene expression imparting biological function to DNA methylation changes. Changes in DNA methylation are therefore implicated in the molecular mechanisms underlying COPD pathogenesis and may represent novel therapeutic targets.
2018-03-06 | GSE111396 | GEO
Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression.
2012-09-11 | GSE27597 | GEO
Project description:ABSTRACT Background: Primary human distal lung/parenchymal fibroblasts (DLF) exhibit a different phenotype from airway fibroblasts (AF), including the expression of high levels of alpha-SMA. The scope of the differences and the mechanisms driving them are unknown. We hypothesized that the distinct fibroblast characteristics based on lung region predicted a broad range of genomic differences which contribute to distinctly different functional pathway activation in AF and DLF. Methods and Findings: To investigate whether comprehensive gene expression patterns vary between AF and DLF, we compared global gene expression profiles of 3 matched pairs of primary human fibroblasts isolated from proximal and distal lung. 194 transcripts were upregulated in AF, and 290 transcripts upregulated in DLF. Quantitative real-time PCR (qRT-PCR) from both asthmatic and normal subjects confirmed the validity of microarray data (n = 8). Further analysis identified distinct pathway activation patterns, including the identification of the TGF-β receptor/SMAD3 signaling pathway as critical to the phenotypic differences in AF and DLF. The functional impact of these molecular differences on AF and DLF was then analyzed using Western blot, qRT-PCR, ELISA and gene knock-down approaches. TGF-β receptor/SMAD2-3 pathway analysis confirmed the contribution of higher TGF-β1 expression and accompanying SMAD3 and JNK activation to the increased alpha-SMA level seen in DLF. There are two limitations associated with our work. First, the microarray sample size was small. Second, for ethical reasons, a large majority of our data were from asthmatic subjects, only one pair of airway and distal lung tissues from a subject without knowing preexisting lung disease matched for age and smoking status was available. In this single normal subject, the same pattern of differences existed, supporting the concept that these genomic differences are regional, rather than disease-related. Conclusions: These findings demonstrated marked molecular and functional differences for these two lung regional fibroblast populations. These results suggest that airway and parenchymal fibroblasts differ in their responses to injury, repair, and remodeling in the lungs. There are likely profound implications of these observations for understanding mechanisms of development of fibrotic lung diseases as well as approaching therapy. In order to identify the underlying molecular differences between airway- and distal lung fibroblasts, microarray analysis was performed on 3 different matched pairs of fibroblasts.
2011-07-21 | E-GEOD-19362 | biostudies-arrayexpress
Project description:Myocardial infarctions cause hypoxic injury to downstream tissue and a consequent fibrotic remodeling process to replace injured tissue with a scar. Scar formation occurs through phases of wound healing in which stimuli such as transforming growth factor-beta (TGF-β) drive cardiac fibroblasts to activate into a myofibroblast phenotype and deposit matrix molecules that form a scar. While this is necessary to repair injured tissue, excessive fibrosis commonly occurs which is correlated with heart failure. Therefore, defining cardiac fibroblast phenotypes under hypoxic stimuli and TGF-β is essential for understanding and treating pathological fibrosis. We robustly characterized fibroblast phenotype through immunofluorescence, quantitative RT-PCR, and proteomic analysis, after either TGF-β treatment or hypoxia durations that mimic acute hypoxic injury post-infarction. We find that hypoxic fibroblasts respond to low oxygen with increased hypoxia inducible factor 1 (HIF-1) but not HIF-2 activity by 4h. This is accompanied by increased gene and protein levels of VEGFA and LOX, respectively, which are both targets of HIF-1. Both TGF-β1 and hypoxia inhibit proliferation by 24h. While TGF-β1 treatment upregulated various fibrotic pathways, hypoxia causes a global reduction in protein synthesis, including collagen biosynthesis. This study discerns overlapping from distinctive outcomes of TGF-β1 and hypoxia treatment, which is important for elucidating their roles in fibrotic remodeling post-MI.
2024-07-03 | PXD051197 | Pride
Project description:To elucidate how TGF-β1 regulates translation, we treated human lung fibroblasts (HLF) with TGF-β1 and used RNA-seq to determine the effect of TGF-β1 on total RNAs, and mRNA polysome/monosome ratios.
2022-04-28 | GSE201506 | GEO
Project description:In idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), epithelial abnormalities are present including bronchiolization and alveolar cell death and dysfunction. As epithelial progenitor cells are directed by their microenvironment, we hypothesized that changes in the microenvironment disrupt normal epithelial growth and differentiation. We therefore mimicked the soluble factor microenvironment in IPF using an IPF cocktail (IPFc), composed of 9 factors which are increased in IPF lungs (CCL2, IL-1β, IL-4, IL-8, IL-13, IL-33, TGF-β, TNFα and TSLP) and in COPD exacerbations using an exacerbation cocktail (EC) composed of 4 factors that are increased during an exacerbation of COPD (TNFα, IL-1β, IL-6, IL-8). We asked whether the soluble factor milieu in IPF and COPD exacerbations affects epithelial growth and differentiation. Mouse lung organoids (primary EpCAM+ cells co-cultured with CCL206 fibroblasts) were used to study epithelial growth and differentiation. Organoids exposed to IPFc, EC or TGF-β (as a comparator) were resorted into EpCAM+ and CCL206 fractions, and subjected to RNA-sequencing.
2024-04-30 | GSE245259 | GEO
Project description:Transforming growth factor-β (TGF-β) is considered to play a role in the maintenance of quiescent hematopoietic stem cells (HSCs) in vivo. We asked a question of whether TGF-β could be used to control the cell cycle status of HSCs in vitro. To examine the effect of TGF-β on the HSC function, we used in vitro culture system in which HSCs divide with retention of short- and long-term reconstitution ability. Single-cell analyses showed that regardless of its concentrations, TGF-β slowed down cell cycle progression of HSCs, but consequently suppressed the self-renewal potential, particularly in cycling HSCs. This study highlighted a role of TGF-β in the negative regulation of HSC number and function.
2018-07-23 | GSE110116 | GEO
Project description:To assess the transcriptomic response of human lung fibroblast to TGF-β, human MRC5 pulmonary fibroblasts (CCL-171) were exposed to TGF-β at 10 ng/mL. RNA samples were harvested 24 hours after TGF-β exposition. Three independent experiments were carried out.
2019-04-11 | GSE97832 | GEO