Basal-like cell-conditioned medium exerts anti-fibrotic effects in vitro and in vivo
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE145439 | GEO | 2022/02/16
REPOSITORIES: GEO
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Project description:We performed a single-cell transcriptome analysis of alveolar basal cells from peripheral lung tissue of patients with idiopathic pulmonary fibrosis (IPF), cultured in DMEM or Cnt-PR-A growth medium.
2022-06-15 | GSE198153 | GEO
Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA
2008-11-20 | E-GEOD-11196 | biostudies-arrayexpress
Project description:Basal-like cell-conditioned medium exerts anti-fibrotic effects in vitro and in vivo
| PRJNA607230 | ENA
Project description:Analysis of Idiopathic pulmonary fibrosis (IPF) at gene expression level. The hypothesis tested in the present study was that Epigenetic mechanisms are likely to be associated with pathogenesis in IPF. To determine the DNA methylation change, and their effects on gene expression, we compared microarray data of DNA methylation and RNA expression. Results provide that among the genes whose DNA methylation status and RNA expression were both significantly altered between IPF-rapid and normal controls. Total RNA obtained from Idiopathic pulmonary fibrosis samples.
2015-10-31 | E-GEOD-71351 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF), a chronic progressive lung disease of unknown etiology, is characterized by the expansion of myofibroblasts and abnormal deposition of extracellular matrix in the lung parenchyma. To elucidate the molecular mechanisms that lead to IPF, we analyzed myofibroblasts established from patients with IPF by oligonucleotide microarrays. Gene expression profiles revealed a novel pathophysiologic function of myofibroblasts as a generator of reactive oxygen species, and a self-defense mechanism against oxidative stress of their own generating. Experiment Overall Design: We isolated two myofibroblast cell culture from patients with idiopathic pulmonary fibrosis. Embryonic pulmonary fibroblast was used for the reference.
2008-06-15 | E-GEOD-6804 | biostudies-arrayexpress
Project description:Idiopathic Pulmonary Fibrosis (IPF) is a progressive chronic lung disease characterized by excess deposition of extracellular matrix (ECM) proteins in the lung. TGFα is a is a ligand for the epidermal growth factor receptor, and found elevated in several fibrotic lung diseases including IPF. Notably, lung-specific overexpression of TGFα alone in adult mice can cause progressive and extensive adventitial and subpleural fibrosis similar to IPF. Pirfenidone, an FDA approved drug has been shown to improve the decline in lung function in IPF patients. However, the mechanism of action of pirfenidone largely unknown. In the current study, we investigated the effects of pirfenidone using a mouse model of TGFα-induced pulmonary fibrosis and fibroblasts isolated from IPF lungs. Total lung transcriptome analysis suggest a significant overlap in dysregulated gene transcripts between TGFα model and IPF. In vivo studies demonstrate a significant improvement in lung function with pirfenidone therapy compared to vehicle-treated TGFα mice on Dox for six wks. However, pirfenidone treatment did not affect fibroproliferation, myofibroblast transformation, and ECM deposition during TGFα-induced pulmonary fibrosis. In summary, pirfenidone treatment improved lung function but had a limited or no effect on the expression of collagen, ECM genes, fibroproliferation and migration of lung-resident fibroblasts.
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Project description:Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we show an association between KRT5+ cells in human fibrotic lung and regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry-based proteomics revealed compositional differences in the matrisome secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrisome restricts KRT5+ cell migration in vitro. Together, our findings demonstrate that changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.
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Project description:The activated fibroblast is the putative effector cell for the progressive fibrotic phenotype idiopathic pulmonary fibrosis (IPF). Recent studies investigating global gene expression differences between normal and IPF fibroblasts indicate that changes in gene expression occur in these fibroblasts in culture. Employing a technique that minimizes cellular phenotypic alterations, we characterized the global gene expression changes in pulmonary fibroblasts by comparing both cultured and non-cultured IPF and normal cells. The results revealed dramatic difference between IPF and normal fibroblast as they progressed in culture. While there are significant differences in gene expression between IPF and normal fibroblast at P0, after 3 passages in culture, no statistically significant difference was observed. This study is a comprehensive investigation of gene expression within IPF and normal fibroblasts in culture and sheds light on the efficacy of in vitro models of pulmonary fibroblasts.
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Project description:Pulmonary fibrosis (PF) is associated with many chronic lung diseases including Systemic sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF) and Cystic Fibrosis (CF) which are characterized by the progressive accumulation of mesenchymal cells and formation of scar tissue. Pulmonary fibrosis is a dysregulated response to alveolar injury which causes a progressive decline in lung function and refractory to current pharmacological therapies. Airway and alveolar epithelial cells and mesenchymal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Our new findings have identified the aberrant activation of Sox9 in lung resident fibroblasts and myofibroblasts in IPF lung biopsies and the mouse model of transforming growth factor-α (TGFα) and bleomycin-induced pulmonary fibrosis. In this study, we sought to determine Sox9-driven gene networks in lung resident fibroblast during pulmonary fibrosis. Our results showed that Sox9 regulates the transcriptional changes that are required for the fibroblast activation including migration, myofibroblast transformation, survival and extracellular matrix deposition during pulmonary fibrosis. In summary, this new study demonstrates that Sox9 is a critical regulator of fibroblast activation in IPF and hence serve as a target for therapeutic intervention.
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Project description:Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme (DUB) that is very highly expressed in human brain. UCHL1 has been proposed as a potential therapeutic target in neurodegeneration, cancer, and liver and lung fibrosis, however bona fide molecular functions of UCHL1 are yet to be elucidated. Herein we characterize a potent and selective inhibitor and activity-based probe (IMP-1710) for UCHL1 based on a covalent inhibitor scaffold, and its application to identify and quantify target proteins in intact human cells. IMP-1710 stereoselectively labels the catalytic cysteine of UCHL1 at low nanomolar concentration, and we show that a previously claimed UCHL1 inhibitor (LDN-57444) fails to engage UCHL1 in cells. We further demonstrate that potent UCHL1 inhibitors selectively block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis (IPF), supporting a potential therapeutic role for UCHL1 inhibition.
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