Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Wilms’ tumor 1 impairs apoptotic clearance of fibroblasts in distal fibrotic lung lesions

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease characterized by impaired fibroblast clearance, accumulation, and excessive extracellular matrix (ECM) protein production. Wilms' Tumor 1 (WT1), a transcription factor, is selectively upregulated in IPF fibroblasts. However, the mechanisms by which WT1 contributes to fibroblast accumulation and ECM production remain unknown. Here, we investigated the heterogeneity of WT1-expressing fibroblasts using single-nucleus RNA sequencing on the distal lung tissues of IPF patients and healthy controls. WT1 was selectively upregulated in a subset of IPF fibroblasts that co-expressed several pro-survival genes. Both the loss-of-function and gain-of-function studies support the idea that WT1 functions as a positive regulator of multiple pro-survival genes to impair apoptotic clearance and promote ECM production. In support, fibroblast-specific overexpression of WT1 augmented fibroproliferation, myofibroblast accumulation, and ECM production during bleomycin-induced pulmonary fibrosis in both young and old mice. Together, these findings identify WT1 as a potential therapeutic target to attenuate fibroblast expansion, and ECM production in the distal areas of fibrosing lungs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279404 | GEO | 2025/05/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Loss of Fas-signaling in pro-fibrotic fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.

2020-11-18 | GSE161648 | GEO

An extracellular matrix-driven positive feedback loop regulates translation in Idiopathic Pulmonary Fibrosis

Project description:Analysis of gene expression of lung fibroblasts seeded onto decellularized extracellular matrix (ECM). Experiment had 2x2 design where fibroblasts from idiopathic pulmonary fibrosis (IPF) or control patients were seeded onto decelluarized lung tissue from IPF or control patients allowing for determination of gene expression differences that were driven by IPF ECM and which differences were driven by the IPF fibroblast. Lung fibroblasts from 5 patients with idiopathic pulmonary fibrosis and 5 control patients were cultured on decellularized ECM from IPF or control lung. Total RNA and polyribosome RNA were isolated after the cells were cultured on the decellularized ECM for 18 hours. When possible, a control cell line and a diseased cell line were cultured (and processed) simultaneously to minimize the effect of experimental variance induced by running the experiment at different times.Samples with the same batch number (provied in the sample 'characteristics' field) were cultured and processed at the same time.

2014-03-04 | E-GEOD-45686 | biostudies-arrayexpress

An extracellular matrix-driven positive feedback loop regulates translation in Idiopathic Pulmonary Fibrosis

2014-03-04 | GSE45686 | GEO

Alteration in the transcriptome of lung resident fibroblast upon genetic knockdown of Wilms' tumor1 transcription factor

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 stromal 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 stromal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Recent published reports from our lab demonstrated the aberrant activation of Wilms' tumor1 (WT1) transcription factor in lung resident fibroblast and myofibroblast in IPF lung biopsies and the mouse model of transforming growth factor-α (TGFα) and bleomycin induced fibrosis. In this study, we sought to determine the role of WT1 in transcriptome changes in lung resident fibroblast during pulmonary fibrosis. Our results showed that WT1 regulates the transcriptional changes that are required for the fibroblast activation processes such fibroproliferation, myofibroblast transformation and extracellular matrix deposition during pulmonary fibrosis. Finally, this study demonstrates that WT1 is a critical regulator of fibroblast activation in IPF and hence serve as a target for therapeutic intervention.

2018-08-01 | GSE110177 | GEO

Targeted immunotherapy rescues pulmonary fibrosis by reducing activated fibroblasts and regulating alveolar cell profile

Project description:Idiopathic pulmonary fibrosis (IPF) is a severe lung disease in the world, but has limited clinical therapies. Fibrosis maintains dynamic balance with overactivated fibroblasts. Given pulmonary cell regeneration, the lung may have self-repairing ability if fibrosis is removed by clearance of overactivated fibroblasts. The aim of the study is to evaluate therapeutic activity of transient CAR-T cells generated via a novelly designed LNP-mRNA system and address the relevant mechanism to epithelial cell polarization in a mouse model of bleomycin-induced IPF. Studies on proteomes and histology showed that fibrosis-induced ECM stiffening impaired epithelial cell polarization that limited cell’s self-healing ability. The proposed LNP-mRNA therapy eliminated overactivated fibroblasts and removed pulmonary fibrosis successfully. The decreased ECM stiffness and the improvement of extracellular environment facilitated re-establishment of cell polarity and restored the self-repairing ability of epithelial cell. Hence, LNP-mRNA treatment for IPF can recover pulmonary structure and function close to a healthy lung. This therapy shows a potential treatment for IPF patients.

2025-03-19 | PXD053333 | Pride

Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis

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.

2023-09-28 | PXD037236 | Pride

Analysis of globle gene expression changes observed in an in vitro fibroblast model of IPF

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.

2017-09-07 | GSE87175 | GEO

Increased Cell Surface Fas Expression is Necessary to Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis.

Project description:Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the pro-inflammatory cytokines, TNF-α and IFN-γ reverses fibroblast resistance to apoptosis. The goal of this study was to investigate the underlying mechanism. Based on an initial interrogation of the transcriptomes of unstimulated and TNF-α and IFN-γ-stimulated primary lung fibroblasts and the lung fibroblast cell line, MRC5, we show here that among Fas-signaling pathway molecules, Fas expression was increased ~6-fold in an NF-κB and p38mapk-dependent fashion. Prevention of the increase in Fas expression using Fas siRNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation induced-apoptosis; while enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. They also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant. To investigate the mechanism by which TNF-α and IFN-γ reprogram fibroblasts from resistance to sensitivity to Fas-ligation-induce apoptosis, we exposed human primary lung fibroblasts from an IPF patient (FS087) and non-disease control subject (N78) and the human fetal lung fibroblast cell lung (MRC-5) to TNF-α (10 ng/ml) and IFN-γ (50 U/ml) for 36 hr and analyzed changes in their transcriptomes using Affymetrix microarrays.

2011-01-13 | E-GEOD-26594 | biostudies-arrayexpress

The antifibrotic activity of the selective IP receptor agonist ACT-333679 is mediated through inhibition of YAP/TAZ signaling

Project description:Idiopathic pulmonary fibrosis (IPF) is a life-threatening and progressive scarring disease of the lung. Loss of alveolar epithelial cells, inflammation, activation of fibroblasts, appearance of myofibroblasts and excessive deposition of extracellular matrix (ECM) are central features of IPF pathogenesis, ultimately resulting in changes in tissue architecture and lung dysfunction. The two currently approved therapies, pirfenidone (Esbriet®) and nintedanib (Ofev®), significantly slow the rate of disease progression, but they do not halt or reverse tissue remodeling. Therefore, disease modifying strategies that influence (myo)fibroblast activity and ECM deposition could lead to promising new treatments. Here we demonstrate potent and effective in vitro antifibrotic properties of the selective prostacyclin (IP) receptor agonist, ACT-333679, on TGFβ1-stimulated primary human lung fibroblasts from non-diseased and IPF donors. We demonstrate that ACT-333679 inhibited fibrotic processes through elevation of cAMP, inhibition of YAP/TAZ signaling and subsequent suppression of YAP/TAZ-induced gene transcription. Our results describe attenuation of YAP/TAZ signaling through IP receptor activation as a novel mechanism that suppresses pro-fibrotic (myo)fibroblast activity and we offer a rationale to further explore the potential of IP receptor agonists for the treatment of IPF .

2019-01-24 | GSE109585 | GEO

IL-11 is a therapeutic target in idiopathic pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here we show that IL-11 is upregulated in the lung of IPF patients, associated with disease severity and is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive, ACTA2+ve, collagen secreting myofibroblasts, in an ERK-dependent fashion. In mice, fibroblast-specific transgenic expression or administration of Il-11 drives lung fibroblast-to-myofibroblast transformation and causes lung fibrosis. Il11ra1 deleted mice, whose lung fibroblasts are unresponsive to pro-fibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11 neutralising antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment both prevented and reversed lung fibrosis, which was accompanied by diminished Erk activation. These data prioritise IL-11 as a drug target for lung fibrosis and IPF.

2022-05-06 | GSE130983 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data