Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Non-canonical WNT5A controls the activation of latent TGFβ to drive fibroblast activation and tissue fibrosis

ABSTRACT: Transforming growth factor β (TGFβ) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGFβ remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGFβ in fibrotic diseases. WNT5A was identified as predominant non-canonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGFβ. The activation of latent TGFβ requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional Knockout of WNT5A or its downstream targets prevented activation of latent TGFβ, rebalanced TGFβ signaling and ameliorated experimental fibrosis. We thus uncovered a novel mechanism for the aberrant activation of latent TGFβ in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222916 | GEO | 2024/02/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Engrailed 1 coordinates cytoskeletal re-organization to induce myofibroblast differentiation

Project description:Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases including systemic sclerosis. Here we show that Engrailed 1 (EN1) is re-expressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and, in turn, EN1 mediates the pro-fibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a pro-fibrotic gene expression profile functionally related to the cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP-transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the re-organization of cytoskeleton during myofibroblast differentiation both in standard fibroblast culture systems and in in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.

2021-05-19 | GSE174598 | GEO

Engrailed 1 coordinates cytoskeletal re-organization to induce myofibroblast differentiation

2021-05-18 | GSE174580 | GEO

Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

Project description:Fibrotic diseases impose a major socioeconomic challenge on modern societies with limited treatment options. Adropin, a peptide hormone encoded by the energy-homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize Adropin/ENHO as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent downregulation of Adropin/ENHO in SSc skin across different SSc cohorts. The prototypical profibrotic cytokine TGFβ reduced Adropin/ENHO expression in a JNK-dependent manner. Restoration of Adropin signaling by therapeutic application of bioactive Adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, the mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices (PCSS). Knockdown of GPR19, receptor of Adropin, abrogated the antifibrotic effects of Adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of Adropin34-76 were functionally linked to deactivation of GLI1 dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo and ex vivo. ChIP-seq confirmed Adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study thus characterizes the TGFβ-induced downregulation of Adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling. We also provide evidence in multiple preclinical models that Adropin34-76 might offer potential for the treatment of fibrosis.

2024-04-29 | GSE252139 | GEO

Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

2024-04-29 | GSE252425 | GEO

PFKFB3-mediated glycolysis boosts fibroblast activation and subsequent kidney fibrosis

Project description:<p>Renal fibrosis, a hallmark of chronic kidney diseases, is driven by the activation of renal fibroblasts. Recent studies have highlighted the role of glycolysis in this process. Nevertheless, one critical glycolytic activator, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), remains unexplored in renal fibrosis. Upon reanalyzing the single-cell sequencing data from Dr. Humphreys' lab, we noticed an upregulation of glycolysis, gluconeogenesis, and TGFβ signaling pathway in myofibroblasts from fibrotic kidneys after unilateral ureter obstruction (UUO) or kidney ischemia/reperfusion. Furthermore, our experiments showed significant induction of PFKFB3 in mouse kidneys following UUO or kidney ischemia/reperfusion. To delve deeper into the role of PFKFB3, we generated mice with Pfkfb3 deficiency specifically in myofibroblasts (Pfkfb3f/fPostnMCM). Following UUO or kidney ischemia/reperfusion, a substantial decrease of fibrosis in injured kidneys of Pfkfb3f/fPostnMCM mice was identified compared to their wild-type littermates. Additionally, in cultured renal fibroblast NRK-49F cells, PFKFB3 was elevated upon exposure to TGFβ1, accompanied by the increase of α-SMA and fibronectin. Notably, this upregulation was significantly diminished with PFKFB3 knockdown, correlated with a glycolysis suppression. Mechanistically, the glycolytic metabolite lactate promoted the fibrotic activation of NRK-49F. In conclusion, our study demonstrates the critical role of PFKFB3 in driving fibroblast activation and subsequent renal fibrosis.</p>

2024-03-12 | MTBLS8281 | MetaboLights

Non-canonical WNT5A controls the activation of latent TGFβ to drive fibroblast activation and tissue fibrosis

Project description:Non-canonical WNT5A controls the activation of latent TGFβ to drive fibroblast activation and tissue fibrosis

| PRJNA924025 | ENA

Metabolic dysfunction is integral to TGFb signaling and tissue fibrosis

Project description:Fibrosis, or the accumulation of extracellular matrix, causes loss of organ function and is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross–examine human primary cells from various tissues treated with TGFβ, as well as rodent kidney and liver fibrosis models. Transcriptome analyses reveal that in addition to the known TGFβ signature, cluster of genes involved in fatty acid oxidation are significantly perturbed. Furthermore, defective mitochondrial oxidative phosphorylation and acylcarnitine accumulation are found in fibrotic tissues. Substantial down-regulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for all tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo. Altogether, our work demonstrate that metabolic defect is integral to TGFβ signaling and fibrosis, targeting which represents a promising therapeutic approach for multiple fibrotic diseases.

2020-11-24 | GSE152250 | GEO

Knock down effect of Ror2 on gene expression profiling in human osteosarcoma cells (SaOS2)

Project description:Ror2 is a member of the Ror-family of receptor tyrosine kinases acting as a receptor for Wnt5a. Wnt5a/Ror2 signaling activates primarily the ß-catenin-independent pathway, which involves various signal mediators, such as Dishevelled, c-Jun N-terminal kinase (JNK), filamin A, c-Src, and Ca2+. Wnt5a/Ror2 signaling has also been shown to inhibit the ß-catenin-dependent pathway. Wnt5a and Ror2 are overexpressed in various types of tumor cells, including osteosarcoma and melanoma cells, resulting in constitutive activation of Wnt5a/Ror2 signaling in a cell-autonomous manner. Constitutively activated Wnt5a/Ror2 signaling has been shown to play important roles in promoting invadopodia formation and invasiveness of tumor cells. However, little is known about the mechanisms underlying these processes. As an attempt to understand the mechanism by which Wnt5a/Ror2 signaling, activated constitutively in osteosarcoma cells, contributes to their highly invasive properties, we performed DNA microarray analysis using a human osteosarcoma cell line, SaOS2.

2017-01-01 | GSE76535 | GEO

MiR-199a-5p determines fibroblast activation and pulmonary fibrogenesis

Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFβ exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-02-01 | E-GEOD-34818 | biostudies-arrayexpress

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Project description:Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβ-mediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene PPARGC1A (PGC1α) in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose RNAi-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together these results provide novel mechanistic insight into the essential role HDACs play in TGFβ-mediated fibroblast activation via targeted gene repression.

2019-08-29 | GSE136534 | 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