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Human bronchial epithelial cell-derived extracellular vesicles attenuate pulmonary fibrosis through inhibiting TGF-β-WNT crosstalk [miRNA-Seq]

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal ﬁbrosis with poor prognosis. An aberrant recapitulation of lung developmental genes including transforming growth factor (TGF)-β and WNT has been widely implicated in the abnormal wound healing process following repetitive alveolar epithelial injury during IPF pathogenesis. Extracellular vesicles (EVs) including exosomes and microvesicles have been shown to carry various bioactive molecules and are involved in a variety of physiological and pathological processes. Here, we demonstrate that human bronchial epithelial cell-derived EVs (HBEC EVs) inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling. To ask how HBEC-EVs inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling, miRNA RNA-seq of HBEC-EVs was performed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156572 | GEO | 2021/08/18

REPOSITORIES: GEO

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Human bronchial epithelial cell-derived extracellular vesicles attenuate pulmonary fibrosis through inhibiting TGF-β-WNT crosstalk [RNA-Seq]

Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal ﬁbrosis with poor prognosis. An aberrant recapitulation of lung developmental genes including transforming growth factor (TGF)-β and WNT has been widely implicated in the abnormal wound healing process following repetitive alveolar epithelial injury during IPF pathogenesis. Extracellular vesicles (EVs) including exosomes and microvesicles have been shown to carry various bioactive molecules and are involved in a variety of physiological and pathological processes. Here, we demonstrate that human bronchial epithelial cell-derived EVs (HBEC EVs) inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling. To ask how HBEC-EVs inhibited TGF-β-induced both myofibroblast differentiation and lung epithelial cellular senescence through attenuating WNT signaling, miRNA RNA-seq of HBEC-EVs was performed.

2021-08-18 | GSE158623 | GEO

MicroRNA microarray between smoking-induced human bronchial epithelial cell (HBEC)-derived extracellular vesicles (EVs) and non-treated HBEC-derived Evs

Project description:To identify exosomal miRNAs that regulate smoking-induced lung myofibroblast differentiation, we conducted a miRNA microarray between smoking-induced HBEC-derived EVs and non-treated HBEC-derived EVs.

2018-02-19 | GSE66119 | GEO

To examine the expression of Sulf1 and Sulf2, as well as other glycan-related genes, in human Idiopathic pulmonary fibrosis (IPF) lungs compared to normal lung samples

Project description:Microarray analysis to examine glycan-related gene expression in idiopathic pulmonary fibrosis Heparan sulfate 6-O-endosulfatases (Sulf1 and Sulf2) remove 6-O sulfate groups from heparan sulfate intra-chain sites on the cell surface and in the extracellular matrix, and modulate the functions of many growth factors and morphogens including FGF, Wnt and TGF-beta. Works from our laboratory have shown that TGF-beta 1 induces Sulf1 and Sulf2 expression in a cell-type specific manner in the lung, specifically Sulf1 in lung fibroblasts and Sulf2 in type II alveolar epithelial cells. Interestingly TGF-beta 1-induced Sulf1 and Sulf2 in turn modulate TGF-beta 1 function in culture. The aim of this study is to examine the expression of Sulf1 and Sulf2 as well as other glycan-related genes (heparan biosynthetic enzymes, TGF-beta, FGF and Wnt signaling pathway components) in human idiopathic pulmonary fibrosis (IPF) lungs compared to normal lung samples. We will examine gene expression in triplicate samples from RNA of total lung homogenates from IPF and control (normal) lungs

2011-09-05 | E-GEOD-31934 | biostudies-arrayexpress

The DNM3OS lncRNA is a reservoir of fibromiRs with major functions in fibroblast response to TGF-beta and fibrogenesis

Project description:RATIONALE: Given the paucity of effective treatments for Idiopathic Pulmonary Fibrosis (IPF), new insights into the deleterious mechanisms controlling lung fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. Transforming growth factor β (TGF-β) is the main pro-fibrotic factor, but its inhibition is associated with severe side effects due to its pleiotropic role. OBJECTIVES: We hypothesized that downstream non-coding effectors of TGF-β in fibroblasts may represent new effective therapeutic targets whose modulation may be well-tolerated. METHODS: We investigated the whole non-coding fraction of TGF-β-stimulated lung fibroblast transcriptome to identify new genomic determinants of lung fibroblast differentiation into myofibroblast. Differential expression of the long non-coding RNA DNM3OS and its associated miRNAs was validated in a murine model of pulmonary fibrosis and in IPF tissue samples. Distinct and complementary antisense oligonucleotide-based strategies aiming at interfering with DNM3OS were used to elucidate the role of DNM3OS and its associated miRNAs in IPF pathogenesis. MEASUREMENTS AND MAIN RESULTS: We identified DNM3OS as a fibroblast-specific critical downstream effector of TGF-β-induced lung myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to three distinct profibrotic mature miRNAs (i.e. miR-199a-5p/3p and miR-214-3p), which influence both SMAD and non-SMAD components of TGF-β signaling in a multifaceted way. In vivo, we showed that interfering with DNM3OS function not only prevents lung fibrosis but also improves established pulmonary fibrosis. CONCLUSION: Pharmacological approaches aiming at interfering with DNM3OS may represent new effective therapeutic strategies in IPF. This SuperSeries is composed of the SubSeries listed below.

2019-04-10 | GSE97834 | GEO

The profile of miRNAs in lung fibroblast-derived extracellular vesicles from idiopathic pulmonary fibrosis (IPF) patients or non-IPF individuals.

Project description:Accelerated senescence in lung epithelial cells is known to play a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the exact mechanisms underlying the IPF-related epithelial cell phenotype have yet to be elucidated. Increasing evidence supports the concept that extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communication that contributes to diverse aspects of physiology and pathogenesis. Here, we demonstrate that lung fibroblasts (LFs) from IPF patients accelerate epithelial cell senescence via EV-mediated transfer of LF-derived pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increase mitochondrial reactive oxygen species (mtROS) and associated mitochondrial damage in lung epithelial cells, leading to mtROS-mediated activation of the DNA damage response and subsequent epithelial cell senescence. We show that IPF LF-derived EVs contain elevated levels of miR-23b-3p and miR-494-3p that are responsible for suppressing SIRT3, resulting in the EV-induced phenotypic changes of lung epithelial cells. Furthermore, we observe that miR-23b-3p and miR-494-3p expression increases in lung epithelial cells from IPF patients’ lungs. Finally, the levels of miR-23b-3p and 494-3p found in IPF LF-derived EVs correlate positively with IPF disease severity. These findings reveal that the accelerated epithelial cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel mechanism in which SIRT3 is suppressed by miR-containing EVs derived from IPF fibroblasts.

2020-08-04 | GSE124665 | GEO

The mRNA profile of human bronchial epithelial cells transfected with miR-23b-3p, miR-145-5p and miR-494-3p

2020-08-04 | GSE124502 | GEO

Growth Factor Levels in the Blood of Patients Undergoing Radiation Therapy for Epithelial Cancer

Project description:RATIONALE: Measuring levels of transforming growth factor-beta (TGF-beta) in the blood of patients with epithelial cancers (head and neck, lung, breast, colorectal, and prostate) may help doctors predict how patients will respond to treatment with radiation therapy. PURPOSE: This research study is measuring levels of TGF-beta in patients with epithelial cancers who are undergoing radiation therapy.

| 2072028 | ecrin-mdr-crc

Identification of microRNA expression patterns in human myofibroblasts with/without the JQ-1 treatment and/or TGF-b

Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that normal parenchyma is progressively replaced by fibrotic foci comprised of myofibroblasts, active differentiated fibroblasts. IPF has an overall poor prognosis with median survival ranging from 2.5 to 3.5 years. The underlying disease mechanisms in IPF are largely unknown, and there is still no effective drug that prolongs survival of patients with IPF. It has been known that JQ-1, a BET bromodomain inhibitor, prevents TGF-β-mediated fibroblast to myofibroblast differentiation. Moreover, JQ-1 modulates miRNAs expression in various types of cancer cell. In this study, to gain understanding of the relationship between miRNAs expression and the effect of JQ-1 on the dedifferentiation of established myofibroblast, we investigated miRNA profiles in human myofibroblasts with/without the JQ-1 treatment and/or TGF- using miRNA microarray assay.

2020-07-11 | GSE140475 | GEO

Bi-directional epithelial-mesenchymal crosstalk provides self-sustaining pro-fibrotic signals in pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2-4 years. Injury to and/or dysfunction of alveolar epithelium are strongly implicated in IPF disease initiation, but what factors determine why fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that ZEB1-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments TGF-β-induced profibrogenic responses in underlying lung fibroblasts by paracrine signalling. Here we investigated bi-directional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA sequencing (RNA-seq) of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced EMT identified many differentially expressed genes including those involved in cell migration and extracellular matrix (ECM) regulation. We confirmed that paracrine signalling between AS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a ZEB1-tissue plasminogen activator (tPA) axis. In a reciprocal fashion, paracrine signalling from TGF-β-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially via the secreted protein, SPARC. Together these data identify that aberrant bi-directional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining pro-fibrotic signals.

2021-08-19 | PXD025821 | Pride

Retinoic Acids Exposure Alters TGFbeta1 -Induced Epithelial Mesenchymal Transition via Wnt5b expression.

Project description:Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease; EBV has previously been localised to alveolar epithelial cells of IPF patients. The molecular process of the epithelial mesenchymal transition (EMT) in IPF remains still unknown. Using an oligonucleotide array analysis, we observed dysregulated expression of members of non-canonical Wnt family in EBV infected A549 after TGF?1 exposure. TGF?1 exposure induced EMT increasing ?-Smooth Muscle Actin (ACTC) and Wnt5b gene expression, but decreasing E-cadherin and DKK1. When data were analyzed as a function of Wnt5b in EMT, significance differences in ACTC and E-cadherin gene expression, active TGF?1 protein levels and collagen deposition could be detected. Treatment with 9-cis Retinoic Acid (9-cisRA) significantly inhibited Wnt5b expression in both EBV infected and non-infected A549, followed by decreased collagen deposition and active TGF?1 protein level. Specific non-canonical Wnt-signalling genes are dysregulated in EBV infected cells and A549 treated with TGF?1; while, 9-cisRA treatment appears to attenuate EMT process in vitro. Keywords: EBV infection, EMT and non-canonical Wnt pathway in A549 detected by oligonucleotide array

2006-08-05 | GSE5457 | GEO

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