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TGF or TNF Time series in ARPE19

ABSTRACT: Aberrant epithelial-mesenchymal transition (EMT) is involved in　pathological processes including fibrotic disorders and cancer invasion and metastasis. Alterations of the cell-extracellular matrix　(ECM) interaction also contribute to those pathological settings.　However, the functional interplay between EMT and cell-ECM　interaction is poorly understood. Here, we show that tumor necrosis factor (TNF)-α, a potent mediator of inflammation, induces　EMT-associated fibrosis in retinal pigment epithelial cells, and that this is regulated by hyaluronan (HA)-CD44-Moesin interaction. TNF-α elicits both HA synthesis and Moesin phosphorylation through protein kinase C activation, promoting binding of CD44 to the newly synthesized HA. The HA-CD44-Moesin interaction leads to cell-cell dissociation through actin remodeling and increased cellular motility associated with mesenchymal phenotype. Furthermore, we　established an in vivo model of TNF-α-induced fibrosis in the mouse eye, and the ocular fibrosis was completely suppressed in CD44-null mice. Therefore, HA production and its interaction with CD44 plays essential role in TNF-α-induced-EMT, and the interference of the complex formation can be a new strategy for the fibrotic disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15205 | GEO | 2010/03/11

SECONDARY ACCESSION(S): PRJNA114967

REPOSITORIES: GEO

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TGF or TNF Time series in ARPE19

Project description:Aberrant epithelial-mesenchymal transition (EMT) is involved in pathological processes including fibrotic disorders and cancer invasion and metastasis. Alterations of the cell-extracellular matrix (ECM) interaction also contribute to those pathological settings. However, the functional interplay between EMT and cell-ECM interaction is poorly understood. Here, we show that tumor necrosis factor (TNF)-alpha, a potent mediator of inflammation, induces EMT-associated fibrosis in retinal pigment epithelial cells, and that this is regulated by hyaluronan (HA)-CD44-Moesin interaction. TNF-alpha elicits both HA synthesis and Moesin phosphorylation through protein kinase C activation, promoting binding of CD44 to the newly synthesized HA. The HA-CD44-Moesin interaction leads to cell-cell dissociation through actin remodeling and increased cellular motility associated with mesenchymal phenotype. Furthermore, we established an in vivo model of TNF-alpha-induced fibrosis in the mouse eye, and the ocular fibrosis was completely suppressed in CD44-null mice. Therefore, HA production and its interaction with CD44 plays essential role in TNF-alpha-induced-EMT, and the interference of the complex formation can be a new strategy for the fibrotic disorders. ARPE19 cell lines were treated with TGF and TNF for 6 and 42 hour. Each experiment were repeated three times. But 1hour experiment was repeated two times. For this submission, total RNA was extracted from TGF- or TNF-treated ARPE-19 cells and differential gene expression between each time point (6 and 42 hours) was determined using genechip arrays (Affymetrix, Human Genome U133).

2010-03-23 | E-GEOD-15205 | biostudies-arrayexpress

Modeling of Aberrant Epithelial Reprogramming in Idiopathic Pulmonary Fibrosis using Human Induced Pluripotent Stem Cell-derived Alveolar Organoids

Project description:Alveolar type 2 (AT2) organoids, derived from induced pluripotent stem cells, were stimulated with a fibrosis cocktail containing the pro-fibrotic and inflammatory cytokines TGF-β (5 ng/ml), TNF-α (10 ng/ml), PDGF-AB (10 ng/ml) and LPA (5 μM) or control cocktail containing diluents for 72 h.

2023-05-22 | E-MTAB-11676 | biostudies-arrayexpress

beta 1 integrin signaling governs necroptosis via the chromatin remodeling factor CHD4

Project description:Fibrosis, characterized by sustained activation of myofibroblasts and excessive extracellular matrix (ECM) deposition, is known to be associated with chronic inflammation. RIPK3, a key kinase mediating TNF-driven necroptosis signaling, is upregulated in fibrosis and contributes to the TNF-mediated inflammation. In bile duct ligation-induced liver fibrosis, we found that myofibroblasts are the major cell type expressing RIPK3. Genetic ablation of beta1 integrins, the major profibrotic ECM receptors in fibroblasts, not only abolished ECM fibrillogenesis but also blunted RIPK3 expression via an epigenetic mechanism mediated by the chromatin remodeling factor CHD4. While the function of CHD4 has been conventionally linked to NuRD and ChAHP complexes, we found that CHD4 potently repressed a set of genes, including Ripk3, with high locus specificity but independent of either the NuRD or ChAHP complex. Thus, our data uncover that beta1 integrin intrinsically links fibrotic signaling to RIPK3-driven inflammation via a novel mode of action of CHD4.

2023-10-30 | PXD041505 | Pride

Blockade of pentraxin 3/CD44 interaction on attenuation and reversal of lung injury-induced fibrosis

Project description:Fibrosing interstitial lung disease (fILD) is a fatal fibrotic lung disease with limited therapeutic options and no effective therapeutic strategies to reverse pulmonary fibrosis. Here, we found that PTX3 is upregulated in the lungs of bleomycin-treated mice and fILD patients. Lung injury and fibrosis were significantly attenuated in inducible conditional Ptx3-deficient mice in response to bleomycin treatment. Moreover, we dissected mechanistic insights into PTX3/CD44-dependent fibrotic pathways and effectors in lung myofibroblast activation and collagen production. Importantly, αPTX3i disrupts the interaction of PTX3 and CD44 and effectively attenuated bleomycin-treated lung injury and fibrosis in vivo and myofibroblast activation in vitro. Our study provides new insight into the regulation of PTX3 in pulmonary fibrosis and a potential target for developing future novel therapy for fILDs.

2022-08-04 | GSE210165 | GEO

b1 integrin signaling governs necroptosis via the chromatin remodeling factor CHD4

Project description:Fibrosis, characterized by sustained activation of myofibroblasts and excessive extracellular matrix (ECM) deposition, is known to be associated with chronic inflammation. RIPK3, a key kinase mediating TNF-driven necroptosis signaling, is upregulated in fibrosis and contributes to the TNF-mediated inflammation. In biliary duct ligation-induced liver fibrosis, we found that myofibroblasts are the major cell type expressing RIPK3. Genetic ablation of b1 integrins, the major profibrotic ECM receptors in fibroblasts, not only abolished ECM fibrillogenesis but also blunted RIPK3 expression via an epigenetic mechanism mediated by the chromatin remodeling factor CHD4. While the function of CHD4 has been conventionally linked to NuRD and ChAHP complexes, we found that CHD4 potently repressed a set of genes, including Ripk3, with high locus specificity but independent of either the NuRD or ChAHP complex. Thus, our data uncover that b1 integrin intrinsically links fibrotic signaling to RIPK3-driven inflammation via a novel mode of action of CHD4.

2023-10-23 | GSE229795 | GEO

Three Distinct Cell Types Express Extracellular Matrix Proteins In Different Niches During Skeletal Muscle Fibrosis

Project description:Tissue extracellular matrix provides structural support and creates unique niches for resident cells . However, the identities of cells responsible for creating specific ECM niches have not been determined. In striated muscle, the identity of these cells becomes important in disease when ECM changes result in fibrosis and subsequent increased tissue stiffness and dysfunction. Here we describe a novel approach to isolate and identify cells that maintain ECM niches in both healthy and fibrotic muscle. Using a collagen I reporter mouse, we show that there are three distinct cell populations that express collagen I in both healthy and fibrotic skeletal muscle. Interestingly, the number of collagen I expressing cells in all three cell populations increase proportionally in fibrotic muscle indicating that all cell types participate in the fibrosis process. Furthermore, it is shown that the ECM gene expression profile is not qualitatively altered in fibrotic muscle. This suggests that muscle fibrosis in this model results from an increased number of collagen I expressing cells and not the initiation of a specific fibrotic gene expression program. Finally, in fibrotic muscle, we show that these collagen I expressing cell populations differentially express distinct ECM proteins – fibroblasts express the fibrillar components of ECM, fibro/adipogenic progenitors cells differentially express basal laminar proteins and skeletal muscle progenitor cells differentially express genes important for the satellite cell niche.

2016-12-04 | GSE89633 | GEO

Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is a natural stabilizer of hyaluronan that modulates biological processes in the skin

Project description:Hyaluronan (HA) is a major component of the skin that exerts a variety of biological functions. Inter-α-trypsin inhibitor heavy chain (ITIH) proteins comprise a family of hyaladherins of which ITIH5 was recently described in skin, playing a functional role in skin morphology and inflammatory skin diseases including allergic contact dermatitis (ACD). The current study focused on the ITIH5-HA interaction and its potential clinical and functional impact in extracellular matrix (ECM) stabilization. Using murine skin models, ITIH5 knockdown fibroblasts and a reactive oxygen species (ROS)-mediated HA degradation assay we proved that ITIH5 binds to HA thereby acting as a stabilizer of HA. Moreover, micro-array profiling revealed the impact of ITIH5 on biological processes such as skin development and ECM homeostasis. To understand more precisely the role of ITIH5 in inflammatory skin diseases such as ACD we generated ITIH5 knockout cells of the KeratinoSens cell line. Performing the in vitro KeratinoSens skin sensitization assay, we detected that ITIH5 decreases the sensitizing potential of moderate and strong contact sensitizers. Taken together, our experiments revealed that ITIH5 forms complexes with HA, thereby on the one hand stabilizing HA and facilitating the formation of ECM structures and on the other hand modulating inflammatory responses.

2019-12-05 | GSE141495 | 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

Analysis of conditioned media cytokine levels of breast cancer cell lines

Project description:To identify the cytokines secreted by mesenchymal-like cancer cells that activate macrophages, the cytokine profiles of conditioned media from MCF7, MCF7 induced to undergo EMT by treatment of TGF-β, TNF-α and prolonged mammosphere culture, and MDA-MB-231 cells were analyzed by RayBio® Human Cytokine Antibody Array V. 5 samples. There are 5 groups: MCF7, MCF7 induced to undergo EMT by treatment of TGF-β (TGF-β-MCF7), TNF-α (TNF-α-MCF7), prolonged mammosphere culture (MCF7M), and MDA-MB-231 cells

2013-11-01 | E-GEOD-51938 | biostudies-arrayexpress

Characterization of the Limbal Epithelial Stem Cell Niche

Project description:Limbal epithelial stem cells (LESCs) reside within the LSC niche (LSCN), located at the annular transition zone between the cornea and conjunctiva. LESCs are important for the long-term maintenance of the corneal epithelium and critical for repopulating the corneal epithelium after injury. We have recently identified that a hyaluronan (HA)-rich extracellular matrix (ECM) exists within the LSCN, and that this HA matrix is necessary for maintaining LESCs in the “stem cell” state. Herein we further characterized the composition of the LSCN, identifying key components of the HA-rich matrix. We identified that the hyaladherins IαI, TSG-6 and versican are highly expressed in the limbus when compared to the cornea. For IαI, Heavy chain 5 (HC5) was found to be the most highly expressed HC in the mouse and human cornea, and associates with HA forming HA/HC5 specific matrices. CD44 is the most likely receptor that mediates the interaction between LESCs and the HA-specific matrix. The LSCN is composed of a rich HA matrix that contains HA/HC5. HA/HC5 complexes could be used as an improved substrate for culturing LESCs during ex vivo expansion for limbal stem cell transplantation.

2023-11-08 | GSE244412 | GEO

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