β-Catenin/T-cell Factor Signaling Is Activated during Lung Injury and Promotes the Survival and Migration of Alveolar Epithelial Cells

Flozak, Annette S.; Lam, Anna; Russell, Susan; Jain, Manu; Peled, Ofra N.; Sheppard, Kerry A.; Beri, Rohinee; Mutlu, Gökhan M.; Budinger, G. R. Scott; Gottardi, Cara J.

doi:10.1074/jbc.m109.070326

Cited by 113 publications

(131 citation statements)

References 68 publications

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“…Similarly, LPS and CSE exposure also suppresses cell proliferation and levels of beta-catenin protein, e-cadherin protein and caveolin-1 mRNA in our native matrix model. In corroboration, recent studies also show that besides the regulation of barrier functions, tight junctions are important for cell cycle, cell migration, proliferation and regeneration (Kasper et al 1995;Phillips et al 2008;Flozak et al 2010;Shiozaki et al 2012). In addition, MSC exhibited ability to modulate tight junctions-associated proteins e-cadherin and betacatenin when added together with CSE and LPS in our model.…”

Section: Discussionsupporting

confidence: 56%

Native matrix-based human lung alveolar tissue model in vitro: studies of the reparatory actions of mesenchymal stem cells

et al. 2016

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Studies of lung diseases in vitro often rely on flat, plastic-based monocultures, due to short lifespan of primary cells, complicated anatomy, lack of explants, etc. We hereby present a native 3D model with cues for repopulating epithelial cells. Abilities of mesenchymal stem cells (MSC) to modulate bacterial lipopolysaccharide (LPS) and cigarette smoke-induced injury to pulmonary epithelium were tested in our model. Post-mortem human lung tissue was sliced, cut and decellularized. Resulting matrix pads were reseeded with pulmonary epithelium (A549 line). Markers of the layer integrity and certain secreted proteins in the presence of cigarette smoke extract (CSE) and LPS were assessed via Western blot, ELISA and RT-PCR assays. In parallel, the effects of MSC paracrine factors on exposed epithelial cells were also investigated at gene and protein levels. When cultured on native 3D matrix, A549 cells obtain dual, type I-and II-like morphology. Exposure to CSE and LPS leads to downregulation of several epithelial proteins and suppressed proliferation rate. MSC medium added to the model restores proliferation rate and some of the epithelial proteins, i.e. e-cadherin and beta-catenin. CSE also increases secretion of proinflammatory cytokines by epithelial cells and upregulates transcription factor NFjB. Some of these effects might be counteracted by MSC in our model. We introduce repopulated decellularized lung matrix that highly resembles in vivo situation and is convenient for studies of disease pathogenesis, cytotoxicology and for exploring therapeutic strategies in the human lung context in vitro. MSC paracrine products have produced protecting effects in our model.

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Section: Discussionsupporting

confidence: 56%

Native matrix-based human lung alveolar tissue model in vitro: studies of the reparatory actions of mesenchymal stem cells

et al. 2016

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“…Studies have shown that Wnt/β-catenin/T-cell factor (TCF) signaling is activated during lung injury and promotes the survival and migration of alveolar epithelial cells (5). β-catenin is a key player of canonical Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to lung cancer, whether the RBM5 level is also reduced in other cigarette smoke-induced lung injury has not been determined. Meanwhile, the activation of the Wnt/β-catenin signaling pathway plays an important role in diseases associated with cigarette smoking (5,14,15). Alveolar epithelial cells are the major components of the airway epithelium that are directly affected by cigarette smoking.…”

Section: Introductionmentioning

confidence: 99%

RNA-binding motif protein 5 negatively regulates the activity of Wnt/β-catenin signaling in cigarette smoke-induced alveolar epithelial injury

Hao

et al. 2015

Oncology Reports

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Abstract. Cigarette smoking is closely associated with various respiratory diseases. Oxidants and carcinogens in cigarettes are reported to induce various airway epithelial injuries. However, the underlying mechanisms remain unclear. The aims of the present study were to determine the involvement of RNA-binding motif protein 5 (RBM5) and Wnt/β-catenin signaling in cigarette smoke-induced alveolar epithelial injury, as well as the interaction between both. A549 cells were treated with cigarette smoke extract (CSE). The MTT assay was used to assess the effects of CSE on cell viability. The levels of RBM5 and Wnt/β-catenin/GSK3β were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. A luciferase assay was used to assess the activity of β-catenin/T-cell factor (TCF) signaling. The results revealed that CSE inhibited A549 cell viability in both a dose-and time-dependent manner. Cytosolic and nuclear β-catenin levels were significantly increased following CSE treatment, compared with those in the control cells (P<0.05). The luciferase activity in CSE-exposed cells transfected with the TCF luciferase reporter wild-type plasmid (pGL3-OT) was significantly greater than that in cells without CSE exposure (33,167±3,085 vs. 19,978±1,916, respectively, P<0.05). Both the mRNA and protein levels of RBM5 in the CSE-treated cells were significantly reduced compared to the levels in the controls (all P<0.05). The overexpression of RBM5 inhibited Wnt/β-catenin signaling in the A549 cells, while silencing of RBM5 enhanced Wnt/β-catenin signaling. The β-catenin/TCF signaling inhibitor ICG-001 had no apparent effect on the RBM5 levels. Downregulation of RBM5 and activation of Wnt/β-catenin signaling are involved in CSE-induced alveolar epithelial injury. RBM5 acts as an upstream molecule that negatively regulates the activity of Wnt/β-catenin signaling.

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“…through Wnt signaling, pY654 could promote nuclear translocation and transcriptional activity of ␤-catenin on its target genes. Prior studies have provided evidence of active Wnt signaling during experimental and human fibrosis (11)(12)(13), and recent observations indicate that one function of Wnt signaling in the lung is likely an epithelial cytoprotective effect following injury (14). It is also unclear mechanistically why the epithelial integrin ␣3␤1 is required for TGF␤1-induced Tyr-654 phosphorylation.…”

mentioning

confidence: 99%

Axin Pathway Activity Regulates in Vivo pY654-β-catenin Accumulation and Pulmonary Fibrosis

Ulsamer

Wei

Kim

et al. 2012

Journal of Biological Chemistry

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Background: TGF␤1-induced pY654-␤-catenin correlates with epithelial mesenchymal transition (EMT) and pulmonary fibrosis, but whether pY654-␤-catenin is functionally important is unknown. Results: ␤-Catenin point mutants reveal that pY654 is critical to EMT, and pY654-␤-catenin accumulation is blocked by axin-dependent ␤-catenin turnover. Conclusion: Raised axin levels in vivo attenuate EMT and fibrosis after bleomycin injury. Significance: Targeting axin levels could attenuate fibrosis without blocking TGF␤1 homeostatic functions.

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β-Catenin/T-cell Factor Signaling Is Activated during Lung Injury and Promotes the Survival and Migration of Alveolar Epithelial Cells

Cited by 113 publications

References 68 publications

Native matrix-based human lung alveolar tissue model in vitro: studies of the reparatory actions of mesenchymal stem cells

Native matrix-based human lung alveolar tissue model in vitro: studies of the reparatory actions of mesenchymal stem cells

RNA-binding motif protein 5 negatively regulates the activity of Wnt/β-catenin signaling in cigarette smoke-induced alveolar epithelial injury

Axin Pathway Activity Regulates in Vivo pY654-β-catenin Accumulation and Pulmonary Fibrosis

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