Epithelial cell α3β1 integrin links β-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis

Pulmonary and Critical Care Division, Department of Medicine, and Cardiovascular Research Institute, UCSF, San Francisco, CA 94143, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 01/2009; 119(1):213-24. DOI: 10.1172/JCI36940
Source: PubMed


Pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), results from aberrant wound healing and scarification. One population of fibroblasts involved in the fibrotic process is thought to originate from lung epithelial cells via epithelial-mesenchymal transition (EMT). Indeed, alveolar epithelial cells (AECs) undergo EMT in vivo during experimental fibrosis and ex vivo in response to TGF-beta1. As the ECM critically regulates AEC responses to TGF-beta1, we explored the role of the prominent epithelial integrin alpha3beta1 in experimental fibrosis by generating mice with lung epithelial cell-specific loss of alpha3 integrin expression. These mice had a normal acute response to bleomycin injury, but they exhibited markedly decreased accumulation of lung myofibroblasts and type I collagen and did not progress to fibrosis. Signaling through beta-catenin has been implicated in EMT; we found that in primary AECs, alpha3 integrin was required for beta-catenin phosphorylation at tyrosine residue 654 (Y654), formation of the pY654-beta-catenin/pSmad2 complex, and initiation of EMT, both in vitro and in vivo during the fibrotic phase following bleomycin injury. Finally, analysis of lung tissue from IPF patients revealed the presence of pY654-beta-catenin/pSmad2 complexes and showed accumulation of pY654-beta-catenin in myofibroblasts. These findings demonstrate epithelial integrin-dependent profibrotic crosstalk between beta-catenin and Smad signaling and support the hypothesis that EMT is an important contributor to pathologic fibrosis.

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Available from: Paul J Wolters, Dec 09, 2014
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    • "While the transcriptional programs controlling EMT have been widely studied, the importance of cytoskeletal signaling in regulating EMT initiation and progression has only recently been appreciated. EMT can be induced by a variety of stimuli including growth factors and cytokines [Valles et al., 1990; Miettinen et al., 1994; Elliott et al., 2002; Xie et al., 2003], hypoxia [Higgins et al., 2007; Sahlgren et al., 2008], extracellular matrix (ECM) components [Zeisberg et al., 2001; Kim et al., 2009; Espinosa Neira and Perez Salazar, 2012], and mechanical cues [O'Connor and Gomez, 2014] . Transforming growth factor (TGF)-b, a multifunctional cytokine that promotes development, differentiation, and survival [Shi and Massague, 2003; Derynck and Akhurst, 2007], is regarded as a key mediator of EMT and has been found to contribute to EMT in the contexts of development, fibrosis, and cancer [Zavadil and Bottinger, 2005; Xu et al., 2009]. "
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    ABSTRACT: Epithelial mesenchymal transition (EMT) is a physiological process that plays an important role in embryonic development and wound healing and is appropriated during pathological conditions including fibrosis and cancer metastasis. EMT can be initiated by a variety of factors, including transforming growth factor (TGF)-β, and is characterized by loss of epithelial features including cell-cell contacts and apicobasal polarity and acquisition of a motile, mesenchymal phenotype. A key feature of EMT is reorganization of the cytoskeleton and recent studies have elucidated regulation mechanisms governing this process. This review describes changes in gene expression patterns of cytoskeletal associated proteins during TGFβ-induced EMT. It further reports TGFβ-induced intracellular signaling cascades that regulate cytoskeletal reorganization during EMT. Finally, it highlights how changes in cytoskeletal architecture during EMT can regulate gene expression, thus further promoting EMT progression. This article is protected by copyright. All rights reserved.
    Preview · Article · Nov 2015 · Cytoskeleton
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    • "EMT is triggered by a variety of soluble factors including epidermal growth factor (EGF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), and TGFβ [55,78-85]. Other stimuli, such as hypoxia [86,87] and adhesion to ECM components can also induce EMT [69,88,89]. TGFβ, a ubiquitously expressed cytokine, is a potent inducer of EMT and is regarded as a key mediator of wound healing [90,91], fibrosis [92,93], and cancer [94,95]. "
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    ABSTRACT: Fibrosis, a disease that results in loss of organ function, contributes to a significant number of deaths worldwide and sustained fibrotic activation has been suggested to increase the risk of developing cancer in a variety of tissues. Fibrogenesis and tumor progression are regulated in part through the activation and activity of myofibroblasts. Increasing evidence links myofibroblasts found within fibrotic lesions and the tumor microenvironment to a process termed epithelial-mesenchymal transition (EMT), a phenotypic change in which epithelial cells acquire mesenchymal characteristics. EMT can be stimulated by soluble signals, including transforming growth factor (TGF)-β, and recent studies have identified a role for mechanical cues in directing EMT. In this review, we describe the role that EMT plays in fibrogenesis and in the progression of cancer, with particular emphasis placed on biophysical signaling mechanisms that control the EMT program. We further describe specific TGFβ-induced intracellular signaling cascades that are affected by cell- and tissue-level mechanics. Finally, we highlight the implications of mechanical induction of EMT on the development of treatments and targeted intervention strategies for fibrosis and cancer.
    Full-text · Article · Jul 2014 · Clinical and Translational Medicine
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    • "Exposure of primary alveolar cells to fibronectin or fibrin led to robust EMT, a phenomenon dependent on αVβ6 integrin [12]. In a follow-up study, deletion of α3 integrin in lung epithelium prevented mice from developing fibrosis and led to a decrease in myofibroblast population and collagen I expression after bleomycin injury [61]. These findings strongly suggest that EMT is regulated by contextual factors such as cytokines and ECM interactions through integrin signaling. "
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    ABSTRACT: A pathological hallmark of asthma is chronic injury and repair, producing dysfunction of the epithelial barrier function. In this setting, increased oxidative stress, growth factor- and cytokine stimulation, together with extracellular matrix contact produces transcriptional reprogramming of the epithelial cell. This process results in epithelial-mesenchymal transition (EMT), a cellular state associated with loss of epithelial polarity, expression of mesenchymal markers, enhanced mobility and extracellular matrix remodeling. As a result, the cellular biology of the EMT state produces characteristic changes seen in severe, refractory asthma: myofibroblast expansion, epithelial trans-differentiation and subepithelial fibrosis. EMT also induces profound changes in epithelial responsiveness that affects innate immune signaling that may have impact on the adaptive immune response and effectiveness of glucocorticoid therapy in severe asthma. We discuss how this complex phenotype is beginning to be understood using systems biology-level approaches through perturbations coupled with high throughput profiling and computational modeling. Understanding the distinct changes induced by EMT at the systems level may provide translational strategies to reverse the altered signaling and physiology of refractory asthma.
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