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: 13.77). 01/2009; 119(1):213-24. DOI: 10.1172/JCI36940
Source: PubMed

ABSTRACT 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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    • "Myofibroblasts were originally believed to be derived from tissue fibroblasts (Serini and Gabbiani, 1999), but there is now mounting evidence for alternative origins, depending on the tissue location and surrounding microenvironment. These include epithelial cells (via epithelial-mesenchymal transition; EMT; Iwano et al., 2002; Zeisberg et al., 2007; Kim et al., 2009), smooth muscle cells (Humphreys et al., 2010) and fibrocytes (Bucala et al., 1994; Abe et al., 2001; Quan et al., 2006). As major cellular constituents of the healthy peritoneal membrane, mesothelial cells are also thought to be a source of myofibroblasts within the peritoneal cavity, via EMT (Pollock, 2005). "
    Regenerative Medicine and Tissue Engineering - Cells and Biomaterials, 08/2011; , ISBN: 978-953-307-663-8
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    • "Myofibroblasts are recruited to the lung interstitium 7–14 d after bleomycin injury and dissipate through apoptosis by 21 d (Zhang et al., 1996). Although considerable evidence has accumulated defin­ ing mediators such as TGF­ that are essential for fibroblasts to express ASMA and assume contractile functions (Kim et al., 2009), there has been no in vivo demonstration that con­ trolling ASMA­expressing cells regulates chronic tissue fibrosis. "
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    ABSTRACT: Tissue fibrosis is a major cause of morbidity, and idiopathic pulmonary fibrosis (IPF) is a terminal illness characterized by unremitting matrix deposition in the lung. The mechanisms that control progressive fibrosis are unknown. Myofibroblasts accumulate at sites of tissue remodeling and produce extracellular matrix components such as collagen and hyaluronan (HA) that ultimately compromise organ function. We found that targeted overexpression of HAS2 (HA synthase 2) by myofibroblasts produced an aggressive phenotype leading to severe lung fibrosis and death after bleomycin-induced injury. Fibroblasts isolated from transgenic mice overexpressing HAS2 showed a greater capacity to invade matrix. Conditional deletion of HAS2 in mesenchymal cells abrogated the invasive fibroblast phenotype, impeded myofibroblast accumulation, and inhibited the development of lung fibrosis. Both the invasive phenotype and the progressive fibrosis were inhibited in the absence of CD44. Treatment with a blocking antibody to CD44 reduced lung fibrosis in mice in vivo. Finally, fibroblasts isolated from patients with IPF exhibited an invasive phenotype that was also dependent on HAS2 and CD44. Understanding the mechanisms leading to an invasive fibroblast phenotype could lead to novel approaches to the treatment of disorders characterized by severe tissue fibrosis.
    Journal of Experimental Medicine 06/2011; 208(7):1459-71. DOI:10.1084/jem.20102510 · 13.91 Impact Factor
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    • "Recently it has been shown that WNT and TGF-b1 pathways are important in the development of pulmonary fibrosis through the effect of a3b1 integrins. This integrin facilitates the binding of b-catenin to Smad2, promoting EMT and the development of lung fibrosis [Kim et al. 2009]. Thus, it is possible that disruption of WNT signalling following initial activation of epithelial cell integrin mediated TGF-b activation pathways may lead to the propagation of fibrosis, at the expense of normal repair. "
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an appalling prognosis. The failure of anti-inflammatory therapies coupled with the observation that deranged epithelium overlies proliferative myofibroblasts to form the fibroblastic focus has lead to the emerging concept that IPF is a disease of deregulated epithelial-mesenchymal crosstalk. IPF is triggered by an as yet unidentified alveolar injury that leads to activation of transforming growth factor-β (TGF-β) and alveolar basement membrane disruption. In the presence of persisting injurious pathways, or disrupted repair pathways, activated TGF-β can lead to enhanced epithelial apoptosis and epithelial-to-mesenchymal transition (EMT) as well as fibroblast, and fibrocyte, transformation into myofibroblasts which are resistant to apoptosis. The resulting deposition of excess disrupted matrix by these myofibroblasts leads to the development of IPF.
    Therapeutic Advances in Respiratory Disease 10/2010; 4(6):367-88. DOI:10.1177/1753465810379801 · 1.95 Impact Factor
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