Alveolar Epithelial Cell Mesenchymal Transition Develops in vivo during Pulmonary Fibrosis and Is Regulated by the Extracellular Matrix

Mechanisms leading to fibroblast accumulation during pulmonary fibrogenesis remain unclear. Although there is in vitro evidence of lung alveolar epithelial-to-mesenchymal transition (EMT), whether EMT occurs within the lung is currently unknown. Biopsies from fibrotic human lungs demonstrate epithel...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-08, Vol.103 (35), p.13180-13185
Main Authors: Kim, Kevin K., Kugler, Matthias C., Wolters, Paul J., Robillard, Liliane, Galvez, Michael G., Brumwell, Alexis N., Sheppard, Dean, Chapman, Harold A.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
beta-Galactosidase - metabolism
Biological Sciences
Cells
Cells, Cultured
Collagen - metabolism
Cultured cells
Cystic fibrosis
Drug Combinations
Epithelial cells
Epithelial Cells - cytology
Extracellular Matrix - metabolism
Fibroblasts
Fibronectins - metabolism
Fibrosis
Gene expression
Genes, Reporter
Humans
Idiopathic pulmonary fibrosis
Laminin - metabolism
Lungs
Mesoderm - cytology
Mice
Mice, Transgenic
Proteoglycans - metabolism
Pulmonary alveoli
Pulmonary Alveoli - cytology
Pulmonary Alveoli - pathology
Pulmonary Fibrosis - pathology
Rodents
Transforming Growth Factor beta - metabolism
Transforming Growth Factor beta1
Transgenic animals
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Summary:Mechanisms leading to fibroblast accumulation during pulmonary fibrogenesis remain unclear. Although there is in vitro evidence of lung alveolar epithelial-to-mesenchymal transition (EMT), whether EMT occurs within the lung is currently unknown. Biopsies from fibrotic human lungs demonstrate epithelial cells with mesenchymal features, suggesting EMT. To more definitively test the capacity of alveolar epithelial cells for EMT, mice expressing β-galactosidase (β-gal) exclusively in lung epithelial cells were generated, and their fates were followed in an established model of pulmonary fibrosis, overexpression of active TGF-β1. β-gal-positive cells expressing mesenchymal markers accumulated within 3 weeks of in vivo TGF-β1 expression. The increase in vimentin-positive cells within injured lungs was nearly all β-gal-positive, indicating epithelial cells as the main source of mesenchymal expansion in this model. Ex vivo, primary alveolar epithelial cells cultured on provisional matrix components, fibronectin or fibrin, undergo robust EMT via integrin-dependent activation of endogenous latent TGFβ1. In contrast, primary cells cultured on laminin/collagen mixtures do not activate the TGF-β1 pathway and, if exposed to active TGF-β1, undergo apoptosis rather than EMT. These data reveal alveolar epithelial cells as progenitors for fibroblasts in vivo and implicate the provisional extracellular matrix as a key regulator of epithelial transdifferentiation during fibrogenesis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0605669103