Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix
Kevin K. Kim,Matthias C. Kugler,Paul J. Wolters,Liliane Robillard,Michael G. Galvez,Alexis N. Brumwell,Dean Sheppard,Harold A. Chapman +7 more
TLDR
Alveolar epithelial cells are revealed as progenitors for fibroblasts in vivo and implicate the provisional extracellular matrix as a key regulator of epithelial transdifferentiation during fibrogenesis.Abstract:
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 TGF-β1. 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.read more
Citations
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Epithelial-Mesenchymal Transitions in Development and Disease
Jean Paul Thiery,Jean Paul Thiery,Hervé Acloque,Ruby Yun-Ju Huang,Ruby Yun-Ju Huang,M. Angela Nieto +5 more
TL;DR: The mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
Journal ArticleDOI
The basics of epithelial-mesenchymal transition
Raghu Kalluri,Robert A. Weinberg +1 more
TL;DR: Processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias and the identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes.
Journal ArticleDOI
Biomarkers for epithelial-mesenchymal transitions
Michael Zeisberg,Eric G. Neilson +1 more
TL;DR: It is believed that context and various changes in plasticity biomarkers can help identify at least three types of EMT and that using a collection of criteria for EMT increases the likelihood that everyone is studying the same phenomenon - namely, the transition of epithelial and endothelial cells to a motile phenotype.
Journal ArticleDOI
The Myofibroblast: One Function, Multiple Origins
Boris Hinz,Sem H. Phan,Victor J. Thannickal,Andrea Galli,Marie-Luce Bochaton-Piallat,Giulio Gabbiani +5 more
TL;DR: A better knowledge of the molecular mechanisms conducive to the appearance of differentiated myofibroblasts in each pathological situation will be useful for the understanding of fibrosis development in different organs and the planning of strategies aiming at their prevention and therapy.
Journal ArticleDOI
Idiopathic pulmonary fibrosis
TL;DR: In this article, the authors reviewed recent data on the clinical course, therapeutic options, and underlying mechanisms thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis.
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