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TGF-β1-induced deposition of provisional extracellular matrix by tracheal basal cells promotes epithelial-to-mesenchymal transition in a c-Jun NH2-terminal kinase-1-dependent manner

van der Velden, Jos L.; Wagner, Darcy E. LU ; Lahue, Karolyn G.; Abdalla, Sarah T.; Lam, Ying Wai; Weiss, Daniel J. and Janssen-Heininger, Yvonne M.W. (2018) In American Journal of Physiology - Lung Cellular and Molecular Physiology 314(6). p.984-997
Abstract

Epithelial cells have been suggested as potential drivers of lung fibrosis, although the epithelial-dependent pathways that promote fibrogenesis remain unknown. Extracellular matrix is increasingly recognized as an environment that can drive cellular responses in various pulmonary diseases. In this study, we demonstrate that transforming growth factor-β1 (TGF-β1)-stimulated mouse tracheal basal (MTB) cells produce provisional matrix proteins in vitro, which initiate mesenchymal changes in subsequently freshly plated MTB cells via Rho kinase-and c-Jun NH2-terminal kinase (JNK1)-dependent processes. Repopulation of decellularized lung scaffolds, derived from mice with bleomycin-induced fibrosis or from patients with idiopathic... (More)

Epithelial cells have been suggested as potential drivers of lung fibrosis, although the epithelial-dependent pathways that promote fibrogenesis remain unknown. Extracellular matrix is increasingly recognized as an environment that can drive cellular responses in various pulmonary diseases. In this study, we demonstrate that transforming growth factor-β1 (TGF-β1)-stimulated mouse tracheal basal (MTB) cells produce provisional matrix proteins in vitro, which initiate mesenchymal changes in subsequently freshly plated MTB cells via Rho kinase-and c-Jun NH2-terminal kinase (JNK1)-dependent processes. Repopulation of decellularized lung scaffolds, derived from mice with bleomycin-induced fibrosis or from patients with idiopathic pulmonary fibrosis, with wild-type MTB cells resulted in a loss of epithelial gene expression and augmentation of mesenchymal gene expression compared with cells seeded into decellularized normal lungs. In contrast, Jnk1-/- basal cells seeded into fibrotic lung scaffolds retained a robust epithelial expression profile, failed to induce mesenchymal genes, and differentiated into club cell secretory protein-expressing cells. This new paradigm wherein TGF-β1-induced extracellular matrix derived from MTB cells activates a JNK1-dependent mesenchymal program, which impedes subsequent normal epithelial cell homeostasis, provides a plausible scenario of chronic aberrant epithelial repair, thought to be critical in lung fibrogenesis. This study identifies JNK1 as a possible target for inhibition in settings wherein reepithelialization is desired.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ECM, Epithelial, Fibrosis, JNK
in
American Journal of Physiology - Lung Cellular and Molecular Physiology
volume
314
issue
6
pages
984 - 997
publisher
American Physiological Society
external identifiers
  • scopus:85048225136
ISSN
1040-0605
DOI
10.1152/ajplung.00053.2017
language
English
LU publication?
yes
id
adcfa663-7960-415c-b3c1-018c3a5c8e80
date added to LUP
2018-06-21 14:41:27
date last changed
2019-09-17 04:34:37
@article{adcfa663-7960-415c-b3c1-018c3a5c8e80,
  abstract     = {<p>Epithelial cells have been suggested as potential drivers of lung fibrosis, although the epithelial-dependent pathways that promote fibrogenesis remain unknown. Extracellular matrix is increasingly recognized as an environment that can drive cellular responses in various pulmonary diseases. In this study, we demonstrate that transforming growth factor-β1 (TGF-β1)-stimulated mouse tracheal basal (MTB) cells produce provisional matrix proteins in vitro, which initiate mesenchymal changes in subsequently freshly plated MTB cells via Rho kinase-and c-Jun NH<sub>2</sub>-terminal kinase (JNK1)-dependent processes. Repopulation of decellularized lung scaffolds, derived from mice with bleomycin-induced fibrosis or from patients with idiopathic pulmonary fibrosis, with wild-type MTB cells resulted in a loss of epithelial gene expression and augmentation of mesenchymal gene expression compared with cells seeded into decellularized normal lungs. In contrast, Jnk1<sup>-/-</sup> basal cells seeded into fibrotic lung scaffolds retained a robust epithelial expression profile, failed to induce mesenchymal genes, and differentiated into club cell secretory protein-expressing cells. This new paradigm wherein TGF-β1-induced extracellular matrix derived from MTB cells activates a JNK1-dependent mesenchymal program, which impedes subsequent normal epithelial cell homeostasis, provides a plausible scenario of chronic aberrant epithelial repair, thought to be critical in lung fibrogenesis. This study identifies JNK1 as a possible target for inhibition in settings wherein reepithelialization is desired.</p>},
  author       = {van der Velden, Jos L. and Wagner, Darcy E. and Lahue, Karolyn G. and Abdalla, Sarah T. and Lam, Ying Wai and Weiss, Daniel J. and Janssen-Heininger, Yvonne M.W.},
  issn         = {1040-0605},
  keyword      = {ECM,Epithelial,Fibrosis,JNK},
  language     = {eng},
  month        = {06},
  number       = {6},
  pages        = {984--997},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology - Lung Cellular and Molecular Physiology},
  title        = {TGF-β1-induced deposition of provisional extracellular matrix by tracheal basal cells promotes epithelial-to-mesenchymal transition in a c-Jun NH<sub>2</sub>-terminal kinase-1-dependent manner},
  url          = {http://dx.doi.org/10.1152/ajplung.00053.2017},
  volume       = {314},
  year         = {2018},
}