Dataset Information

TGF-?1-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.

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-?1 (TGF-?1)-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-?1-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.

SUBMITTER: van der Velden JL

PROVIDER: S-EPMC6032072 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

van der Velden Jos L JL Wagner Darcy E DE Lahue Karolyn G KG Abdalla Sarah T ST Lam Ying-Wai YW Weiss Daniel J DJ Janssen-Heininger Yvonne M W YMW

American journal of physiology. Lung cellular and molecular physiology 20180222 6

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 subseq ...[more]

PMID: 29469614

Similar Datasets

Project description:The contribution of hyaluronan-dependent pericellular matrix to TGF-β1-driven induction and maintenance of myofibroblasts is not understood. Hyaluronan is an extracellular matrix (ECM) glycosaminoglycan important in cell adhesion, proliferation and migration, and is implicated in myofibroblast formation and maintenance. Reduced turnover of hyaluronan has been linked to differentiation of myofibroblasts and potentiation of lung fibrosis. Fibronectin is a fibril forming adhesive glycoprotein that is also upregulated following induction with TGF-β1. Although they are known to bind each other, the interplay between hyaluronan and fibronectin in the pericellular matrix during myofibroblast induction and matrix assembly is not clear. This study addresses the role of hyaluronan and its interaction with fibrillar matrix components during myofibroblast formation. Hyaluronan and fibronectin were increased and co-localized in the ECM following myofibroblast induction by TGF-β1. Inhibition of hyaluronan synthesis in TGF-β1-induced lung myofibroblasts over a 4day period with 4-methyl umbelliferone (4-MU) further enhanced myofibroblast morphology, caused increased deposition of fibronectin and type I collagen in the ECM, and increased expression of alpha-smooth muscle actin and hyaluronan synthase 2 (HAS2) mRNA. Hyaluronan oligosaccharides or hyaluronidase treatment, which more effectively disrupted the pericellular matrix, had similar effects. CD44 and β1 integrins co-localized in the cell membrane and along some stress fibers. However, CD44 and hyaluronan were specifically excluded from focal adhesions, and associated primarily with cortical actin. Time-lapse imaging of the immediate effects of hyaluronidase digestion showed that hyaluronan matrix primarily mediates attachment of membrane and cortical actin between focal contacts, suggesting that surface adhesion through hyaluronan and CD44 is distinct from focal adhesion through β1 integrins and fibronectin. Fluorescein-labeled hyaluronan bound regularly along fibronectin fibers and co-localized more with β1 integrin and less with CD44. Therefore, the hyaluronan matrix can interfere with the assembly of fibrillar ECM components, and this interplay regulates the degree of myofibroblast formation. These data also suggest that adhesion through hyaluronan matrix impacts cytoskeletal organization, and is potentially part of a clutch mechanism that regulates stick and slip of myofibroblasts by affecting the adhesion to and organization of fibronectin and collagen.

Dataset Information

TGF-?1-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.

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets