Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition.
In chronic obstructive pulmonary disease (COPD), epithelial changes and subepithelial fibrosis are salient features in conducting airways. Epithelial-to-mesenchymal transition (EMT) has been recently suggested in COPD, but the mechanisms and relationship to peribronchial fibrosis remain unclear. We hypothesised that de-differentiation of the COPD respiratory epithelium through EMT could participate in airway fibrosis and thereby, in airway obstruction. Surgical lung tissue and primary broncho-epithelial cultures (in air-liquid interface (ALI)) from 104 patients were assessed for EMT markers. Cell cultures were also assayed for mesenchymal features and for the role of transforming growth factor (TGF)-β1. The bronchial epithelium from COPD patients showed increased vimentin and decreased ZO-1 and E-cadherin expression. Increased vimentin expression correlated with basement membrane thickening and airflow limitation. ALI broncho-epithelial cells from COPD patients also displayed EMT phenotype in up to 2 weeks of culture, were more spindle shaped and released more fibronectin. Targeting TGF-β1 during ALI differentiation prevented vimentin induction and fibronectin release. In COPD, the airway epithelium displays features of de-differentiation towards mesenchymal cells, which correlate with peribronchial fibrosis and airflow limitation, and which are partly due to a TGF-β1-driven epithelial reprogramming.
Université Catholique de Louvain (UCL), Institute of Experimental & Clinical Research - Pole of Pneumology, ENT and Dermatology, Brussels, Belgium Department of Pneumology, Cliniques universitaires St-Luc, Brussels, Belgium.
Sophie T
ST
Gohy
Université Catholique de Louvain (UCL), Institute of Experimental & Clinical Research - Pole of Pneumology, ENT and Dermatology, Brussels, Belgium.
Cloé
C
Hupin
Université Catholique de Louvain (UCL), Institute of Experimental & Clinical Research - IREC Imaging Platform, Brussels, Belgium.
Chantal
C
Fregimilicka
Université Catholique de Louvain (UCL), Institute of Experimental & Clinical Research - Pole of Pneumology, ENT and Dermatology, Brussels, Belgium.
Bruno R
BR
Detry
Université Catholique de Louvain (UCL), Institute of Experimental & Clinical Research - IREC Imaging Platform, Brussels, Belgium.
Caroline
C
Bouzin
Université Catholique de Louvain (UCL), CELL Unit, de Duve Institute, Brussels, Belgium.
Héloïse
H
Gaide Chevronay
Université Catholique de Louvain (UCL), Institute of Experimental & Clinical Research - Pole of Pneumology, ENT and Dermatology, Brussels, Belgium.
Marylène
M
Lecocq
Department of Pathology, CHU Godinne, Yvoir, Belgium.
Birgit
B
Weynand
Université Catholique de Louvain (UCL), Institute of Experimental & Clinical Research - Pole of Pneumology, ENT and Dermatology, Brussels, Belgium Institute for Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Brussels, Belgium.
Maha Z
MZ
Ladjemi
Université Catholique de Louvain (UCL), CELL Unit, de Duve Institute, Brussels, Belgium.
Christophe E
CE
Pierreux
INSERM UMR-S 903, SFR CAP-Santé, University of Reims-Champagne-Ardenne, Reims, France.
Philippe
P
Birembaut
INSERM UMR-S 903, SFR CAP-Santé, University of Reims-Champagne-Ardenne, Reims, France.
Myriam
M
Polette
Université Catholique de Louvain (UCL), Institute of Experimental & Clinical Research - Pole of Pneumology, ENT and Dermatology, Brussels, Belgium Department of Pneumology, Cliniques universitaires St-Luc, Brussels, Belgium Institute for Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Brussels, Belgium charles.pilette@uclouvain.be.
Charles
C
Pilette
D000368:Aged; D000402:Airway Obstruction; D015703:Antigens, CD; D001980:Bronchi / Q000166:cytology; D015820:Cadherins / Q000378:metabolism; D054337:Cell Dedifferentiation; D004847:Epithelial Cells / Q000166:cytology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D020545:Respiratory Mucosa / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D005353:Fibronectins; C508960:TGFB1 protein, human; C569042:TJP1 protein, human; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D062826:Zonula Occludens-1 Protein