Proliferation Genes Repressed by TGF-β Are Downstream of Slug/Snail2 in Normal Bronchial Epithelial Progenitors and Are Deregulated in COPD

• Published in: Stem cell reviews and reports Vol. 17; no. 3; pp. 703 - 718
• Main Authors: Ben Brahim, Chamseddine, Courageux, Charlotte, Jolly, Ariane, Ouine, Bérengère, Cartier, Aurélie, de la Grange, Pierre, de Koning, Leanne, Leroy, Pascale
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2021; Springer Nature B.V
• Subjects: Adult; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Bronchi - cytology; Bronchi - drug effects; Bronchi - metabolism; Cell Biology; Cell culture; Cell Proliferation; Chronic obstructive pulmonary disease; E-cadherin; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial-Mesenchymal Transition; Epithelium; Humans; Life Sciences; Mesenchyme; Progenitor cells; Pulmonary Disease, Chronic Obstructive - genetics; Pulmonary Disease, Chronic Obstructive - metabolism; Regenerative Medicine/Tissue Engineering; Respiratory diseases; Smad3 protein; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Stem Cells; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Transcription factors; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; β-Catenin; Adult stem/progenitor cells; Chronic obstructive pulmonary disease (COPD); Slug/Snail2 transcription factor; Proliferation genes; Human primary bronchial basal/progenitor cells; Transforming growth factor (TGF-β)
• ISSN: 2629-3269; 2629-3277; 2629-3277
• DOI: 10.1007/s12015-021-10123-z

Slug/Snail2 belongs to the Epithelial-Mesenchymal Transition (EMT)-inducing transcription factors involved in development and diseases. Slug is expressed in adult stem/progenitor cells of several epithelia, making it unique among these transcription factors. To investigate Slug role in human bronchial epithelium progenitors, we studied primary bronchial basal/progenitor cells in an air-liquid interface culture system that allows regenerating a bronchial epithelium. To identify Slug downstream genes we knocked down Slug in basal/progenitor cells from normal subjects and subjects with COPD, a respiratory disease presenting anomalies in the bronchial epithelium and high levels of TGF-β in the lungs. We show that normal and COPD bronchial basal/progenitors, even when treated with TGF-β, express both epithelial and mesenchymal markers, and that the epithelial marker E-cadherin is not a target of Slug and, moreover, positively correlates with Slug. We reveal that Slug downstream genes responding to both differentiation and TGF-β are different in normal and COPD progenitors, with in particular a set of proliferation-related genes that are among the genes repressed downstream of Slug in normal but not COPD. In COPD progenitors at the onset of differentiation in presence of TGF-β,we show that there is positive correlations between the effect of differentiation and TGF-β on proliferation-related genes and on Slug protein, and that their expression levels are higher than in normal cells. As well, the expression of Smad3 and β-Catenin, two molecules from TGF-βsignaling pathways, are higher in COPD progenitors, and our results indicate that proliferation-related genes and Slug protein are increased by different TGF-β-induced mechanisms. Graphical abstract