Slug/Snail2 belongs to the Epithelial-Mesenchymal Transition (EMT)-inducing transcription factors that are involved in development and diseases. Slug is also highly expressed in normal adult stem/progenitor cells of several epitheliums, and in such is unique among these transcription factors. By comparing primary bronchial basal cells from normal subjects to those from subjects with Chronic Obstructive Pulmonary Disease (COPD), a respiratory disease in which subjects present many anomalies of their bronchial epithelium and higher levels of Transforming Growth Factor (TGF)-β in their lungs, in an air-liquid interface culture system that allows regenerating a bronchial epithelium similar to the one in vivo, we reveal that Slug has higher expression levels in basal/progenitor cells from COPD when in presence of TGF-β but that it does not repress the epithelial marker E-cadherin either in normal or in COPD cells, even when treated with TGF-β. To investigate Slug role in human primary bronchial basal/progenitor cells we performed loss of function experiments to determine Slug downstream genes and we characterized the impact of TGF-β on these genes. We show that Slug downstream genes are different in normal and COPD subjects. In particular, we identified a set of proliferation-related genes whose expression is decreased by TGF-β when cells are induced to differentiate, and that are among the genes repressed downstream of Slug in normal but not in COPD cells. In COPD the levels of expression of these genes are higher than in normal cells in presence of TGF-β, and they positively correlate with the effect of TGF-β on Slug. Our findings show that Slug is involved in the repression of proliferation genes by TGF-β in normal basal/progenitor cells, but that in contrast, in subjects that present many anomalies in their bronchial epithelium this function of Slug is lost and Slug and proliferation genes are simultaneously but independently regulated by TGF-β.
Patients with COPD have many anomalies in their airway epithelium, and their basal stem/progenitor cells show a decrease in self-renewal and differentiation potential. The objective of this study was to identify deregulations in the genetic program of COPD bronchial basal stem/progenitor cells that could account for their exhaustion. TGF- is found at higher levels in the lungs of COPD subjects. It has been shown to play a role in stem/progenitor cell fate and also to regulate the expression of the EMT-inducing transcription factor Slug/Snail2. In contrast to other transcription factors of the Snail family, Slug is highly expressed in basal progenitor cells, the adult stem/progenitors of human airway epithelium. We aimed at identifying genes downstream of Slug that respond to TGF-, and whose expression is deregulated in COPD airway basal stem/progenitor cells, and could account for the decrease in count and functional ability of these cells observed in COPD. For this, we knocked down Slug in primary bronchial basal progenitor cells from COPD and normal subjects and, among the genes downstream of Slug, we selected those responding to TGF- and differentiation. We identified 5 genes coding for transcription factors involved in stem cell maintenance that are repressed downstream of Slug and by TGF- in COPD but not normal basal progenitor cells. Our results bring a molecular perspective to the exhaustion of airway basal stem/progenitor cells observed in COPD by revealing that stem cell maintenance genes are repressed in these cells, with TGF- and Slug being involved in this deregulation.
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