Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial epithelial progenitors from Chronic Obstructive Pulmonary Disease

Objectives: Patients with Chronic Obstructive Pulmonary Disease (COPD) have a bronchial epithelium with many anomalies and basal/progenitor cells showing a decrease of self-renewal and differentiation potential. The objective of this study was to identify deregulations in the genetic program of COPD bronchial progenitors that could account for their exhaustion. The transcription factor Slug/Snail2 is highly expressed in bronchial progenitors and we aimed at identifying genes downstream of Slug whose expression is deregulated in COPD progenitors. Results: We knocked down Slug in primary basal cells from COPD subjects and, since COPD subjects have higher levels of Transforming Growth Factor (TGF)-β and Slug is regulated by TGF-β, we selected genes downstream of Slug involved in differentiation that respond to TGF-β. We identified transcription factors involved in stem cell maintenance downstream of Slug and repressed by TGF-β in COPD but not normal progenitors. We found that the effect of TGF-β on the expression of these genes is correlated to Slug knockdown effect. We also found a correlation between the mRNA levels of Slug and these genes only in presence of TGF-β. These results reveal that stem cell maintenance genes are deregulated in COPD bronchial progenitors, Slug and TGF-β being involved in that deregulation.