Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial basal stem/progenitor cells from COPD

Abstract

22Objectives: Patients with Chronic Obstructive Pulmonary Disease (COPD) have a bronchial 23 epithelium with many anomalies and basal/progenitor cells showing a decrease of self-renewal 24 and differentiation potential. The objective of this study was to identify deregulations in the 25 genetic program of COPD bronchial progenitors that could account for their exhaustion. The 26 transcription factor Slug/Snail2 is highly expressed in bronchial progenitors and we aimed at 27 identifying genes downstream of Slug whose expression is deregulated in COPD progenitors. 28 Results:We knocked down Slug in primary basal cells from COPD subjects and, since COPD 29 subjects have higher levels of Transforming Growth Factor (TGF)-β and Slug is regulated by 30 TGF-β, we selected genes downstream of Slug involved in differentiation that respond to We identified transcription factors involved in stem cell maintenance downstream of Slug and 32 repressed by TGF-β in COPD but not normal progenitors. We found that the effect of TGF-β on 33 the expression of these genes is correlated to Slug knockdown effect. We also found a correlation 34 between the mRNA levels of Slug and these genes only in presence of TGF-β. These results 35 reveal that stem cell maintenance genes are deregulated in COPD bronchial progenitors, Slug and 36 TGF-β being involved in that deregulation. 37