Genes coding for transcription factors involved in stem cell maintenance are repressed by TGF-β and downstream of Slug/Snail2 in COPD bronchial epithelial progenitors.

Abstract

Basal stem/progenitor cells of airway epithelium from chronic obstructive pulmonary disease (COPD) patients have a decrease in differentiation and self-renewal potential. Our study aimed at identifying deregulations in the genetic program of these cells that could account for their exhaustion, focusing on genes downstream of the epithelial-mesenchymal transition-inducing transcription factor Slug/Snail2 and responding to transforming growth factor (TGF)-β. TGF-β is at higher levels in COPD patient lungs, plays a role in stem/progenitor cell fate and regulates the expression of Slug/Snail2 that is highly expressed in airway basal stem/progenitors. We reanalyzed a gene expression dataset that we generated from COPD and normal primary bronchial basal progenitor cells knocked down for Slug/Snail2 gene. Among the genes that we identified to be repressed downstream of Slug/Snail2 in COPD, we selected those responding to differentiation and TGF-β. The large majority of these genes are upregulated with differentiation but repressed by TGF-β. Pathway and ontology enrichment analysis revealed a set of genes coding for transcription factors involved in stem cell maintenance that are repressed downstream of Slug/Snail2 and by TGF-β in COPD but not normal basal progenitor cells. We also reveal a link between Slug/Snail2 expression and the repressive effect of TGF-β on these stem cell maintenance genes. Our work brings a new insight and molecular perspective to the exhaustion of basal stem/progenitor cells observed in the airway epithelium of COPD patients, revealing that stem cell maintenance genes are repressed in these cells, with TGF-β and Slug/Snail2 being involved in this deregulation.