Wnt/ß-catenin signalling is upregulated in the COPD bronchial epithelium

Rationale: Research into pathways that drive COPD pathophysiology are key to unravel novel therapeutic targets. In contrast with the alveolar epithelium, the role of Wnt in the COPD bronchial epithelium (BE) remains unclear. Methods: We performed a targeted RNA sequencing (RNA-seq) of 92 preselected canonical Wnt-related genes in air/liquid interface-reconstituted BE from 47 patients (9 non-smoker controls, 10 smoker controls, 9 mild COPD, 10 moderate COPD and 9 very severe COPD). Quantification of active and total β-catenin was performed in immunostained BE. In addition, a pilot in vitro modulation experiment was carried out using CHIR99021 and XAV939 to activate or inhibit, respectively, the canonical Wnt pathway, to assess its role in broncho-epithelial differentiation. Results: RNA-seq data of Wnt genes was consistent with a global activation of the canonical Wnt pathway in COPD, as evidenced by the upregulation of PORCN, FZD7, CTNNB1, CSNK2A1&2, SOX4, TCF7L2, and MMP2&7 amongst others. This activation was more pronounced in very severe disease. Increased levels of both active and total β-catenin were observed in BE. In the pilot modulation experiment, CHIR99021 strongly inhibited epithelial differentiation for both goblet (SPDEF, MUC5AC) and ciliated cells (FOXJ1, DNAI1&2), as well as epithelial polarization (pIgR), while XAV939 promoted broncho-epithelial polarization. Conclusions: Canonical Wnt signalling is activated in the COPD bronchial epithelium, and could contribute to the COPD airway epithelial phenotype which will be further assessed through modulation experiments and in situ BE laser microdissection.