Exaggerated BMP4 signalling alters human airway basal progenitor cell differentiation to cigarette smoking-related phenotypes [array]

Airway remodelling in chronic obstructive pulmonary disease (COPD) originates, in part, from smoking-induced changes in airway basal stem/progenitor cells (BCs). Based on the knowledge that bone morphogenetic protein 4 (BMP4) influences epithelial progenitor function in the developing and adult mouse lung, we hypothesised that BMP4 signalling may regulate the biology of adult human airway BCs relevant to COPD. BMP4 signalling components in human airway epithelium were analysed at the mRNA and protein levels, and the differentiation of BCs was assessed using the BC expansion and air-liquid interface models in the absence/presence of BMP4, BMP receptor inhibitor and/or small interfering RNAs against BMP receptors and downstream signalling. The study demonstrates that in cigarette smokers, BMP4 is up-regulated in ciliated and intermediate undifferentiated cells and BMP4 receptor BMPR1A is enriched in BC. In vitro, mediated by BMPR1A/Smad signaling, BMP4-induced BC to acquire a COPD-like abnormal phenotypes, characterized by decreased capacity to differentiate into the normal mucociliary epithelium, generating a hypoplastic squamous metaplasia. In summary, smoking-induced exaggerated BMP4 signaling promotes COPD-relevant airway epithelial remodeling by inducing abnormal phenotypes in human airway BC progenitor cells. Targeting of BMP4 signaling in airway BC may represent a novel approach to prevent/treat COPD-associated airway disease. Array profiling of 208 samples (small airway epithelium cells at various collection times from COPD smokers and nonsmokers).