Exaggerated BMP4 signalling alters human airway basal progenitor cell differentiation to cigarette smoking-related phenotypes. Issue 5 (18th May 2019)

• Record Type: Journal Article
• Authors: Zuo, Wu-Lin; Yang, Jing; Strulovici-Barel, Yael; Salit, Jacqueline; Rostami, Mahboubeh; Mezey, Jason G.; O'Beirne, Sarah L.; Kaner, Robert J.; Crystal, Ronald G.
• Is Part Of: European respiratory journal. Volume 53:Issue 5(2019)
• Publication Date: 2019-05-18
• Subjects: Respiratory organs -- Diseases -- Periodicals; Respiration -- Periodicals; 616.2
• DOI: 10.1183/13993003.02553-2017
• Languages: English
• ISSNs: 0903-1936

Abstract

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 data demonstrate that in cigarette smokers, BMP4 is upregulated in ciliated and intermediate undifferentiated cells, and expression of the BMP4 receptor BMPR1A is enriched in BCs. BMP4 induced BCs to acquire a smoking-related abnormal phenotype in vitro mediated by BMPR1A/Smad signalling, characterised by decreased capacity to differentiate into normal mucociliary epithelium, while generating squamous metaplasia. Exaggerated BMP4 signalling promotes cigarette smoking-relevant airway epithelial remodelling by inducing abnormal phenotypes in human airway BCs. Targeting of BMP4 signalling in airway BCs may represent a novel target to prevent/treat COPD-associated airway disease. COPD pathogenesis is mediated by BMP4 reprogrammed stem/progenitor cells in human airway http://ow.ly/iWAI30nuWor