PT - JOURNAL ARTICLE AU - Wu-Lin Zuo AU - Jing Yang AU - Yael Strulovici-Barel AU - Jacqueline Salit AU - Mahboubeh Rostami AU - Jason G. Mezey AU - Sarah L. O'Beirne AU - Robert J. Kaner AU - Ronald G. Crystal TI - Exaggerated BMP4 Signalling Alters Human Airway Basal Progenitor Cell Differentiation to Cigarette Smoking-related Phenotypes AID - 10.1183/13993003.02553-2017 DP - 2019 Jan 01 TA - European Respiratory Journal PG - 1702553 4099 - http://erj.ersjournals.com/content/early/2019/01/23/13993003.02553-2017.short 4100 - http://erj.ersjournals.com/content/early/2019/01/23/13993003.02553-2017.full AB - Airway remodelling in chronic obstructive pulmonary disease (COPD) originates, in part, from smoking-induced changes in airway basal stem/progenitor cells (BC). Based on the knowledge that the 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 BC relevant to COPD. BMP4 signalling components in human airway epithelium were analysed at the mRNA and protein levels, and the differentiation of BC was assessed using the BC expansion and air-liquid interface models in the absence/presence of BMP4, BMP receptor inhibitor and/or siRNAs against BMP receptors and downstream signalling. The data demonstrates that in cigarette smokers, BMP4 is up-regulated in ciliated and intermediate undifferentiated cells and expression of the BMP4 receptor BMPR1A is enriched in BC. BMP4-induced BC to acquire a smoking-related abnormal phenotype in vitro mediated by BMPR1A/Smad signalling, characterised by decreased capacity to differentiate into the normal mucociliary epithelium, while generating squamous metaplasia. In summary, exaggerated BMP4 signalling promotes cigarette smoking-relevant airway epithelial remodelling by inducing abnormal phenotypes in human airway BC progenitor cells. Targeting of BMP4 signalling in airway BC may represent a novel target to prevent/treat COPD-associated airway disease.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Crystal has nothing to disclose.Conflict of interest: Dr. Zuo has nothing to disclose.Conflict of interest: Dr. Yang has nothing to disclose.Conflict of interest: Dr. Strulovici-Barel has nothing to disclose.Conflict of interest: Ms. Salit has nothing to disclose.Conflict of interest: Dr. Kaner has nothing to disclose.Conflict of interest: Dr. O'Beirne has nothing to disclose.Conflict of interest: Dr. Mezey has nothing to disclose.Conflict of interest: Dr. Rostami has nothing to disclose.