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Stoleriu, M.-G. ; Ansari, M. ; Strunz, M. ; Schamberger, A.C. ; Heydarian, M. ; Ding, Y. ; Voss, C. ; Schneider, J.J. ; Gerckens, M. ; Burgstaller, G. ; Castelblanco, A. ; Kauke, T.* ; Fertmann, J.* ; Schneider, C.* ; Behr, J. ; Lindner, M.* ; Stacher-Priehse, E.* ; Irmler, M. ; Beckers, J. ; Eickelberg, O. ; Schubert, B. ; Hauck, S.M. ; Schmid, O. ; Hatz, R.A.* ; Stöger, T. ; Schiller, H. ; Hilgendorff, A.

COPD basal cells are primed towards secretory to multiciliated cell imbalance driving increased resilience to environmental stressors.

Thorax 79, 524-537 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
INTRODUCTION: Environmental pollutants injure the mucociliary elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised. METHODS: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air-liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation. RESULTS: COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC+) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub+), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5+ (P=0.018) and LAMB3+ (P=0.050) expression, as well as a significant activation of Wnt-specific (P=0.014) and Notch-specific (P=0.021) genes, especially in precursors of suprabasal and secretory cells. CONCLUSION: We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Airway Epithelium ; Copd Pathology ; Copd Exacerbations Mechanisms ; Occupational Lung Disease ; Thoracic Surgery; Zinc-oxide Nanoparticles; Particulate Matter; Airway Epithelium; In-vitro; Inflammation; Mechanisms; Metaplasia; Surface; Model; Lung
ISSN (print) / ISBN 0040-6376
e-ISSN 1468-3296
Journal Thorax
Quellenangaben Volume: 79, Issue: 6, Pages: 524-537 Article Number: , Supplement: ,
Publisher BMJ Publishing Group
Publishing Place British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Lung Health and Immunity (LHI)
Institute of Experimental Genetics (IEG)
CF Metabolomics & Proteomics (CF-MPC)
Grants European Union
BMBF (Federal Network 3R, KLIMA study)
Stiftung AtemWeg (LSS AIRR)
Research Training Group Targets in Toxicology of the German Science and Research Organization (DFG)
German Center for Lung Research (DZL, German Ministry of Education and Health (BMBF))
Helmholtz Zentrum Muenchen, Germany
Helmholtz Foundation