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

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.

• Stoleriu, M. G.
• Ansari, M.
• Strunz, M.
• Schamberger, A.
• 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.
• Stoeger, T.
• Schiller, H.
• Hilgendorff, A.