Science and Research

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.

Keywords

  • Airway Epithelium
  • COPD Pathology
  • COPD exacerbations mechanisms
  • Occupational Lung Disease
  • Thoracic Surgery
Publication details
DOI: 10.1136/thorax-2022-219958
Journal: Thorax
Work Type: Original
Location: CPC-M
Disease Area: COPD
Partner / Member: ASK, HMGU, KUM
Access-Number: 38286613

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