Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium

Nat Commun. 2020 May 19;11(1):2485. doi: 10.1038/s41467-020-16239-z.


Cigarette smoke first interacts with the lung through the cellularly diverse airway epithelium and goes on to drive development of most chronic lung diseases. Here, through single cell RNA-sequencing analysis of the tracheal epithelium from smokers and non-smokers, we generate a comprehensive atlas of epithelial cell types and states, connect these into lineages, and define cell-specific responses to smoking. Our analysis infers multi-state lineages that develop into surface mucus secretory and ciliated cells and then contrasts these to the unique specification of submucosal gland (SMG) cells. Accompanying knockout studies reveal that tuft-like cells are the likely progenitor of both pulmonary neuroendocrine cells and CFTR-rich ionocytes. Our smoking analysis finds that all cell types, including protected stem and SMG populations, are affected by smoking through both pan-epithelial smoking response networks and hundreds of cell-specific response genes, redefining the penetrance and cellular specificity of smoking effects on the human airway epithelium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Epithelial Cells / metabolism*
  • Gene Expression Profiling / methods*
  • Gene Knockout Techniques
  • Gene Regulatory Networks
  • Humans
  • Lung / cytology
  • Lung / metabolism*
  • Mice
  • NIH 3T3 Cells
  • Non-Smokers / statistics & numerical data
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism*
  • Sequence Analysis, RNA / methods
  • Single-Cell Analysis / methods
  • Smokers / statistics & numerical data
  • Smoking / genetics*
  • Trachea / cytology
  • Trachea / metabolism*