Exposure to cigarette smoke enhances the stemness of alveolar type 2 cells

Akihiro Tsutsumi, Mari Ozaki, Shotaro Chubachi, Hidehiro Irie, Minako Sato, Naofumi Kameyama, Mamoru Sasaki, Makoto Ishii, Ahmed E. Hegab, Tomoko Betsuyaku, Koichi Fukunaga

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


Chronic exposure to cigarette smoke (CS) causes chronic inflammation, oxidative stress, and apoptosis of epithelial cells, which results in destruction of the lung matrix. However, the mechanism by which the lung fails to repair the CS-induced damage, thereby succumbing to emphysema, remains unclear. Alveolar type 2 (AT2) cells comprise the stem cells of the alveolar compartments and are responsible for repairing and maintaining lung tissues. In this study, we examined the effect of chronic CS on AT2 stem cells. Adult mice expressing GFP in their AT2 cells were exposed to CS for > 3 months. Histological assessment showed that CS not only induced emphysematous changes but also increased the number of AT2 cells compared with that of air-exposed lungs. Assessment of sorted GFP1/AT2 cells via the stem cell three-dimensional organoid/colony-forming assay revealed that the number and size of the colonies formed by the CS-exposed AT2 stem cells were significantly higher than those of air-exposed control AT2 cells. Although CS-exposed lungs had more apoptotic cells, examination of the surviving AT2 stem cells in two-dimensional in vitro culture revealed that they developed a higher ability to resist apoptosis. Microarray analysis of CS-exposed AT2 stem cells revealed the upregulation of genes related to circadian rhythm and inflammatory pathways. In conclusion, we provide evidence that AT2 stem cells respond to chronic CS exposure by activating their stem cell function, thereby proliferating and differentiating faster and becoming more resistant to apoptosis. Disturbances in expression levels of several circadian rhythm-related genes might be involved in these changes.

Original languageEnglish
Pages (from-to)293-305
Number of pages13
JournalAmerican journal of respiratory cell and molecular biology
Issue number3
Publication statusPublished - 2020 Sep


  • Alveolar type 2 cell
  • Cigarette smoke
  • Colony-forming assay
  • Emphysema
  • Lung stem cell

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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