Enhanced radiation sensitivity, decreased DNA damage repair, and differentiation defects in airway stem cells derived from patients with chronic obstructive pulmonary disease

Lorena Giuranno, Jolanda A. F. Piepers, Evelien Korsten, Reitske Borman, Gerarda van de Kamp, Dirk De Ruysscher, Jeroen Essers, Marc A. Vooijs*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Radiation therapy (RT) is a common treatment for lung cancer. Still, it can lead to irreversible loss of pulmonary function and a significant reduction in quality of life for one-third of patients. Preexisting comorbidities, such as chronic obstructive pulmonary disease (COPD), are frequent in patients with lung cancer and further increase the risk of complications. Because lung stem cells are crucial for the regeneration of lung tissue following injury, we hypothesized that airway stem cells from patients with COPD with lung cancer might contribute to increased radiation sensitivity. We used the air-liquid interface model, a three-dimensional (3D) culture system, to compare the radiation response of primary human airway stem cells from healthy and patients with COPD. We found that COPD-derived airway stem cells, compared to healthy airway stem cell cultures, exhibited disproportionate pathological mucociliary differentiation, aberrant cell cycle checkpoints, residual DNA damage, reduced survival of stem cells and self-renewal, and terminally differentiated cells post-irradiation, which could be reversed by blocking the Notch pathway using small-molecule γ-secretase inhibitors. Our findings shed light on the mechanisms underlying the increased radiation sensitivity of COPD and suggest that airway stem cells reflect part of the pathological remodeling seen in lung tissue from patients with lung cancer receiving thoracic RT.

Original languageEnglish
Pages (from-to)927-939
Number of pages13
JournalStem Cells Translational Medicine
Volume13
Issue number9
Early online date1 Jun 2024
DOIs
Publication statusPublished - 1 Sept 2024

Keywords

  • COPD
  • radiation therapy
  • lung
  • basal airway stem cells
  • DNA damage response
  • NOTCH pathway
  • LUNG
  • NOTCH
  • PNEUMONITIS
  • REGENERATION
  • MECHANISMS
  • EPITHELIUM
  • EXPANSION

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