Chronic airway disease as a disorder of epithelial homeostasis: Mechanistic insights and the emerging role of hiPSC-Derived Airway Models

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a disorder of epithelial instability and defective tissue repair rather than a disease driven solely by chronic inflammation. This review examines the role of airway epithelial homeostasis, regional progenitor cell dysfunction, and impaired regenerative mechanisms in COPD pathogenesis, while highlighting the emerging applications of human induced pluripotent stem cell (hiPSC)-derived airway systems. The airway epithelium functions as an active interface that regulates barrier integrity, immune signaling, mucociliary clearance, and responses to environmental and mechanical stimuli. Disruption of these functions results in persistent epithelial injury, abnormal differentiation, mucus dysregulation, and progressive airway remodeling. Because different regions of the respiratory tract depend on distinct progenitor populations, including basal cells, club cells, and alveolar type II cells, regional impairment of these progenitors contributes to defective repair and disease progression. Recent evidence also suggests that COPD may originate from impaired lung development and early-life susceptibility, with distal airway abnormalities preceding advanced structural damage. hiPSC-derived airway models overcome many limitations of conventional animal models by generating renewable, patient-specific human airway epithelium that faithfully reproduces key developmental and pathological features of COPD. These platforms provide valuable tools for investigating disease mechanisms, testing therapeutic interventions, and advancing regenerative strategies. Although significant translational challenges remain, hiPSC-based airway reconstruction represents a promising approach for future precision medicine and regenerative therapies in COPD.