Epithelial-Mesenchymal Niche Dysfunction in COPD: Emerging Opportunities for Targeting Cellular Plasticity and Crosstalk

Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality, characterized by progressive airway and alveolar remodeling. The disease pathogenesis is commonly driven by chronic environmental insults, leading to airway obstruction, emphysema, and chronic bronchitis. This review synthesizes emerging evidence that altered epithelial cell behavior and dysfunctional epithelial-mesenchymal interactions serve as pivotal drivers of COPD pathogenesis, orchestrating failed repair and structural degeneration. We detail how altered responses of airway (ciliated, club, basal, goblet) and alveolar (AT1 and AT2) epithelial cells lead to cellular senescence, metaplasia, defective regeneration, and barrier disruption, acting as primary instigators of pathogenesis. We also summarize current knowledge on the mechanisms of activation and pathogenic role of mesenchymal cells, which drive peribronchiolar fibrosis, alveolar destruction, and metabolic reprogramming, alongside the compromised reparative function of mesenchymal stem cells (MSCs). We emphasize how distinct mesenchymal niches (e.g., PDGFRαPos MANCs, FGF10Pos lipofibroblasts, SFRP1Pos fibroblasts) and distinct epithelial stem/progenitor subpopulations critically contribute to pathogenesis. Key signaling pathways—including FGF10/FGFR2b, WNT, Hippo, NOTCH, and TGF-β—mediate epithelial-mesenchymal transition (EMT), stem cell niche function, and structural remodeling. By dissecting how epithelial injury responses and mesenchymal niche failure collaboratively drive COPD progression, we identify actionable targets to disrupt pathogenesis and restore endogenous repair. We propose targeting EMT, including inhibiting EMT/fibrosis, promoting alveolar regeneration, MSC-based therapies, exosome-delivered biomolecules, and precision cell transplantation strategies, as promising future therapeutic strategies.