Mechanistic Insights and Therapeutic Potential of Wnt5a Signaling in Alveolar Epithelial Cell Development and Bronchopulmonary Dysplasia.

Wnt5a is a key regulator of non-canonical Wnt signaling, critically influencing alveolar epithelial cell dynamics during development and injury responses. Emerging evidence has revealed two conserved Wnt5a mediated mechanisms: ROR-dependent planar cell polarity signaling that orchestrates cytoskeletal reorganization during alveolar septation, and calcium-regulated transcriptional networks balancing type II alveolar epithelial progenitor maintenance and differentiation. Developmental studies demonstrate Wnt5a deficiency disrupts myofibroblast differentiation and alveologenesis, recapitulating bronchopulmonary dysplasia pathology, while its pathological elevation in hyperoxia models promotes extracellular matrix remodeling through LOX/YAP-mediated mechanotransduction. Therapeutic modulation of Wnt5a signaling shows promise, as ROR2 activation enhances mesenchymal stem cell-mediated alveolar repair, and Wnt5a supplementation rescues epithelial transdifferentiation defects in hyperoxia-induced injury. These findings position Wnt5a signaling as a pivotal node connecting developmental mechanisms with regenerative strategies for alveolar pathologies.