Matricellular Regulation of Alveolar Epithelial Cell Plasticity in Neonatal Lung Injury: Insights from CCN5 and Beyond.

Neonatal lung injury remains a major cause of morbidity among preterm infants and is a leading antecedent of bronchopulmonary dysplasia (BPD), a condition characterized by arrested alveolar development, inflammation, and extracellular matrix (ECM) remodeling. Despite significant advances in neonatal care, the mechanisms governing lung repair and regeneration remain incompletely understood. Recent research highlights the crucial role of matricellular proteins that orchestrate cell signaling, differentiation, and tissue remodeling in modulating-epithelial responses to injury. Among these, the CCN (CYR61/CTGF/NOV) family of proteins has emerged as a pivotal regulator of epithelial mesenchymal communication, with diverse and context-dependent functions in development, fibrosis, and regeneration. This review examines the distinct role of CCN5 (WISP2) within this family as a modulator of alveolar epithelial cell (AEC) plasticity in neonatal lung injury. We integrate findings from our own work with recent advances in CCN biology to elucidate how CCN5 influences epithelial survival, epithelial-mesenchymal transition (EMT), mitochondrial homeostasis, and intercellular signaling in hyperoxic injury. The review also contrasts CCN5 with other CCN members implicated in fibrotic lung diseases and situates it within broader matricellular signaling networks. By defining how CCN5 mediates epithelial resilience and tissue homeostasis, we propose it as a potential therapeutic target for mitigating BPD and enhancing regenerative outcomes in premature infants.