Composition and Function of Decellularized Human Lung Extracellular Matrix from Congenital Pulmonary Airway Malformation.

Background: Congenital pulmonary airway malformation (CPAM) is a rare developmental disorder characterized by cystic lung lesions, yet its extracellular matrix (ECM) composition remains poorly understood. This study employed decellularization and data-independent acquisition (DIA) proteomics to compare ECM profiles between cystic (CPAM) and histologically normal non-diseased (ND) regions from the lungs of four patients. Results: The decellularized scaffolds retained their native architecture with minimal residual DNA (<50 ng/mg). Proteomic analysis revealed 431 differentially expressed proteins (DEPs), with 171 upregulated and 260 downregulated in CPAM. Key findings revealed CPAM-specific enrichment of collagens (COL4A6, COL4A2, COL10A1, COL21A1 and PIIINP), glycoproteins (SPP1, FRAS1, FREM1, FREM2, LTBP1 and FBLN7), ECM regulators (TENM2, ROR2 and OMD), and ECM-affiliated proteins (ANXA7), alongside downregulation of glycoproteins (VASN and ABI3BP), proteoglycans (PODN and MXRA7), ECM regulators (SCARA5, PAPPA, SAA4, CPXM1, CTSC, THY1, SERPINA6/A1/D1, BSG, LYVE1, ITIH4 and CD44), and ECM-affiliated proteins (LGALSL). Pathway analysis highlighted the dysregulation of TGF-β, PI3K-AKT, and mTOR signaling in CPAM and aberrant ECM-cell interactions in pathogenesis. We also evaluated their functional properties and investigated the impact of ECM-based hydrogels on recellularization. Conclusions: These findings provide a comprehensive proteomic atlas of CPAM ECM alterations, offering insights into disease mechanisms and potential therapeutic targets.