Localized COUP‐TFII pDNA Delivery Modulates Stem/Progenitor Cell Differentiation to Enhance Endothelialization and Inhibit Calcification of Decellularized Allografts

Decellularized allografts have emerged as promising candidates for vascular bypass grafting, owing to their inherent bioactivity and minimal immunogenicity. However, graft failure that results from suboptimal regeneration and pathological remodeling has hindered their clinical adoption. Recent advances in vascular biology highlight the pivotal role of COUP-TFII in orchestrating endothelial identity, angiogenesis, safeguarding against atherosclerosis, and mitigating vascular calcification. Here, plasmid DNA (pDNA) encoding COUP-TFII is incorporated into decellularized allografts to realize localized delivery. Comprehensive in vitro investigation complemented by a bone marrow transplantation model on genetic-lineage-tracing mouse revealed the underlying mechanisms of COUP-TFII in regulating vascular regeneration and remodeling. COUP-TFII augmented endothelialization and inhibited calcification in decellularized allografts by modulating the Ang1/Tie2/PI3K/AKT signaling pathway that dictates the fate of Sca-1