Localized COUP-TFII pDNA Delivery Modulates Stem/Progenitor Cell Differentiation to Enhance Endothelialization and...

Area of Science:

• Biomaterials Science
• Vascular Biology
• Regenerative Medicine

Background:

• Decellularized allografts show promise for vascular bypass but face challenges due to poor regeneration and pathological remodeling.
• COUP-TFII plays a critical role in endothelial cell function, angiogenesis, atherosclerosis prevention, and vascular calcification.
• Current strategies lack effective methods for localized and sustained delivery of therapeutic genes to allografts.

Purpose of the Study:

• To investigate the potential of incorporating plasmid DNA (pDNA) encoding COUP-TFII into decellularized allografts for enhanced vascular regeneration and remodeling.
• To elucidate the underlying mechanisms of COUP-TFII in regulating vascular repair and preventing pathological changes.
• To develop a novel nanocarrier system for stable and long-term delivery of COUP-TFII pDNA to decellularized allografts.

Main Methods:

• Decellularized allografts were modified with heparin-polyethyleneimine nanoparticles carrying COUP-TFII pDNA (COUP-TFII@HPEI).
• In vitro studies and a bone marrow transplantation model in mice were used to assess COUP-TFII's mechanisms.
• Functionalized grafts were evaluated in rat abdominal artery replacement models to assess regeneration and calcification.

Main Results:

• COUP-TFII delivery augmented endothelialization and inhibited calcification in decellularized allografts.
• The Ang1/Tie2/PI3K/AKT signaling pathway was modulated by COUP-TFII, influencing Sca-1+ stem/progenitor cell fate.
• Functionalized grafts demonstrated enhanced neo-artery regeneration without calcification in vivo.

Conclusions:

• Localized delivery of COUP-TFII via nanocarrier-modified decellularized allografts is an effective strategy to improve vascular regeneration.
• This approach mitigates pathological remodeling, specifically vascular calcification, enhancing the clinical applicability of allografts.
• The study highlights the translational potential of COUP-TFII gene-modified decellularized allografts for vascular bypass grafting.