Targeting NRP1 in Endothelial Cells Facilitates the Normalization of Scar Vessels and Prevents Fibrotic Scarring.

Summary

Using multi-modal analyses and scRNA-seq, the study identifies an NRP1-high endothelial subset driving endothelial-to-mesenchymal transition and abnormal scar vasculature. Inhibiting NRP1 normalizes vessels and prevents scarring in mice, and a peptide-loaded hydrogel spray translates this mechanism into a tractable anti-scar strategy.

Key Findings

• Scars exhibit increased neovascular density, branching complexity, and incomplete wall coverage by dermatoscopy/SEM/IF.
• Single-cell RNA-seq revealed an NRP1-high endothelial subset with mesenchymal traits and upregulated oxidative phosphorylation.
• NRP1 knockdown blocked TGF-β/SMAD2 signaling, reduced EndMT, normalized vascular function, and prevented scarring in mice.
• An NRP1-targeting peptide hydrogel spray effectively prevented scar formation by promoting vascular normalization.

Clinical Implications

NRP1-targeted approaches could become adjuncts to surgical and laser therapies to prevent hypertrophic scars and keloids by normalizing vasculature rather than ablating it.

Limitations

• Preclinical mouse models may not fully capture human scar biology and heterogeneity.
• Safety, dosing, and delivery parameters for NRP1-targeting peptide hydrogel in humans remain untested.

Future Directions

Conduct phase I/II clinical trials of NRP1-targeted topical systems in high-risk scar populations; map NRP1-EC prevalence across scar subtypes and stages; evaluate combination with laser/surgical protocols.