Nature Communications (Dec 2023)

Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function

  • Horacio Maldonado,
  • Bryan D. Savage,
  • Harlan R. Barker,
  • Ulrike May,
  • Maria Vähätupa,
  • Rahul K. Badiani,
  • Katarzyna I. Wolanska,
  • Craig M. J. Turner,
  • Toini Pemmari,
  • Tuomo Ketomäki,
  • Stuart Prince,
  • Martin J. Humphries,
  • Erkki Ruoslahti,
  • Mark R. Morgan,
  • Tero A. H. Järvinen

DOI
https://doi.org/10.1038/s41467-023-43848-1
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 23

Abstract

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Abstract CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.