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

Abstract CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has an inherent ability to promote wound healing; wounds close and re-epithelialise faster in CAR-treated mice. CAR promotes keratinocyte migration in vitro. Syndecan-4 (SDC4) is a heparan sulfate proteoglycan that regulates cell migration and is crucial for wound healing. We report that SDC4 expression is restricted to epidermis and blood vessels in skin wounds. SDC4 regulates cell binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces SDC4-dependent activation of the small GTPase Arf6 (ARF6) and promotes SDC4- and ARF6-mediated keratinocyte migration. Finally, we show that genetic ablation of SDC4 in mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates SDC4 function to selectively promote re-epithelialisation. Thus, CAR peptide provides an entirely new therapeutic approach to enhance wound healing; systemic, yet target organ- and cell-specific.