Fibronectin Binding Modulates CXCL11 Activity and Facilitates Wound Healing

Engineered biomatrices offer the potential to recapitulate the regenerative microenvironment, with important implications in tissue repair. In this context, investigation of the molecular interactions occurring between growth factors, cytokines and extracellular matrix (ECM) has gained increasing interest. Here, we sought to investigate the possible interactions between the ECM proteins fibronectin (FN) and fibrinogen (Fg) with the CXCR3 ligands CXCL9, CXCL10 and CXCL11, which are expressed during wound healing. New binding interactions were observed and characterized. Heparin-binding domains within Fg (residues 15-66 of the beta chain, Fg beta 15-66) and FN (FNI1-5, but not FNIII12-14) were involved in binding to CXCL10 and CXCL11 but not CXCL9. To investigate a possible influence of FN and Fg interactions with CXCL11 in mediating its role during re-epithelialization, we investigated human keratinocyte migration in vitro and wound healing in vivo in diabetic db/db mice. A synergistic effect on CXCL11-induced keratinocyte migration was observed when cells were treated with CXCL11 in combination with FN in a transmigration assay. Moreover, wound healing was enhanced in full thickness excisional wounds treated with fibrin matrices functionalized with FN and containing CXCL11. These findings highlight the importance of the interactions occurring between cytokines and ECM and point to design concepts to develop functional matrices for regenerative medicine.