Abstract
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 β chain, Fg β15-66) 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.
Highlights
Regenerative medicine has evolved from an initial focus on transplanted cells to embrace development of advanced biomatrices laden with active biomolecules that enhance tissue repair and control the host response by mimicking the regenerative microenvironment[1,2]
We first investigated the ability of FN and Fg to bind CXCL9, CXCL10 and CXCL11, using an indirect ELISA
We have reported that binding of a growth factor to FN can modulate its signaling for the cases of vascular endothelial growth factor-A (VEGF-A), platelet-derived growth factor-BB (PDGF-BB) and bone morphogenetic protein-2 (BMP-2)[9]
Summary
Regenerative medicine has evolved from an initial focus on transplanted cells to embrace development of advanced biomatrices laden with active biomolecules that enhance tissue repair and control the host response by mimicking the regenerative microenvironment[1,2]. In this context, a full comprehension of the overall signaling network driving wound healing is still missing and the complex pattern of interactions between the different biological moieties involved (i.e. cytokines, growth factors, extracellular matrix (ECM) proteins, integrin ligands) is incompletely understood. A full understanding of the biological processes linking the CXCR3 axis to wound healing is still missing, it is clear that CXCL11, expressed in injured epidermis, plays an important role in enhancing undifferentiated keratinocyte motility, coordinating the resolution and regenerative phase together with signals coming from the ECM [3,7]
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