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Fibroblast Transmigration from Collagen into Fibrin/Fibronectin Gels requires Syndecan‐4 Proteoglycan

Abstract

Fibroblast migration from the peri‐wound collagenous stroma into the fibrin‐laden wound is critical for granulation tissue formation and subsequent healing. Previously we found that fibroblast transmigration from a collagen matrix into a fibrin matrix required the presence of fibronectin (FN). Several cell surface receptors, namely integrins α4β1, α5β1 and αvβ3 were also required for this invasive migration. Here we demonstrated that syndecan‐4, a transmembrane heparan sulfate proteoglycan, known to bind FN at the highly cationic HepII domain is also required for fibroblast invasive migration of a fibrin/FN gel. This conclusion was based on fibroblast migration using two independent means of disrupting syndecan‐4: heparinase degradation of heparan sulfate glycosaminoglycans or suppression of syndecan‐4 core protein with antisense oligodeoxynucleotides. Isolated syndecan‐4 from these fibroblasts bound the Hep II recombinant constructs FN III12–15v > FN III12–15 > FN III12–14 but did not bind the alternatively spliced IIICs (V) domain. Furthermore, we found that platelet‐derived growth factor (PDGF), which is required to stimulate fibroblast migration, markedly increased cell levels of syndecan‐4 core protein in a time and dose dependent fashion. PDGF also induced up‐regulation of syndecan‐4 at transcriptional level as determined by RT‐PCR. These results demonstrate that syndecan‐4 is essential for fibroblast invasive migration into fibrin clot and that PDGF, the stimulus for migration, induces increased syndecan‐4 core protein expression.