Sdc-1 null fibroblasts in wound healing and cancer

Activated fibroblasts are important in wound healing and cancer. Syndecan-1 (sdc-1), an integral membrane cell surface proteoglycan, is upregulated in response to injury. The goal of this study is to determine whether activated dermal fibroblasts lacking sdc-1 show differences in migration, integrin expression and function that could contribute to the delayed wound healing and tumor progression in sdc-1 null mice.;Using primary sdc-1 null and wild type (wt) fibroblasts grown in media containing 10% serum, we show that the loss of sdc-1 altered their proliferation, motility and integrin expression. Timelapse migration studies show that sdc-1 null fibroblasts migrate faster than wt fibroblasts under all conditions studied except quiescence; TGFbeta1 treatment increases while a TGFbeta1 antagonist inhibits these migration differences. When quiescent cells are shifted to media with 10% serum, the migration rates for both genotypes increase to rates significantly higher than those seen for cells maintained in media with 10% serum. Addition of TGFbeta1 further increased migration rates. By activating integrins with manganese or blocking with beta1- and alphav-integrin neutralizing antibodies, we show that wt fibroblasts had activated integrins on their surface impeding their migration whereas the null cells express fewer adhesive integrins enhancing migration. The velocity of fibroblasts, studied in ras-transfected keratinocyte conditioned media, suggest a GMCSF mediated inhibition of migration in the fibroblasts lacking sdc-1 that interferes with TGFbeta pathway. As shown by immunoblots, TGFbeta1 treatment at day 3 increased both alphav- and beta1-integrin expression in sdc-1 null cells but only alphav-integrin in wt cells. The rapidly migrating sdc-1 null cells in 10% serum show elevated alpha5, beta1, and alphav integrin levels compared to quiescent wt and sdc-1 null cells.;Taken together, our data indicate that sdc-1 functions in the activation of integrins. We therefore suggest a model whereby cells, in the absence of sdc-1, cannot achieve optimal integrin function. This supports the hypothesis that impaired wound healing and cancer progression seen in sdc-1 null mice could be due to integrin-mediated defects in fibroblast activation and migration.