Increase in Circulating SDF-1 after Treatment with Sulfated Glycans
SDF-1 is a potent chemoattractant for mature white blood cells and hemopoietic stem/progenitor cells (HPCs). An important role for this chemo-kine in mobilization has been postulated, but in vivo studies directly addressing its effects are lacking. After one injection of fucan sulfate (FucS) or dextran sulfate, plasma levels of SDF-1 are greatly increased in mice or primates. Increases are dose-dependent and correlate with mobilization of HPCs. Elevated levels of circulating SDF-1 appear to be uniquely associated with this treatment, as it was not seen with cytokine or anti-integrin antibody treatments that induce mobilization. In vitro, these sulfated glycans specifically bind to SDF-1 and inhibit SDF-1/heparin binding, suggesting a mechanism of release from sequestration on heparan sulfate proteoglycans in vivo. Although other chemokines including IL8 and cytokines like G-CSF also increase, evidence in GCSFR-deficient mice suggests that at least these two factors are unlikely participants in FucS-induced mobilization. Likewise, although the activity of the metalloprotease MMP9 increases after FucS treatment, experiments in MMP9?/? mice indicate its presence is dispensable for mobilization or SDF-1 release. However, effects of other proteases cannot be ruled out by these experiments. Finally, anti-SDF-1 antibodies partially inhibit FucS-induced mobilization, supporting a causative relationship. Our data offer a unique insight into the mechanism of sulfated glycan-induced mobilization and suggest a novel way of disturbing SDF-1 gradients between bone marrow and peripheral blood.
sdf-1 progenitors mobilization stromal-derived factor 1 hematopoietic stem cells fucoidan