Increase in Circulating SDF‐1 after Treatment with Sulfated Glycans

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Abstract
Abstract: 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.