Sulfated glycans induce rapid hematopoietic progenitor cell mobilization: evidence for selectin-dependent and independent mechanisms.
The adhesive mechanisms leading to the mobilization of hematopoietic progenitor cells (HPCs) from the bone marrow into the blood are poorly understood. We report on a role for selectins and fucoidan in progenitor mobilization. Baseline levels of circulating HPCs are increased in endothelial selectin-deficient (P/E-/-) mice. Similar levels are observed when E-selectin null (E-/-) mice are treated with anti-P-selectin antibody or with fucoidan (which inhibits P- and L-selectin function). In particular, administration of 2 doses of fucoidan (25 mg/kg) over 6 hours produces profound mobilization of progenitors in wild-type mice and the response is greatly enhanced in E-/- and P/E-/- mice. Competitive reconstitution experiments reveal that fucoidan also elicits long-term (more than 6 months) repopulating stem cells. Mobilization assays using chimeric mice harboring L-selectin-deficient progenitors and wild-type progenitors expressing the green fluorescence protein suggest that L-selectin expression is not required but confers an advantage for fucoidan-induced mobilization. Sulfation is critical as desulfated fucoidan is ineffective. In addition, sulphogalactosylceramide (sulfatide) but not heparin can induce HPC mobilization. Our results indicate that administration of sulfated glycans, especially with concurrent inhibition of E-selectin function, represents a powerful novel method for rapid mobilization of long-term-repopulating stem cells. These findings may help elucidate the mechanisms of HPC trafficking during development and adult life.
Frenette
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PS
Mount Sinai School of Medicine, Department of Medicine, New York, NY, USA. paul.frenette@mssm.edu
Weiss
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L
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology; D002452:Cell Count; D015870:Gene Expression; D049452:Green Fluorescent Proteins; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D019041:L-Selectin / Q000276:immunology / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000276:immunology / Q000502:physiology; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D019087:Selectins / Q000502:physiology*; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry; D013433:Sulfoglycosphingolipids / Q000494:pharmacology
D000906:Antibodies; D008164:Luminescent Proteins; D019007:P-Selectin; D011134:Polysaccharides; D019087:Selectins; D013431:Sulfates; D013433:Sulfoglycosphingolipids; D019041:L-Selectin; D049452:Green Fluorescent Proteins; D006493:Heparin; C007789:fucoidan