title: Heparan sulfate mimetics can efficiently mobilize long-term hematopoietic stem cells.
abstract: BACKGROUND
  Although mobilization of hematopoietic stem cells and hematopoietic progenitor cells can be achieved with a combination of granulocyte colony-stimulating factor and plerixafor (AMD3100), improving approaches for hematopoietic progenitor cell mobilization is clinically important.
  
  
  METHODS
  Heparan sulfate proteoglycans are ubiquitous macromolecules associated with the extracellular matrix that regulates biology of hematopoietic stem cells. We studied the effects of a new family of synthetic oligosaccharides mimicking heparan sulfate on hematopoietic stem cell mobilization. These oligosaccharides were administered intravenously alone or in combination with granulocyte colony-stimulating factor and/or AMD3100 in mice. Mobilized hematopoietic cells were counted and phenotyped at different times and the ability of mobilized hematopoietic stem cells to reconstitute long-term hematopoiesis was determined by competitive transplantation into syngenic lethally irradiated mice followed by secondary transplantation.
  
  
  RESULTS
  Mimetics of heparan sulfate induced rapid mobilization of B-lymphocytes, T-lymphocytes, hematopoietic stem cells and hematopoietic progenitor cells. They increased the mobilization of hematopoietic stem cells and hematopoietic progenitor cells more than 3-fold when added to the granulocyte colony-stimulating factor/AMD3100 association. Hematopoietic stem cells mobilized by mimetics of heparan sulfate or by the granulocyte colony-stimulating factor/AMD3100/mimetics association were as effective as hematopoietic stem cells mobilized by the granulocyte colony-stimulating factor/AMD3100 association for primary and secondary hematopoietic reconstitution of lethally irradiated mice.
  
  
  CONCLUSIONS
  This new family of mobilizing agents could alone or in combination with granulocyte colony-stimulating factor and/or AMD3100 mobilize a high number of hematopoietic stem cells that were able to maintain long-term hematopoiesis. These results strengthen the role of heparan sulfates in the retention of hematopoietic stem cells in bone marrow and support the use of small glyco-drugs based on heparan sulfate in combination with granulocyte colony-stimulating factor and AMD3100 to improve high stem cell mobilization, particularly in a prospect of use in human therapeutics.
authors.affiliation: CEA/DSV/iRCM/LRTS, Fontenay-aux-Roses, France.
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Giacomo
authors.forename: Daniel
authors.initials: D
authors.lastname: Lewandowski
authors.forename: Eric
authors.initials: E
authors.lastname: Cabannes
authors.forename: Vanessa
authors.initials: V
authors.lastname: Nancy-Portebois
authors.forename: Maurice
authors.initials: M
authors.lastname: Petitou
authors.forename: Serge
authors.initials: S
authors.lastname: Fichelson
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Romeo
mesh_terms: D000818:Animals; D001596:Benzylamines; D000080027:Cyclams; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006497:Heparan Sulfate / Q000138:chemical synthesis / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D016179:Granulocyte Colony-Stimulating Factor; D006497:Heparan Sulfate; D006571:Heterocyclic Compounds; C088327:plerixafor