Insights into the biology of mobilized hematopoietic stem/progenitor cells through innovative treatment schedules of the CXCR4 antagonist AMD3100.
OBJECTIVE
The CXCR4 antagonist AMD3100 mobilizes hematopoietic stem/progenitor cells (HSPC) in several species. Few data are available on the biology of HSPC mobilized with AMD3100 as single agent. To further study the kinetics and properties of AMD3100-mobilized HSPC, and to explore the size of mobilizable pools of HSPC targeted by AMD3100, we studied the effect of a continuous infusion scheme with saturating doses of AMD3100 [AMDi].


METHODS
Using established procedures, we evaluated mice mobilized with AMD3100, or those transplanted with AMD3100-mobilized HSPC.


RESULTS
Relative to single-bolus AMD3100 [AMDb], the number of circulating CFU-C or CRU was dramatically higher after [AMDi]. During [AMDi], circulating CFU-C accumulated slowly, but after its discontinuation, CFU-C disappeared rapidly. Compared to bone marrow (BM)-c-kit(+) cells, AMD3100-mobilized (AMDb or AMDi) c-kit(+) cells showed reduced expression of several cytoadhesion molecules, similar to granulocyte colony-stimulating factor-mobilized c-kit(+) cells. In contrast to the latter, expression of CXCR4 and CD26 were not reduced on AMD3100-mobilized c-kit(+) cells. BM homing of [AMDi]-mobilized CFU-C was >50% increased over normal BM-CFU-C. Hematopoietic recovery after transplantation of [AMDi]-mobilized peripheral blood was comparable to that of continuous infusion granulocyte colony-stimulating factor-mobilized peripheral blood. AMD3100-mobilized HSPC were predominantly in G(0), and partial bromodeoxyuridine-labeling experiments documented underrepresentation of labeled cells (<5%) among [AMDb]-mobilized c-kit(+) cells, suggesting that cycling cells in BM, or those that recently completed cell cycle, are not targeted for mobilization by AMD3100.


CONCLUSIONS
Our data demonstrate that [AMDi] is an efficacious mobilization scheme fully supporting transplantation demands and expands previous knowledge about properties and size of AMD3100-sensitive BM-HSPC pools.
Bonig
Halvard
H
Department of Medicine/Hematology, University of Washington, Seattle, Wash., USA. hbonig@u.washington.edu
Chudziak
Doreen
D
Priestley
Greg
G
Papayannopoulou
Thalia
T
D000818:Animals; D001596:Benzylamines; D001854:Bone Marrow Cells; D002452:Cell Count; D002465:Cell Movement; D000080027:Cyclams; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D036102:Peripheral Blood Stem Cell Transplantation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors
D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor