Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist.
Improving approaches for hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is clinically important because increased numbers of these cells are needed for enhanced transplantation. Chemokine stromal cell derived factor-1 (also known as CXCL12) is believed to be involved in retention of HSCs and HPCs in bone marrow. AMD3100, a selective antagonist of CXCL12 that binds to its receptor, CXCR4, was evaluated in murine and human systems for mobilizing capacity, alone and in combination with granulocyte colony-stimulating factor (G-CSF). AMD3100 induced rapid mobilization of mouse and human HPCs and synergistically augmented G-CSF-induced mobilization of HPCs. AMD3100 also mobilized murine long-term repopulating (LTR) cells that engrafted primary and secondary lethally-irradiated mice, and human CD34(+) cells that can repopulate nonobese diabetic-severe combined immunodeficiency (SCID) mice. AMD3100 synergized with G-CSF to mobilize murine LTR cells and human SCID repopulating cells (SRCs). Human CD34(+) cells isolated after treatment with G-CSF plus AMD3100 expressed a phenotype that was characteristic of highly engrafting mouse HSCs. Synergy of AMD3100 and G-CSF in mobilization was due to enhanced numbers and perhaps other characteristics of the mobilized cells. These results support the hypothesis that the CXCL12-CXCR4 axis is involved in marrow retention of HSCs and HPCs, and demonstrate the clinical potential of AMD3100 for HSC mobilization.
Broxmeyer
Hal E
HE
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. hbroxmey@iupui.edu
Orschell
Christie M
CM
Clapp
D Wade
DW
Hangoc
Giao
G
Cooper
Scott
S
Plett
P Artur
PA
Liles
W Conrad
WC
Li
Xiaxin
X
Graham-Evans
Barbara
B
Campbell
Timothy B
TB
Calandra
Gary
G
Bridger
Gary
G
Dale
David C
DC
Srour
Edward F
EF
D000818:Animals; D018952:Antigens, CD34; D001596:Benzylamines; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D003114:Colony-Forming Units Assay; D000080027:Cyclams; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D018952:Antigens, CD34; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor