AMD3100 mobilizes hematopoietic stem cells with long-term repopulating capacity in nonhuman primates.
AMD3100, a bicyclam antagonist of the chemokine receptor CXCR4, has been shown to induce rapid mobilization of CD34(+) hematopoietic cells in mice, dogs, and humans, offering an alternative to G-CSF mobilization of peripheral-blood hematopoietic stem cells. In this study, AMD3100-mobilized CD34(+) cells were phenotypically analyzed, marked with Neo(R)-containing retroviral vectors, and subsequently transplanted into myeloablated rhesus macaques. We show engraftment of transduced AMD3100-mobilized CD34(+) cells with Neo(R) gene marked myeloid and lymphoid cells up to 32 months after transplantation, demonstrating the ability of AMD3100 to mobilize true long-term repopulating hematopoietic stem cells. More AMD3100-mobilized CD34(+) cells are in the G(1) phase of the cell cycle and more cells express CXCR4 and VLA-4 compared with G-CSF-mobilized CD34(+) cells. In vivo gene marking levels obtained with AMD3100-mobilized CD34(+) cells were better than those obtained using CD34(+) cells mobilized with G-CSF alone. Overall, these results indicate that AMD3100 mobilizes a population of hematopoietic stem cells with intrinsic characteristics different from those of hematopoietic stem cells mobilized with G-CSF, suggesting fundamental differences in the mechanism of AMD3100-mediated and G-CSF-mediated hematopoietic stem cell mobilization. Thus, AMD3100-mobilized CD34(+) cells represent an alternative source of hematopoietic stem cells for clinical stem cell transplantation and genetic manipulation with integrating retroviral vectors.
Larochelle
André
A
National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg 10 CRC, Rm 4E-5132, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Krouse
Allen
A
Metzger
Mark
M
Orlic
Donald
D
Donahue
Robert E
RE
Fricker
Simon
S
Bridger
Gary
G
Dunbar
Cynthia E
CE
Hematti
Peiman
P
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001483:Base Sequence; D001596:Benzylamines; D000080027:Cyclams; D004247:DNA / Q000235:genetics; D004285:Dogs; D005822:Genetic Vectors; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000276:immunology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D008253:Macaca mulatta; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins; D014182:Transplantation, Autologous
D018952:Antigens, CD34; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D039041:Integrin alpha4beta1; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D004247:DNA; C088327:plerixafor