Mobilization as a preparative regimen for hematopoietic stem cell transplantation.
Current myeloablative conditioning regimens for hematopoietic stem cell (HSC) transplantation are associated with significant morbidity and mortality. Thus, alternative strategies to promote engraftment of infused HSCs with increased safety warrant investigation. Using parabiotic mice, we determined that, after mobilization with AMD3100 (a CXCR4 antagonist), HSCs exited from marrow, transited blood, and engrafted in open niches in partner marrow. We then hypothesized that mobilization before transplantation might vacate niches and improve HSC engraftment. When PeP3(b) mice were treated with AMD3100 at 2 hours before the transplantation of 4 x 10(7) marrow cells, donor cell engraftment was higher (4.6% +/- 1.1%) than in control animals (no AMD3100; 1.0% +/- 0.24%, P < .001). When mice received weekly injections of AMD3100 on 3 consecutive weeks and marrow cells were transplanted 2 hours after each mobilization, donor cell engraftment further increased (9.1% +/- 1.7%, P = .001). In contrast, in similar experiments with Balb/cByJ mice that mobilize poorly, there was no difference between the donor cell engraftment of AMD3100-treated and control recipients. These results indicate that the number of available niches regulates the number of HSCs. In addition, mobilization with AMD3100 may provide a safer preparative approach for HSC transplantation in genetic and other nonmalignant disorders.
Chen
Jing
J
Medicine/Hematology, University of Washington, Box 357710, Seattle, 98195, USA.
Larochelle
André
A
Fricker
Simon
S
Bridger
Gary
G
Dunbar
Cynthia E
CE
Abkowitz
Janis L
JL
D000818:Animals; D001483:Base Sequence; D001596:Benzylamines; D000080027:Cyclams; D004247:DNA / Q000235:genetics; D005260:Female; D024282:Genes, sry; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000008:administration & dosage; D019089:Stem Cell Factor / Q000008:administration & dosage
D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D004247:DNA; C088327:plerixafor