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Stem Cells

Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation

Abstract

The CXCR4 antagonist AMD3100 is progressively replacing cyclophosphamide (CYP) as adjuvant to granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) for autologous transplants in patients who failed prior mobilization with G-CSF alone. It has recently emerged that G-CSF mediates HSC mobilization and inhibits bone formation via specific bone marrow (BM) macrophages. We compared the effect of these three mobilizing agents on BM macrophages, bone formation, osteoblasts, HSC niches and HSC reconstitution potential. Both G-CSF and CYP suppressed niche-supportive macrophages and osteoblasts, and inhibited expression of endosteal cytokines resulting in major impairment of HSC reconstitution potential remaining in the mobilized BM. In sharp contrast, although AMD3100 was effective at mobilizing HSC, it did not suppress osteoblasts, endosteal cytokine expression or reconstitution potential of HSC remaining in the mobilized BM. In conclusion, although G-CSF, CYP and AMD3100 efficiently mobilize HSC into the blood, their effects on HSC niches and bone formation are distinct with both G-CSF and CYP targeting HSC niche function and bone formation, whereas AMD3100 directly targets HSC without altering niche function or bone formation.

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Acknowledgements

During the course of this study, JPL was supported by a Senior Research Fellowship from the Cancer Council Queensland, IGW, LJB, and ARP by Career Development Award fellowships and NAS by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC #488817, #511965, #519744 and #345401, respectively), RNJ by an Australian Post-Graduate Award. This work was supported by NHMRC Project Grants #434515 to JPL and IGW, #345401 to LJR and ARP, and an Anthony Rothe Grant to LJB.

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Correspondence to J-P Lévesque.

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Winkler, I., Pettit, A., Raggatt, L. et al. Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation. Leukemia 26, 1594–1601 (2012). https://doi.org/10.1038/leu.2012.17

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