title: 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.
authors.affiliation: Mater Medical Research Institute, South Brisbane, Queensland, Australia.
authors.forename: I G
authors.initials: IG
authors.lastname: Winkler
authors.forename: A R
authors.initials: AR
authors.lastname: Pettit
authors.forename: L J
authors.initials: LJ
authors.lastname: Raggatt
authors.forename: R N
authors.initials: RN
authors.lastname: Jacobsen
authors.forename: C E
authors.initials: CE
authors.lastname: Forristal
authors.forename: V
authors.initials: V
authors.lastname: Barbier
authors.forename: B
authors.initials: B
authors.lastname: Nowlan
authors.forename: A
authors.initials: A
authors.lastname: Cisterne
authors.forename: L J
authors.initials: LJ
authors.lastname: Bendall
authors.forename: N A
authors.initials: NA
authors.lastname: Sims
authors.forename: J-P
authors.initials: JP
authors.lastname: Lévesque
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001596:Benzylamines; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D000080027:Cyclams; D003520:Cyclophosphamide / Q000494:pharmacology*; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006397:Hematinics / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019380:Anti-HIV Agents; D018906:Antineoplastic Agents, Alkylating; D001596:Benzylamines; D000080027:Cyclams; D006397:Hematinics; D006571:Heterocyclic Compounds; D012333:RNA, Messenger; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; C088327:plerixafor