Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization.
Current evidence suggests that hematopoietic stem/progenitor cell (HSPC) mobilization by granulocyte colony-stimulating factor (G-CSF) is mediated by induction of bone marrow proteases, attenuation of adhesion molecule function, and disruption of CXCL12/CXCR4 signaling in the bone marrow. The relative importance and extent to which these pathways overlap or function independently are uncertain. Despite evidence of protease activation in the bone marrow, HSPC mobilization by G-CSF or the chemokine Grobeta was abrogated in CXCR4(-/-) bone marrow chimeras. In contrast, HSPC mobilization by a VLA-4 antagonist was intact. To determine whether other mobilizing cytokines disrupt CXCR4 signaling, we characterized CXCR4 and CXCL12 expression after HSPC mobilization with Flt3 ligand (Flt3L) and stem cell factor (SCF). Indeed, treatment with Flt3L or SCF resulted in a marked decrease in CXCL12 expression in the bone marrow and a loss of surface expression of CXCR4 on HSPCs. RNA in situ and sorting experiments suggested that the decreased CXCL12 expression is secondary to a loss of osteoblast lineage cells. Collectively, these data suggest that disruption of CXCR4 signaling and attenuation of VLA-4 function are independent mechanisms of mobilization by G-CSF. Loss of CXCL12 expression by osteoblast appears to be a common and key step in cytokine-induced mobilization.
Christopher
Matthew J
MJ
Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Liu
Fulu
F
Hilton
Matthew J
MJ
Long
Fanxin
F
Link
Daniel C
DC
D000818:Animals; D001853:Bone Marrow; D054360:Chemokine CXCL1 / Q000378:metabolism / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D039041:Integrin alpha4beta1 / Q000096:biosynthesis / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism
C514936:CXCR4 protein, mouse; D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; C475895:Cxcl1 protein, mouse; C515256:Cxcl12 protein, mouse; D039041:Integrin alpha4beta1; D008565:Membrane Proteins; D019718:Receptors, CXCR4; D019089:Stem Cell Factor; C084881:flt3 ligand protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor