title: Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells.
abstract: Steady-state egress of hematopoietic progenitor cells can be rapidly amplified by mobilizing agents such as AMD3100, the mechanism, however, is poorly understood. We report that AMD3100 increased the homeostatic release of the chemokine stromal cell derived factor-1 (SDF-1) to the circulation in mice and non-human primates. Neutralizing antibodies against CXCR4 or SDF-1 inhibited both steady state and AMD3100-induced SDF-1 release and reduced egress of murine progenitor cells over mature leukocytes. Intra-bone injection of biotinylated SDF-1 also enhanced release of this chemokine and murine progenitor cell mobilization. AMD3100 directly induced SDF-1 release from CXCR4(+) human bone marrow osteoblasts and endothelial cells and activated uPA in a CXCR4/JNK-dependent manner. Additionally, ROS inhibition reduced AMD3100-induced SDF-1 release, activation of circulating uPA and mobilization of progenitor cells. Norepinephrine treatment, mimicking acute stress, rapidly increased SDF-1 release and progenitor cell mobilization, whereas β2-adrenergic antagonist inhibited both steady state and AMD3100-induced SDF-1 release and progenitor cell mobilization in mice. In conclusion, this study reveals that SDF-1 release from bone marrow stromal cells to the circulation emerges as a pivotal mechanism essential for steady-state egress and rapid mobilization of hematopoietic progenitor cells, but not mature leukocytes.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Dar
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Schajnovitz
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Kfir
authors.initials: K
authors.lastname: Lapid
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Itkin
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Aya
authors.initials: A
authors.lastname: Ludin
authors.affiliation: Department of Medicine, Immunology Institute, and Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Kao
authors.affiliation: Department of Medicine, Immunology Institute, and Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Battista
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Melania
authors.initials: M
authors.lastname: Tesio
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Neta Netzer
authors.initials: NN
authors.lastname: Cohen
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Raanan
authors.initials: R
authors.lastname: Margalit
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Eike C
authors.initials: EC
authors.lastname: Buss
authors.affiliation: Institute Pasteur, Paris, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Baleux
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.affiliation: Molecular Hematopoiesis Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Larochelle
authors.affiliation: Molecular Hematopoiesis Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indianapolis, USA.
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
authors.affiliation: Department of Medicine, Immunology Institute, and Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000818:Animals; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000378:metabolism*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology*; D000080027:Cyclams; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor; D009638:Norepinephrine