title: Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells.
abstract: Interaction between the chemokine receptor CXCR4 and its chief ligand CXCL12 plays a critical role in the retention and migration of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) microenvironment. In this study, qualitative and quantitative effects of long-term pharmacologic inhibition of the CXCR4/CXCL12 axis on the HSPC compartment were investigated by using 3 structurally unrelated small molecule CXCR4 antagonists. A >10-fold increase in mobilization efficiency was achieved by administering the antagonists as a subcutaneous continuous infusion for 2 weeks compared to a single bolus injection. A concurrent increase in self-renewing proliferation leading to a twofold to fourfold expansion of the HSPC pool in the BM was observed. The expanded BM showed a distinct repopulating advantage when tested in serial competitive transplantation experiments. Furthermore, major changes within the HSPC niche associated with previously described HSPC expansion strategies were not detected in bones treated with a CXCR4 antagonist infusion. Our data suggest that prolonged but reversible pharmacologic blockade of the CXCR4/CXCL12 axis represents an approach that releases HSPC with efficiency superior to any other known mobilization strategy and may also serve as an effective method to expand the BM HSPC pool.
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Darja
authors.initials: D
authors.lastname: Karpova
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Ritchey
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Holt
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Grazia
authors.initials: G
authors.lastname: Abou-Ezzi
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Darlene
authors.initials: D
authors.lastname: Monlish
authors.affiliation: Mater Research Institute, The University of Queensland, Faculty of Medicine, Translational Research Institute, Woolloongabba, QLD, Australia.
authors.forename: Lena
authors.initials: L
authors.lastname: Batoon
authors.affiliation: Mater Research Institute, The University of Queensland, Faculty of Medicine, Translational Research Institute, Woolloongabba, QLD, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Millard
authors.affiliation: German Red Cross Blood Service and Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Spohn
authors.affiliation: German Red Cross Blood Service and Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany.
authors.forename: Eliza
authors.initials: E
authors.lastname: Wiercinska
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Ezhil
authors.initials: E
authors.lastname: Chendamarai
authors.affiliation: Genome Technology Access Center, Washington University, St. Louis, MO.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Christ
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Leah
authors.initials: L
authors.lastname: Gehrs
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Schuettpelz
authors.affiliation: Amcure GmbH, Munich, Germany; and.
authors.forename: Klaus
authors.initials: K
authors.lastname: Dembowsky
authors.affiliation: Mater Research Institute, The University of Queensland, Faculty of Medicine, Translational Research Institute, Woolloongabba, QLD, Australia.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Pettit
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Rettig
authors.affiliation: German Red Cross Blood Service and Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany.|Division of Hematology, Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Halvard
authors.initials: H
authors.lastname: Bonig
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055153:Stem Cell Niche / Q000187:drug effects*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4