title: The chemokine GRObeta mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment.
abstract: Mobilized peripheral blood hematopoietic stem cells (PBSCs) demonstrate accelerated engraftment compared with bone marrow; however, mechanisms responsible for enhanced engraftment remain unknown. PBSCs mobilized by GRObeta (GRObeta(Delta4)/CXCL2(Delta4)) or the combination of GRObeta(Delta4) plus granulocyte colony-stimulating factor (G-CSF) restore neutrophil and platelet recovery faster than G-CSF-mobilized PBSCs. To determine mechanisms responsible for faster hematopoietic recovery, we characterized immunophenotype and function of the GRObeta-mobilized grafts. PBSCs mobilized by GRObeta(Delta4) alone or with G-CSF contained significantly more Sca-1(+)-c-kit(+)-lineage(-) (SKL) cells and more primitive CD34(-)-SKL cells compared with cells mobilized by G-CSF and demonstrated superior competitive long-term repopulation activity, which continued to increase in secondary and tertiary recipients. GRObeta(Delta4)-mobilized SKL cells adhered better to VCAM-1(+) endothelial cells compared with G-CSF-mobilized cells. GRObeta(Delta4)-mobilized PBSCs did not migrate well to the chemokine stromal derived factor (SDF)-1alpha in vitro that was associated with higher CD26 expression. However, GRObeta(Delta4)-mobilized SKL and c-Kit(+) lineage(-) (KL) cells homed more efficiently to marrow in vivo, which was not affected by selective CXCR4 and CD26 antagonists. These data suggest that GRObeta(Delta4)-mobilized PBSCs are superior in reconstituting long-term hematopoiesis, which results from differential mobilization of early stem cells with enhanced homing and long-term repopulating capacity. In addition, homing and engraftment of GRObeta(Delta4)-mobilized cells is less dependent on the SDF-1alpha/CXCR4 axis.
authors.affiliation: Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Huimin
authors.initials: H
authors.lastname: Bian
authors.forename: Andrew G
authors.initials: AG
authors.lastname: King
authors.forename: Louis M
authors.initials: LM
authors.lastname: Pelus
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D036102:Peripheral Blood Stem Cell Transplantation; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D014184:Transplantation, Homologous; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D000950:Antigens, Ly; C514936:CXCR4 protein, mouse; D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C515256:Cxcl12 protein, mouse; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019718:Receptors, CXCR4; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit; D018819:Dipeptidyl Peptidase 4