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Blood, 1 August 2007, Vol. 110, No. 3, pp. 860-869.
Prepublished online as a Blood First Edition Paper on April 6, 2007; DOI 10.1182/blood-2006-06-031401.
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HEMATOPOIESIS
The chemokine GROß mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment
Seiji Fukuda1,
Huimin Bian1,
Andrew G. King2, and
Louis M. Pelus1
1 Department of Microbiology and Immunology, the Walther Oncology Center, Indiana University School of Medicine, and the Walther Cancer Institute, Indianapolis; and
2 Microbial, Musculoskeletal, and Proliferative Diseases Centers of Excellence in Drug Discovery (CEDD), GlaxoSmithKline, Collegeville, PA
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 GROß (GROß 4/CXCL24) or the combination of GROß4 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 GROß-mobilized grafts. PBSCs mobilized by GROß4 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. GROß4-mobilized SKL cells adhered better to VCAM-1+ endothelial cells compared with G-CSF–mobilized cells. GROß4-mobilized PBSCs did not migrate well to the chemokine stromal derived factor (SDF)-1 in vitro that was associated with higher CD26 expression. However, GROß4-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 GROß4-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 GROß4-mobilized cells is less dependent on the SDF-1/CXCR4 axis.
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