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Prepublished online as a Blood First Edition Paper on February 20, 2003; DOI 10.1182/blood-2002-09-2741.
Submitted September 9, 2002
Accepted January 31, 2003
The role of G-protein signaling in hemopoietic stem/progenitor cell mobilization
Thalia Papayannopoulou*, Gregory V Priestley, Halvard Bonig, and Betty Nakamoto
Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA
* Corresponding author; email: thalp{at}u.washington.edu.
The directed migration of mature leukocytes to inflammatory sites and the lymphocyte trafficking in vivo are dependent on G protein coupled receptors and delivered through pertussis toxin-sensitive Gi protein signaling. In the present study, we explored the in vivo role of G protein signaling on the redistribution or mobilization of stem/progenitor cells (HPC). A single injection of pertussis toxin (Ptx) in mice elicits a long-lasting leukocytosis and a progressive increase in circulating CFU-C and CFU-S. We found that the prolonged effect is sustained by a continuous slow release of Ptx bound to red blood cells or other cells and is potentially enhanced by an indirect influence on cell proliferation. Plasma levels of certain cytokines (IL-6, G-CSF) increase days post-Ptx treatment, but these are unlikely initiators of mobilization. In addition to normal mice, mice genetically deficient in MCP-1, MMP-9, G-CSF receptor,  2 integrins or Selectins responded to Ptx treatment, suggesting independence of Ptx-response from the expression of these molecules. Combined treatments of Ptx with anti-VLA4, uncovered potentially important insight in the interplay of chemokines/integrins, and the synergy of Ptx with G-CSF appeared to be MMP-9-dependent. As Ptx-mobilized kit+ cells display virtually no response to SDF-1 in vitro, our data suggest that disruption of CXCR4/SDF-1 signaling may be the underlying mechanism of Ptx-induced mobilization and indirectly reinforce the notion that active signaling through this pathway is required for continuous retention of cells within the bone marrow. Collectively, our data unveil a novel example of mobilization through pharmacologic modulation of signaling.
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