The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization.
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 (Ptx)-sensitive Gi-protein signaling. In the present study, we explored the in vivo role of G-protein signaling on the redistribution or mobilization of hematopoietic stem/progenitor cells (HPCs). A single injection of Ptx in mice elicits a long-lasting leukocytosis and a progressive increase in circulating colony-forming unit-culture (CFU-C) and colony-forming unit spleen (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 (interleukin 6 [IL-6], granulocyte colony-stimulating factor [G-CSF]) increase days after Ptx treatment, but these are unlikely initiators of mobilization. In addition to normal mice, mice genetically deficient in monocyte chemotactic protein 1 (MCP-1), matrix metalloproteinase 9 (MMP-9), G-CSF receptor, beta2 integrins, or selectins responded to Ptx treatment, suggesting independence of Ptx-response from the expression of these molecules. Combined treatments of Ptx with anti-very late activation antigen (anti-VLA-4), uncovered potentially important insight in the interplay of chemokines/integrins, and the synergy of Ptx with G-CSF appeared to be dependent on MMP-9. As Ptx-mobilized kit+ cells display virtually no response to stromal-derived factor 1 (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.
Papayannopoulou
Thalia
T
Division of Hematology, University of Washington, Seattle 98195, USA. thalp@u.washington.edu
Priestley
Gregory V
GV
Bonig
Halvard
H
Nakamoto
Betty
B
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D018821:CD18 Antigens / Q000502:physiology; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000172:deficiency; D003114:Colony-Forming Units Assay; D004357:Drug Synergism; D019204:GTP-Binding Proteins / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D016130:Immunophenotyping; D039441:Integrin alpha4 / Q000276:immunology; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors; D007700:Kinetics; D007964:Leukocytosis; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D037342:Pertussis Toxin / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000172:deficiency; D019087:Selectins / Q000502:physiology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology
D000906:Antibodies; D018821:CD18 Antigens; D018932:Chemokine CCL2; D039041:Integrin alpha4beta1; D011134:Polysaccharides; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D019087:Selectins; D016179:Granulocyte Colony-Stimulating Factor; D039441:Integrin alpha4; C007789:fucoidan; D037342:Pertussis Toxin; D020780:Matrix Metalloproteinase 9; D019204:GTP-Binding Proteins