Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Spotlight Review
  • Published:

Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

Leukemia volume 25, pages 211–217 (2011)Cite this article

Subjects

Abstract

Under normal conditions, the great majority of hematopoietic stem/progenitors cells (HSPCs) reside in the bone marrow. The number of HSPCs in the circulation can be markedly increased in response to a number of stimuli, including hematopoietic growth factors, myeloablative agents and environmental stresses such as infection. The ability to ‘mobilize’ HSPCs from the bone marrow to the blood has been exploited clinically to obtain HSPCs for stem cell transplantation and, more recently, to stimulate therapeutic angiogenesis at sites of tissue ischemia. Moreover, there is recent interest in the use of mobilizing agents to sensitize leukemia and other hematopoietic malignancies to cytotoxic agents. Key to optimizing clinical mobilizing regimens is an understanding of the fundamental mechanisms of HSPC mobilization. In this review, we discuss recent advances in our understanding of the mechanisms by which granulocyte colony-stimulating factor (G-CSF), the prototypical mobilizing agent, induces HSPC mobilization.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol 2005; 23: 5074–5087.

    Google Scholar 

  2. Gorin NC, Labopin M, Reiffers J, Milpied N, Blaise D, Witz F et al. Higher incidence of relapse for acute myelocytic leukemia patients infused with higher doses of CD34+ cells from leukapheresis products autografted during the first remission. Blood 2010; 116: 3157–3162.

    CAS  Google Scholar 

  3. Gorin N, Labopin M, Blaise D, Reiffers J, Meloni G, Michallet M et al. Higher incidence of relapse with peripheral blood rather than marrow as a source of stem cells in adults with acute myelocytic leukemia autografted during the first remission. J Clin Oncol 2009; 27: 3987–3993.

    Google Scholar 

  4. Uchida N, He D, Friera AM, Reitsma M, Sasaki D, Chen B et al. The unexpected G0/G1 cell cycle status of mobilized hematopoietic stem cells from peripheral blood. Blood 1997; 89: 465–472.

    CAS  Google Scholar 

  5. Bellucci R, De Propris MS, Buccisano F, Lisci A, Leone G, Tabilio A et al. Modulation of VLA-4 and L-selectin expression on normal CD34+ cells during mobilization with G-CSF. Bone Marrow Transplant 1999; 23: 1–8.

    CAS  Google Scholar 

  6. Dlubek D, Drabczak-Skrzypek D, Lange A . Low CXCR4 membrane expression on CD34+ cells characterizes cells mobilized to blood. Bone Marrow Transplant 2005; 37: 19–23.

    Google Scholar 

  7. Wright DE, Cheshier SH, Wagers AJ, Randall TD, Christensen JL, Weissman IL . Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 2001; 97: 2278–2285.

    CAS  Google Scholar 

  8. Demetri GD, Griffin JD . Granulocyte colony-stimulating factor and its receptor. Blood 1991; 78: 2791–2808.

    CAS  Google Scholar 

  9. Bussolino F, Ziche M, Wang JM, Alessi D, Morbidelli L, Cremona O et al. In vitro and in vivo activation of endothelial cells by colony-stimulating factors. J Clin Invest 1991; 87: 986–995.

    CAS  Google Scholar 

  10. Liu F, Poursine-Laurent J, Link D . Expression of the G-CSF receptor on hematopoietic progenitor cells is not required for their mobilization by G-CSF. Blood 2000; 95: 3025–3031.

    CAS  Google Scholar 

  11. Katayama Y, Battista M, Kao W, Hidalgo A, Peired A, Thomas S et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 2006; 124: 407–421.

    Article  CAS  Google Scholar 

  12. Pelus LM, Bian H, King AG, Fukuda S . Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells. Blood 2004; 103: 110–119.

    CAS  Google Scholar 

  13. Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSC. Blood 2010, doi: 10.1182/blood-2009-11-253534.

    CAS  Google Scholar 

  14. Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 2006; 12: 657–664.

    CAS  Google Scholar 

  15. Takamatsu Y, Simmons PJ, Moore RJ, Morris HA, To LB, Levesque J . Osteoclast-mediated bone resorption is stimulated during short-term administration of granulocyte colony-stimulating factor but is not responsible for hematopoietic progenitor cell mobilization. Blood 1998; 92: 3465–3473.

    CAS  Google Scholar 

  16. Orlic D, Fischer R, Nishikawa S, Nienhuis AW, Bodine DM . Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c-kit receptor. Blood 1993; 82: 762–770.

    CAS  Google Scholar 

  17. Thoren LA, Liuba K, Bryder D, Nygren JM, Jensen CT, Qian H et al. Kit regulates maintenance of quiescent hematopoietic stem cells. J Immunol 2008; 180: 2045–2053.

    CAS  Google Scholar 

  18. Miller CL, Rebel VI, Helgason CD, Lansdorp PM, Eaves CJ . Impaired steel factor responsiveness differentially affects the detection and long-term maintenance of fetal liver hematopoietic stem cells in vivo. Blood 1997; 89: 1214–1223.

    CAS  Google Scholar 

  19. Lévesque J, Hendy J, Winkler IG, Takamatsu Y, Simmons PJ . Granulocyte colony-stimulating factor induces the release in the bone marrow of proteases that cleave c-KIT receptor (CD117) from the surface of hematopoietic progenitor cells. Exp Hematol 2003; 31: 109–117.

    Google Scholar 

  20. Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 Mediated release of kit-ligand. Cell 2002; 109: 625–637.

    CAS  Google Scholar 

  21. Roberts MM, Swart BW, Simmons PJ, Basser RL, Begley CG, To LB . Prolonged release and c-kit expression of haemopoietic precursor cells mobilized by stem cell factor and granulocyte colony stimulating factor. Br J Haematol 1999; 104: 778–784.

    CAS  Google Scholar 

  22. Ishiga K, Kawatani T, Tajima F, Omura H, Nanba E, Kawasaki H . Serum-soluble c-kit levels during mobilization of peripheral blood stem cells correlate with stem cell yield. Int J Hematol 2000; 72: 186–193.

    CAS  Google Scholar 

  23. Nakamura Y, Tajima F, Ishiga K, Yamazaki H, Oshimura M, Shiota G et al. Soluble c-kit receptor mobilizes hematopoietic stem cells to peripheral blood in mice. Exp Hematol 2004; 32: 390–396.

    CAS  Google Scholar 

  24. Molineux G, Migdalska A, Szmitkowski M, Zsebo K, Dexter TM . The effects on hematopoiesis of recombinant stem cell factor (ligand for c-kit) administered in vivo to mice either alone or in combination with granulocyte colony-stimulating factor. Blood 1991; 78: 961–966.

    CAS  Google Scholar 

  25. Papayannopoulou T, Priestley GV, Nakamoto B . Anti-VLA4/VCAM-1-induced mobilization requires cooperative signaling through the kit/mkit ligand pathway. Blood 1998; 91: 2231–2239.

    CAS  Google Scholar 

  26. Roberts AW, Foote S, Alexander WS, Scott C, Robb L, Metcalf D . Genetic influences determining progenitor cell mobilization and leukocytosis induced by granulocyte colony-stimulating factor. Blood 1997; 89: 2736–2744.

    CAS  Google Scholar 

  27. Levesque J, Liu F, Simmons P, Betsuyaku T, Senior R, Pham C et al. Characterization of hematopoietic progenitor mobilization in protease-deficient mice. Blood 2004; 104: 65–72.

    CAS  Google Scholar 

  28. Robinson SN, Pisarev VM, Chavez JM, Singh RK, Talmadge JE . Use of matrix metalloproteinase (MMP)-9 knockout mice demonstrates that MMP-9 activity is not absolutely required for G-CSF or Flt-3 ligand-induced hematopoietic progenitor cell mobilization or engraftment. Stem Cells 2003; 21: 417–427.

    CAS  Google Scholar 

  29. Papayannopoulou T, Priestley GV, Bonig H, Nakamoto B . The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization. Blood 2003; 101: 4739–4747.

    CAS  Google Scholar 

  30. Robinson SN, Seina SM, Gohr JC, Sharp JG . Hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor and erythropoietin in the absence of matrix metalloproteinase-9. Stem Cells Dev 2005; 14: 317–328.

    CAS  Google Scholar 

  31. Jung Y, Wang J, Havens A, Sun Y, Wang J, Jin T et al. Cell-to-cell contact is critical for the survival of hematopoietic progenitor cells on osteoblasts. Cytokine 2005; 32: 155–162.

    CAS  Google Scholar 

  32. Papayannopoulou T, Craddock C, Nakamoto B, Priestley GV, Wolf NS . The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proc Natl Acad Sci USA 1995; 92: 9647–9651.

    CAS  Google Scholar 

  33. Jacobsen K, Kravitz J, Kincade PW, Osmond DG . Adhesion receptors on bone marrow stromal cells: in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and gamma-irradiated mice. Blood 1996; 87: 73–82.

    CAS  Google Scholar 

  34. Williams DA, Rios M, Stephens C, Patel VP . Fibronectin and VLA-4 in haematopoietic stem cell-microenvironment interactions. Nature 1991; 352: 438–441.

    CAS  Google Scholar 

  35. Priestley GV, Scott LM, Ulyanova T, Papayannopoulou T . Lack of alpha4 integrin expression in stem cells restricts competitive function and self-renewal activity. Blood 2006; 107: 2959–2967.

    CAS  Google Scholar 

  36. Ulyanova T, Scott L, Priestley G, Jiang Y, Nakamoto B, Koni P et al. VCAM-1 expression in adult hematopoietic and nonhematopoietic cells is controlled by tissue-inductive signals and reflects their developmental origin. Blood 2005; 106: 86–94.

    CAS  Google Scholar 

  37. Papayannopoulou T, Nakamoto B . Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin. Proc Natl Acad Sci USA 1993; 90: 9374–9378.

    CAS  Google Scholar 

  38. Zohren F, Toutzaris D, Klärner V, Hartung H, Kieseier B, Haas R . The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood 2008; 111: 3893–3895.

    CAS  Google Scholar 

  39. Ramirez P, Rettig MP, Uy GL, Deych E, Holt MS, Ritchey JK et al. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood 2009; 114: 1340–1343.

    CAS  Google Scholar 

  40. Levesque J, Takamatsu Y, Nilsson SK, Haylock DN, Simmons PJ . Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 2001; 98: 1289–1297.

    CAS  Google Scholar 

  41. Lévesque J, Hendy J, Takamatsu Y, Williams B, Winkler IG, Simmons PJ . Mobilization by either cyclophosphamide or granulocyte colony-stimulating factor transforms the bone marrow into a highly proteolytic environment. Exp Hematol 2002; 30: 440–449.

    Google Scholar 

  42. Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999; 283: 845–848.

    CAS  Google Scholar 

  43. Kawabata K, Ujikawa M, Egawa T, Kawamoto H, Tachibana K, Iizasa H et al. A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. Proc Natl Acad Sci USA 1999; 96: 5663–5667.

    CAS  Google Scholar 

  44. Cashman J, Clark-Lewis I, Eaves A, Eaves C . Stromal-derived factor 1 inhibits the cycling of very primitive human hematopoietic cells in vitro and in NOD/SCID mice. Blood 2002; 99: 792–799.

    CAS  Google Scholar 

  45. Balabanian K, Lagane B, Infantino S, Chow KYC, Harriague J, Moepps B et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem 2005; 280: 35760–35766.

    CAS  Google Scholar 

  46. Hartmann TN, Grabovsky V, Pasvolsky R, Shulman Z, Buss EC, Spiegel A et al. A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34+ cells. J Leukoc Biol 2008; 84: 1130–1140.

    CAS  Google Scholar 

  47. Boldajipour B, Mahabaleshwar H, Kardash E, Reichman-Fried M, Blaser H, Minina S et al. Control of chemokine-guided cell migration by ligand sequestration. Cell 2008; 132: 463–473.

    CAS  Google Scholar 

  48. Sierro F, Biben C, Martínez-Muñoz L, Mellado M, Ransohoff RM, Li M et al. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci USA 2007; 104: 14759–14764.

    CAS  Google Scholar 

  49. Dubeykovskaya Z, Dubeykovskiy A, Solal-Cohen J, Wang TC . Secreted trefoil factor 2 activates the CXCR4 receptor in epithelial and lymphocytic cancer cell lines. J Biol Chem 2009; 284: 3650–3662.

    CAS  Google Scholar 

  50. Feng Z, Dubyak GR, Lederman MM, Weinberg A . Cutting edge: human beta defensin 3—a novel antagonist of the HIV-1 coreceptor CXCR4. J Immunol 2006; 177: 782–786.

    CAS  Google Scholar 

  51. Wright D, Bowman E, Wagers A, Butcher E, Weissman I . Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J Exp Med 2002; 195: 1145–1154.

    CAS  Google Scholar 

  52. Aiuti A, Webb I, Bleul C, Springer T, Gutierrez-Ramos J . The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 1997; 185: 111–120.

    CAS  Google Scholar 

  53. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635–638.

    CAS  Google Scholar 

  54. Zou Y, Kottmann A, Kuroda M, Taniuchi I, Littman D . Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998; 393: 595–599.

    CAS  Google Scholar 

  55. Ma Q, Jones D, Springer TA . The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 1999; 10: 463–471.

    CAS  Google Scholar 

  56. Christopher MJ, Liu F, Hilton MJ, Long F, Link DC . Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization. Blood 2009; 114: 1331–1339.

    CAS  Google Scholar 

  57. Liles WC, Broxmeyer HE, Rodger E, Wood B, Hübel K, Cooper S et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 2003; 102: 2728–2730.

    CAS  Google Scholar 

  58. Broxmeyer H, Orschell C, Clapp D, Hangoc G, Cooper S, Plett P et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 2005; 201: 1307–1318.

    CAS  Google Scholar 

  59. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 2002; 3: 687–694.

    CAS  Google Scholar 

  60. Semerad C, Christopher M, Liu F, Short B, Simmons P, Winkler I et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 2005; 106: 3020–3027.

    CAS  Google Scholar 

  61. Levesque J, Hendy J, Takamatsu Y, Simmons P, Bendall L . Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 2003; 111: 187–196.

    CAS  Google Scholar 

  62. Méndez-Ferrer S, Lucas D, Battista M, Frenette PS . Haematopoietic stem cell release is regulated by circadian oscillations. Nature 2008; 452: 442–447.

    Google Scholar 

  63. Marquez-Curtis L, Jalili A, Deiteren K, Shirvaikar N, Lambeir A, Janowska-Wieczorek A . Carboxypeptidase M expressed by human bone marrow cells cleaves the C-terminal lysine of stromal cell-derived factor-1alpha: another player in hematopoietic stem/progenitor cell mobilization? Stem Cells 2008; 26: 1211–1220.

    CAS  Google Scholar 

  64. Christopherson KW, Cooper S, Broxmeyer HE . Cell surface peptidase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor cells. Blood 2003; 101: 4680–4686.

    CAS  Google Scholar 

  65. Christopherson KW, Cooper S, Hangoc G, Broxmeyer HE . CD26 is essential for normal G-CSF-induced progenitor cell mobilization as determined by CD26−/− mice. Exp Hematol 2003; 31: 1126–1134.

    CAS  Google Scholar 

  66. Ross E, Freeman S, Zhao Y, Dhanjal T, Ross E, Lax S et al. A novel role for PECAM-1 (CD31) in regulating haematopoietic progenitor cell compartmentalization between the peripheral blood and bone marrow. PLoS ONE 2008; 3: e2338.

    Google Scholar 

  67. Tesio M, Golan K, Corso S, Giordano S, Schajnovitz A, Vagima Y et al. Enhanced c-Met activity promotes G-CSF induced mobilization of hematopoietic progenitor cells via ROS signaling. Blood 2010, doi:10.1182/blood-2009-06-230359.

    Google Scholar 

  68. Kiel M, Yilmaz O, Iwashita T, Terhorst C, Morrison S . SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 2005; 121: 1109–1121.

    CAS  Google Scholar 

  69. Sugiyama T, Kohara H, Noda M, Nagasawa T . Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006; 25: 977–988.

    CAS  Google Scholar 

  70. Yoshimoto M, Shinohara T, Heike T, Shiota M, Kanatsu-Shinohara M, Nakahata T . Direct visualization of transplanted hematopoietic cell reconstitution in intact mouse organs indicates the presence of a niche. Exp Hematol 2003; 31: 733–740.

    Google Scholar 

  71. Nilsson S, Johnston H, Coverdale J . Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 2001; 97: 2293–2299.

    CAS  Google Scholar 

  72. Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 2009; 457: 92–96.

    CAS  Google Scholar 

  73. Xie Y, Yin T, Wiegraebe W, He XC, Miller D, Stark D et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 2009; 457: 97–101.

    CAS  Google Scholar 

  74. Zhang J, Niu C, Ye L, Huang H, He X, Tong W et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003; 425: 836–841.

    CAS  Google Scholar 

  75. Calvi L, Adams G, Weibrecht K, Weber J, Olson D, Knight M et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003; 425: 841–846.

    CAS  Google Scholar 

  76. Visnjic D, Kalajzic Z, Rowe D, Katavic V, Lorenzo J, Aguila H . Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 2004; 103: 3258–3264.

    CAS  Google Scholar 

  77. Morikawa S, Mabuchi Y, Kubota Y, Nagai Y, Niibe K, Hiratsu E et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med 2009; 206: 2483–2496.

    CAS  Google Scholar 

  78. Nagasawa T . The chemokine CXCL12 and regulation of HSC and B lymphocyte development in the bone marrow niche. Adv Exp Med Biol 2007; 602: 69–75.

    Google Scholar 

  79. Froberg M, Garg U, Stroncek D, Geis M, McCullough J, Brown D . Changes in serum osteocalcin and bone-specific alkaline phosphatase are associated with bone pain in donors receiving granulocyte-colony-stimulating factor for peripheral blood stem and progenitor cell collection. Transfusion 1999; 39: 410–414.

    CAS  Google Scholar 

  80. Christopher MJ, Link DC . Granulocyte colony-stimulating factor induces osteoblast apoptosis and inhibits osteoblast differentiation. J Bone Miner Res 2008; 23: 1765–1774.

    Google Scholar 

  81. Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002; 109: 625–637.

    CAS  Google Scholar 

  82. Winkler IG, Hendy J, Coughlin P, Horvath A, Lévesque J . Serine protease inhibitors serpina1 and serpina3 are down-regulated in bone marrow during hematopoietic progenitor mobilization. J Exp Med 2005; 201: 1077–1088.

    CAS  Google Scholar 

  83. van Pel M, van Os R, Velders GA, Hagoort H, Heegaard PMH, Lindley IJD et al. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization. Proc Natl Acad Sci USA 2006; 103: 1469–1474.

    CAS  Google Scholar 

  84. Pruijt JFM, Verzaal P, van Os R, de Kruijf EFM, van Schie MLJ, Mantovani A et al. Neutrophils are indispensable for hematopoietic stem cell mobilization induced by interleukin-8 in mice. Proc Natl Acad Sci USA 2002; 99: 6228–6233.

    CAS  Google Scholar 

  85. Pruijt JFM, Fibbe WE, Laterveer L, Pieters RA, Lindley IJD, Paemen L et al. Prevention of interleukin-8-induced mobilization of hematopoietic progenitor cells in rhesus monkeys by inhibitory antibodies against the metalloproteinase gelatinase B (MMP-9). Proc Natl Acad Sci USA 1999; 96: 10863–10868.

    CAS  Google Scholar 

  86. Blasi F, Carmeliet P . uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3: 932–943.

    CAS  Google Scholar 

  87. Tjwa M, Sidenius N, Moura R, Jansen S, Theunissen K, Andolfo A et al. Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells. J Clin Invest 2009; 119: 1008–1018.

    CAS  Google Scholar 

  88. Selleri C, Montuori N, Ricci P, Visconte V, Carriero MV, Sidenius N et al. Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization. Blood 2005; 105: 2198–2205.

    CAS  Google Scholar 

  89. Selleri C, Montuori N, Ricci P, Visconte V, Baiano A, Carriero MV et al. In vivo activity of the cleaved form of soluble urokinase receptor: a new hematopoietic stem/progenitor cell mobilizer. Cancer Res 2006; 66: 10885–10890.

    CAS  Google Scholar 

  90. Tjwa M, Janssens S, Carmeliet P . Plasmin therapy enhances mobilization of HPCs after G-CSF. Blood 2008; 112: 4048–4050.

    CAS  Google Scholar 

  91. Reca R, Mastellos D, Majka M, Marquez L, Ratajczak J, Franchini S et al. Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells, and C3a enhances their homing-related responses to SDF-1. Blood 2003; 101: 3784–3793.

    CAS  Google Scholar 

  92. Ratajczak J, Reca R, Kucia M, Majka M, Allendorf DJ, Baran JT et al. Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow. Blood 2004; 103: 2071–2078.

    CAS  Google Scholar 

  93. Reca R, Cramer D, Yan J, Laughlin MJ, Janowska-Wieczorek A, Ratajczak J et al. A novel role of complement in mobilization: immunodeficient mice are poor granulocyte-colony stimulating factor mobilizers because they lack complement-activating immunoglobulins. Stem Cells 2007; 25: 3093–3100.

    CAS  Google Scholar 

  94. Jalili A, Shirvaikar N, Marquez-Curtis L, Qiu Y, Korol C, Lee H et al. Fifth complement cascade protein (C5) cleavage fragments disrupt the SDF-1/CXCR4 axis: further evidence that innate immunity orchestrates the mobilization of hematopoietic stem/progenitor cells. Exp Hematol 2010; 38: 321–332.

    CAS  Google Scholar 

  95. Lee HM, Wu W, Wysoczynski M, Liu R, Zuba-Surma EK, Kucia M et al. Impaired mobilization of hematopoietic stem/progenitor cells in C5-deficient mice supports the pivotal involvement of innate immunity in this process and reveals novel promobilization effects of granulocytes. Leukemia 2009; 23: 2052–2062.

    CAS  Google Scholar 

  96. Ratajczak MZ, Lee H, Wysoczynski M, Wan W, Marlicz W, Laughlin MJ et al. Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex. Leukemia 2010; 24: 976–985.

    CAS  Google Scholar 

  97. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, MacArthur BD, Lira SA et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010; 466: 829–834.

    CAS  Google Scholar 

  98. Eash KJ, Greenbaum AM, Gopalan PK, Link DC . CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest 2010; 120: 2423–2431.

    CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Mahil Rao for his generous contribution of Figure 1.

Author information

Authors and Affiliations

  1. Department of Medicine, Washington University School of Medicine, St Louis, MO, USA

    A M Greenbaum & D C Link

Authors
  1. A M Greenbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D C Link.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greenbaum, A., Link, D. Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization. Leukemia 25, 211–217 (2011). https://doi.org/10.1038/leu.2010.248

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.248

Keywords

This article is cited by

Search

Advanced search

Quick links