Abstract
We reported that complement cascade (CC) becomes activated in bone marrow (BM) during mobilization of hematopoietic stem/progenitor cells (HSPCs) induced by granulocyte colony-stimulating factor (G-CSF) and C5 cleavage has an important function in optimal egress of HSPCs. In this work, we explored whether CC is involved in mobilization of HSPCs induced by the CXCR4 antagonist, AMD3100. To address this question, we performed mobilization studies in mice that display a defect in the activation of the proximal steps of CC (Rag−/−, severe combined immune deficient (SCID), C2.Cfb−/−) as well as in mice that do not activate the distal steps of CC (C5−/−). We noticed that proximal CC activation-deficient mice (above C5 level), in contrast to distal step CC activation-deficient C5−/− ones, mobilize normally in response to AMD3100 administration. We hypothesized that this discrepancy in mobilization could be explained by AMD3100-activating C5 in Rag−/−, SCID, and C2.Cfb−/− animals in a non-canonical mechanism involving activated granulocytes. To support this, granulocytes (i) first egress from BM and (ii) secrete several proteases that cleave/activate C5 in response to AMD3100. We conclude that AMD3100-directed mobilization of HSPCs, similarly to G-CSF-induced mobilization, depends on activation of CC; however, in contrast to G-CSF, AMD3100 activates the distal steps of CC directly at the C5 level. Overall, these data support that C5 cleavage fragments and distal steps of CC activation are required for optimal mobilization of HSPCs.
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References
Kyne L, Hausdorff JM, Knight E, Dukas L, Azhar G, Wei JY . Neutrophilia and congestive heart failure after acute myocardial infarction. Am Heart J 2000; 139: 94–100.
Massberg S, Schaerli P, Knezevic-Maramica I, Köllnberger M, Tubo N, Moseman EA et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 2007; 131: 994–1008.
Lee H, Ratajczak MZ . Innate immunity: a key player in the mobilization of hematopoietic stem/progenitor cells. Arch Immunol Ther Exp (Warsz) 2009; 57: 269–278.
Andrews RG, Briddell RA, Knitter GH, Opie T, Bronsden M, Myerson D et al. In vivo synergy between recombinant human stem cell factor and recombinant human granulocyte colony-stimulating factor in baboons enhanced circulation of progenitor cells. Blood 1994; 84: 800–810.
Laterveer L, Lindley IJ, Hamilton MS, Willemze R, Fibbe WE . Interleukin-8 induces rapid mobilization of hematopoietic stem cells with radioprotective capacity and long-term myelolymphoid repopulating ability. Blood 1995; 85: 2269–2275.
Stiff P, Gingrich R, Luger S, Wyres MR, Brown RA, LeMaistre CF et al. A randomized phase 2 study of PBPC mobilization by stem cell factor and filgrastim in heavily pretreated patients with Hodgkin's disease or non-Hodgkin's lymphoma. Bone Marrow Transplant 2000; 26: 471–481.
To LB, Bashford J, Durrant S, MacMillan J, Schwarer AP, Prince HM et al. Successful mobilization of peripheral blood stem cells after addition of ancestim (stem cell factor) in patients who had failed a prior mobilization with filgrastim (granulocyte colony-stimulating factor) alone or with chemotherapy plus filgrastim. Bone Marrow Transplant 2003; 31: 371–378.
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.
Glaspy JA, Shpall EJ, LeMaistre CF, Briddell RA, Menchaca DM, Turner SA et al. Peripheral blood progenitor cell mobilization using stem cell factor in combination with filgrastim in breast cancer patients. Blood 1997; 90: 2939–2951.
Molineux G, McCrea C, Yan XQ, Kerzic P, McNiece I . Flt-3 ligand synergizes with granulocyte colony-stimulating factor to increase neutrophil numbers and to mobilize peripheral blood stem cells with long-term repopulating potential. Blood 1997; 89: 3998–4004.
Papayannopoulou T, Nakamoto B, Andrews RG, Lyman SD, Lee MY . In vivo effects of Flt3/Flk2 ligand on mobilization of hematopoietic progenitors in primates and potent synergistic enhancement with granulocyte colony-stimulating factor. Blood 1997; 90: 620–629.
Pelus LM, Fukuda S . Chemokine-mobilized adult stem cells; defining a better hematopoietic graft. Leukemia 2008; 22: 466–473.
Pruijt JF, Fibbe WE, Laterveer L, Pieters RA, Lindley IJ, 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.
King AG, Horowitz D, Dillon SB, Levin R, Farese AM, MacVittie TJ et al. Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRObeta. Blood 2001; 97: 1534–1542.
Papayannopoulou T . Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood 2004; 103: 1580–1585.
Fruehauf S, Seeger T, Topaly J . Innovative strategies for PBPC mobilization. Cytotherapy 2005; 7: 438–446.
Winkler IG, Levesque JP . Mechanisms of hematopoietic stem cell mobilization: when innate immunity assails the cells that make blood and bone. Exp Hematol 2006; 34: 996–1009.
Bensinger W, Dipersio JF, McCarty JM . Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant 2009; 43: 181–195.
Vos O, Wilschut IJ . Further studies on mobilization of CFUs. Cell Tissue Kinet 1979; 12: 257–267.
Sweeney EA, Priestley GV, Nakamoto B, Collins RG, Beaudet AL, Papayannopoulou T . Mobilization of stem/progenitor cells by sulfated polysaccharides does not require selectin presence. Proc Natl Acad Sci USA 2000; 97: 6544–6549.
Sweeney EA, Lortat-Jacob H, Priestley GV, Nakamoto B, Papayannopoulou T . Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Blood 2002; 99: 44–51.
Lévesque JP, 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.
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.
Pelus LM, Bian H, King AG, Fukuda S . Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GRObeta/CXCL2 and GRObetaT/CXCL2delta4. Blood 2004; 103: 110–119.
Lapidot T, Dar A, Kollet O . How do stem cells find their way home? Blood 2005; 106: 1901–1910.
Peled A, Grabovsky V, Habler L, Sandbank J, Arenzana-Seisdedos F, Petit I et al. The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow. J Clin Invest 1999; 104: 1199–1211.
Lévesque JP, 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.
Sekhsaria S, Fleisher TA, Vowells S, Brown M, Miller J, Gordon I et al. Granulocyte colony-stimulating factor recruitment of CD34+ progenitors to peripheral blood: impaired mobilization in chronic granulomatous disease and adenosine deaminase–deficient severe combined immunodeficiency disease patients. Blood 1996; 88: 1104–1112.
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.
Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA 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.
Flomenberg N, Devine SM, Dipersio JF, Liesveld JL, McCarty JM, Rowley SD et al. The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood 2005; 106: 1867–1874.
Molendijk WJ, van Oudenaren A, van Dijk H, Daha MR, Benner R . Complement split product C5a mediates the lipopolysaccharide-induced mobilization of CFU-s and haemopoietic progenitor cells, but not the mobilization induced by proteolytic enzymes. Cell Tissue Kinet 1986; 19: 407–417.
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.
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.
Ratajczak MZ, Reca R, Wysoczynski M, Kucia M, Baran JT, Allendorf DJ et al. Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells. Leukemia 2004; 18: 1482–1490.
Ratajczak MZ, Reca R, Wysoczynski M, Yan J, Ratajczak J . Modulation of the SDF-1-CXCR4 axis by the third complement component (C3)--implications for trafficking of CXCR4+ stem cells. Exp Hematol 2006; 34: 986–995.
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.
Liu F, Poursine-Laurent J, Link DC . Expression of the G-CSF receptor on hematopoietic progenitor cells is not required for their mobilization by G-CSF. Blood 2000; 95: 3025–3031.
Pruijt JF, Verzaal P, van Os R, de Kruijf EJ, van Schie ML, 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.
Wu W, Lee H, Wysoczynski M, Kucia M, Ratajczak J, Ratajczak MZ . Novel observation that mice lacking the fifth complement cascade protein component (C5) are very poor stem cell mobilizers explained by defective egress of granulocytes: a novel role for bone marrow granulocytes to act as ‘ice breaker’ cells in facilitating egress of hematopoietic stem/progenitor cells. Blood 2008; 112: 32. Abstract 67.
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.
Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S et al. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 2006; 24: 801–812.
Wysoczynski M, Reca R, Lee H, Wu W, Ratajczak J, Ratajczak MZ . Defective engraftment of C3aR-/- hematopoietic stem progenitor cells shows a novel role of the C3a-C3aR axis in bone marrow homing. Leukemia 2009; 23: 1455–1461.
Huber-Lang M, Younkin EM, Sarma JV, Riedemann N, McGuire SR, Lu KT et al. Generation of C5a by phagocytic cells. Am J Pathol 2002; 161: 1849–1859.
Ward PA . The dark side of C5a in sepsis. Nat Rev Immunol 2004; 4: 133–142.
Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 2006; 12: 682–687.
Asberg AE, Mollnes TE, Videm V . Complement activation by neutrophil granulocytes. Scand J Immunol 2008; 67: 354–361.
Zhang WB, Navenot JM, Haribabu B, Tamamura H, Hiramatu K, Omagari A et al. A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists. J Biol Chem 2002; 277: 24515–24521.
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.
Lévesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ . Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 2003; 111: 187–196.
Lévesque JP, 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.
Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 2006; 124: 407–421.
McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I et al. Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem 2001; 276: 43503–43508.
Semerad CL, Christopher MJ, Liu F, Short B, Simmons PJ, Winkler I et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 2005; 106: 3020–3027.
Kollet O, Dar A, Lapidot T . The multiple roles of osteoclasts in host defense: bone remodeling and hematopoietic stem cell mobilization. Annu Rev Immunol 2007; 25: 51–69.
van Pel M, van Os R, Velders GA, Hagoort H, Heegaard PM, Lindley IJ et al. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization. Proc Natl Acad Sci USA 2006; 103: 1469–1474.
Zhang Zhang M, Austen Jr WG, Chiu I, Alicot EM, Hung R, Ma M et al. Identification of a specific self-reactive IgM antibody that initiates intestinal ischemia/reperfusion injury. Proc Natl Acad Sci USA 2004; 101: 3886–3891.
Wysoczynski M, Kucia M, Ratajczak J, Ratajczak MZ . Cleavage fragments of third complement component (C3) enhance SDF-1 mediated platelet production during reactive thrombocytosis. Leukemia 2007; 21: 973–982.
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Supported by NIH grant R01 CA106281, NIH R01 DK074720, and Stella and Henry Endowment to MZR.
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Lee, H., Wysoczynski, M., Liu, R. et al. Mobilization studies in complement-deficient mice reveal that optimal AMD3100 mobilization of hematopoietic stem cells depends on complement cascade activation by AMD3100-stimulated granulocytes. Leukemia 24, 573–582 (2010). https://doi.org/10.1038/leu.2009.271
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DOI: https://doi.org/10.1038/leu.2009.271
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