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.

  • Original Article
  • Published:

Cell Procurement

Degradation of BM SDF-1 by MMP-9: the role in G-CSF-induced hematopoietic stem/progenitor cell mobilization

Bone Marrow Transplantation volume 42, pages 581–588 (2008)Cite this article

Abstract

The major involvement of chemokines and proteolytic enzymes has recently been discovered in the mobilization process. Here, we report that the degradation of BM stromal cell-derived factor (SDF-1) by matrix metalloproteinase (MMP)-9 is important in G-CSF-mediated hematopoietic stem/progenitor cells (HSPCs) mobilization. In this study, the SDF-1 concentration in healthy donors BM plasma decreased significantly after 5 days of G-CSF administration, with no obvious change of SDF-1 in the peripheral blood. We also observed a similar result by immunohistochemical staining on the BM biopsy slides. In vitro, mobilized BM plasma exhibited decreased chemotactic effect on CD34+ cells, compared with steady-state BM plasma. MMP-9 protein and mRNA increased dramatically in the BM plasma in accordance with SDF-1 decrease. MMP-9 enriched supernatant from HT1080 cell-conditioned medium upregulated CXCR4 expression and the migration of BM CD34+ cells toward SDF-1. SDF-1 was a substrate for MMP-9, furthermore, SDF-1 also stimulated MMP-9 proteolytic enzyme activity of BM CD34+ cells, which facilitate HSPCs migration. In BALB/c mice, HSPCs mobilization was significantly inhibited by anti-SDF-1 antibodies or MMP inhibitor, o-phenanthroline. In conclusion, the degradation of BM SDF-1 by MMP-9 is a vital step in 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
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Morrison SJ, Uchida N, Weissman IL . The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol 1995; 11: 35–71.

    Article  CAS  PubMed  Google Scholar 

  2. To LB, Haylock DN, Simmons PJ, Juttner CA . The biology and clinical uses of blood stem cells. Blood 1997; 89: 2233–2258.

    CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. Lévesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ . Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by G-CSF or cyclophosphamide. J Clin Invest 2003; 111: 187–196.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pituch-Noworolska A, Majka M, Janowska-Wieczorek A, Baj-Krzyworzeka M, Urbanowicz B, Malec E et al. Circulating CXCR4-positive stem/progenitor cells compete for SDF-1-positive niches in bone marrow, muscle and neural tissues: an alternative hypothesis to stem cell plasticity. Folia Histochem Cytobiol 2003; 41: 13–21.

    PubMed  Google Scholar 

  6. Hattori K, Heissig B, Tashiro K, Honjo T, Tateno M, Shieh JH et al. Plasma elevation of stromal-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 2001; 97: 3354–3360.

    Article  CAS  PubMed  Google Scholar 

  7. Shen H, Cheng T, Olszak I, Garcia-Zepeda E, Lu Z, Herrmann S et al. CXCR-4 desensitization is associated with tissue localization of hematopoietic progenitor cells. J Immunol 2001; 166: 5027–5033.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Semerad CL, Liu F, Gregory AD, Stumpf K, Link DC . G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 2002; 17: 413–423.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. Larochelle A, Krouse A, Metzger M, Orlic D, Donahue RE, Fricker S et al. AMD3100 mobilizes hematopoietic stem cells with long-term repopulating capacity in nonhuman primates. Blood 2006; 107: 3772–3778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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.

    Article  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Delgado MB, Clark-Lewis I, Loetscher P, Langen H, Thelen M, Baggiolini M et al. Rapid inactivation of stromal cell-derived factor-1 by cathepsin G associated with lymphocytes. Eur J Immunol 2001; 31: 699–707.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  PubMed  Google Scholar 

  18. Kjeldsen L, Sengeløv H, Lollike K, Nielsen MH, Borregaard N . Isolation and characterization of gelatinase granules from human neutrophils. Blood 1994; 83: 1640–1649.

    CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. Levesque JP, Liu F, Simmons PJ, Betsuyaku T, Senior RM, Pham C et al. Characterization of hematopoietic progenitor mobilization in protease-deficient mice. Blood 2004; 104: 65–72.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. Kollet O, Shivtiel S, Chen YQ, Suriawinata J, Thung SN, Dabeva MD et al. HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J Clin Invest 2003; 112: 160–169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhou B, Bi YY, Han ZB, Ren H, Fang ZH, Yu XF et al. G-CSF-mobilized peripheral blood mononuclear cells from diabetic patients augment neovascularization in ischemic limbs but with impaired capability. J Thromb Haemost 2006; 4: 993–1002.

    Article  CAS  PubMed  Google Scholar 

  24. Zhou B, Ma FX, Liu PX, Fang ZH, Wang SL, Han ZB et al. Impaired therapeutic vasculogenesis by transplantation of OxLDL-treated endothelial progenitor cells. J Lipid Res 2007; 48: 518–527.

    Article  CAS  PubMed  Google Scholar 

  25. Sekiya I, Vuoristo JT, Larson BL, Prockop DJ . In vitro cartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis. Proc Natl Acad Sci USA 2002; 99: 4397–4402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jo DY, Rafii S, Hamada T, Moore MA . Chemotaxis of primitive hematopoietic cells in response to stromal cell-derived factor-1. J Clin Invest 2000; 105: 101–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nagasawa T, Tachibana K, Kishimoto T . A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection. Semin Immunol 1998; 10: 179–185.

    Article  CAS  PubMed  Google Scholar 

  28. Masure S, Proost P, Van Damme J, Opdenakker G . Purification and identification of 91-kDa neutrophil gelatinase. Release by the activating peptide interlukin-8. Eur J Biochem 1991; 198: 391–398.

    Article  CAS  PubMed  Google Scholar 

  29. Powell WC, Fingleton B, Wilson CL, Boothby M, Matrisian LM . The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol 1999; 9: 1441–1447.

    Article  CAS  PubMed  Google Scholar 

  30. Levi E, Fridman R, Miao HQ, Ma YS, Yayon A, Vlodavsky I . Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. Proc Natl Acad Sci USA 1996; 93: 7069–7074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Suzuki M, Raab G, Moses MA, Fernandez CA, Klagsbrun M . Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. J Biol Chem 1997; 272: 31730–31737.

    Article  CAS  PubMed  Google Scholar 

  32. Van den Steen PE, Proost P, Wuyts A, Van Damme J, Opdenakker G . Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-α and leaves RANTES and MCP-2 intact. Blood 2000; 96: 2673–2681.

    CAS  PubMed  Google Scholar 

  33. Lapidot T, Kollet O . The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2mnull mice. Leukemia 2002; 16: 1992–2003.

    Article  CAS  PubMed  Google Scholar 

  34. Carion A, Benboubker L, Hérault O, Roingeard F, Degenne M, Senecal D et al. Stromal-derived factor 1 and matrix metalloproteinase 9 levels in bone marrow and peripheral blood of patients mobilized by granulocyte colony-stimulating factor and chemotherapy. Relationship with mobilizing capacity of haematopoietic progenitor cells. Br J Haematol 2003; 122: 918–926.

    Article  CAS  PubMed  Google Scholar 

  35. Jinquan T, Quan S, Jacobi HH, Madsen HO, Glue C, Skov PS et al. CXC chemokine receptor 4 expression and stromal cell-derived factor-1alpha-induced chemotaxis in CD4+ T lymphocytes are regulated by interleukin-4 and interleukin-10. Immunology 2000; 99: 402–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Valenzuela-Fernandez A, Palanche T, Amara A, Magerus A, Altmeyer R, Delaunay T et al. Optimal inhibition of X4 HIV isolates by the CXC chemokine SDF-1a requires interaction with cell-surface heparan sulfate proteoglycans. J Biol Chem 2002; 277: 15677–15689.

    Article  CAS  PubMed  Google Scholar 

  37. Kollet O, Petit I, Kahn J, Samira S, Dar A, Peled A et al. Human CD34+CXCR4− sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation. Blood 2002; 100: 2778–2786.

    Article  CAS  PubMed  Google Scholar 

  38. Tang CH, Tan TW, Fu WM, Yang RS . Involvement of matrix metalloproteinase-9 in stromal cell-derived factor-1/CXCR4 pathway of lung cancer metastasis. Carcinogenesis 2008; 29: 35–43.

    Article  CAS  PubMed  Google Scholar 

  39. Papayannopoulou T, Scadden DT . Stem-cell ecology and stem cell in motion. Blood 2008; 111: 3923–3930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. Ballen KK, Shpall EJ, Avigan D, Yeap BY, Fisher DC, McDermott K et al. Phase I trial of parathyroid hormone to facilitate stem cell mobilization. Biol Blood Marrow Transplant 2007; 13: 838–843.

    Article  CAS  PubMed  Google Scholar 

  43. Brunner S, Theiss HD, Murr A, Negele T, Franz WM . Primary hyperparathyroidism is associated with increased circulating bone marrow-derived progenitor cells. Am J Physiol Endocrinol Metab 2007; 293: E1670–E1675.

    Article  CAS  PubMed  Google Scholar 

  44. Zaruba MM, Huber BC, Brunner S, Deindl E, David R, Fischer R et al. Parathyroid hormone treatment after myocardial infarction promotes cardiac repair by enhanced neovascularization and cell survival. Cardiovasc Res 2008; 77: 722–731.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We grateful acknowledge XJ Wang for providing HUVECs and BZ Li for culturing Stromal cell. This work was supported by grants from the Science and Technology Development Program of Tianjin (project: 06YFSYSF01900), the Natural Sciences Foundation of Tianjin (project: 06YFJMSC08500 and 08JCYBJ6200) and Project supported by the Scientific Research Foundation of the State Human Resource Ministry for Returned Chinese Scholars, China (2008).

Author information

Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union of Medical College, Tianjin, China

    F Jin, Q Zhai, L Qiu, D Zou, Y Wang, Q Li, Z Yu, J Han & Q Li

  2. Jilin Province Tumor Hospital, Changchun, China

    F Jin

  3. Department of Pathology, Tianjin Medical University Cancer Hospital, Tianjin, China

    Q Zhai

  4. Tianjin Cord Blood Bank of National Research Center for Stem Cell Engineering and Technology, Tianjin, China

    L Qiu, H Meng, J Han & Q Li

  5. Cardiology Department, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA

    B Zhou

Authors
  1. F Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Q Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Q Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Z Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Q Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. B Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Qiu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jin, F., Zhai, Q., Qiu, L. et al. Degradation of BM SDF-1 by MMP-9: the role in G-CSF-induced hematopoietic stem/progenitor cell mobilization. Bone Marrow Transplant 42, 581–588 (2008). https://doi.org/10.1038/bmt.2008.222

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2008.222

Keywords

This article is cited by

Search

Advanced search

Quick links