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:

Murine Models

Synergistic effects of pegylated recombinant human megakaryocyte growth and development factor and granulocyte colony-stimulating factor on mobilization of hematopoietic progenitor and stem cells with long-term repopulating ability into peripheral blood in mice

Abstract

We investigated the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on peripheral blood progenitor cell (PBPC) mobilization and the combined effect of PEG-rHuMGDF plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) in C57BL/6 mice. Treatment of mice with PEG-rHuMGDF increased the numbers of day 8 and day 12 spleen colony-forming units (CFU-S), and pre-CFU-S in the PB. Ten days administration of PEG-rHuMGDF could mobilize higher numbers of days 8 and day 12 CFU-S than 5 days administration. An optimal dose of PEG-rHuMGDF mobilized a higher number of committed progenitor cells (day 8 CFU-S) and a lower number of immature progenitor cells (pre-CFU-S) into PB than rhG-CSF. The combined administration of optimal or suboptimal doses of PEG-rHuMGDF and rhG-CSF induced synergistic effects on mobilization of CFU-S and pre-CFU-S into PB compared to either factor alone. Four months after sex-mismatched PBPC transplantation, long-term donor-derived engraftment was observed in all recipients that had been transplanted with PBPCs mobilized by rhG-CSF and/or PEG-rHuMGDF, as determined by Y-chromosome polymerase chain reaction (PCR) analysis. Our data suggest that cytokine-induced pathways for PBPC mobilization may be different between PEG-rHuMGDF and rhG-CSF and indicate that PEG-rHuMGDF alone or the combination with rhG-CSF may be useful in effective PBPC mobilization. Bone Marrow Transplantation (2001) 28, 329–334.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Molineux G, Pojda Z, Hampson IN et al. Transplantation potential of peripheral blood stem cells induced by granulocyte colony-stimulating factor Blood 1990 76: 2153–2158

    CAS  PubMed  Google Scholar 

  2. Neben S, Marcus K, Mauch P . Mobilization of hematopoietic stem and progenitor cell subpopulations from the marrow to the blood of mice following cyclophosphamide and/or granulocyte colony-stimulating factor Blood 1993 81: 1960–1967

    CAS  PubMed  Google Scholar 

  3. Stroncek DF, Clay ME, Petzoldt ML et al. Treatment of normal individuals with granulocyte colony-stimulating factor: donor experiences and the effects on peripheral blood CD34+ cell counts and on the collection of peripheral blood stem cells Transfusion 1996 36: 601–610

    Article  CAS  PubMed  Google Scholar 

  4. Briddell RA, Hartley CA, Smith KA, McNiece IK . Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential Blood 1993 82: 1720–1723

    CAS  PubMed  Google Scholar 

  5. Yan XQ, Briddell R, Hartley C et al. Mobilization of long-term hematopoietic reconstituting cells in mice by the combination of stem cell factor plus granulocyte colony-stimulating factor Blood 1994 84: 795–799

    CAS  PubMed  Google Scholar 

  6. Lord BI, Woolford LB, Wood LM et al. Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein-1α Blood 1995 85: 3412–3415

    CAS  PubMed  Google Scholar 

  7. Suzuki H, Okano A, Suzuki C et al. A synergistic increase in transplantable peripheral blood stem cells in mice by co-administration of recombinant human interleukin 6 and recombinant human granulocyte colony-stimulating factor Transplantation 1995 59: 1596–1600

    Article  CAS  PubMed  Google Scholar 

  8. Grzegorzewski KJ, Komschlies KL, Franco JL et al. Quantitative and cell-cycle differences in progenitor cells mobilized by recombinant human interleukin-7 and recombinant human granulocyte colony-stimulating factor Blood 1996 88: 4139–4148

    CAS  PubMed  Google Scholar 

  9. Sudo Y, Shimazaki C, Ashihara E et al. Synergistic effect of FLT-3 ligand on the granulocyte colony-stimulating factor-induced mobilization of hematopoietic stem cells and progenitor cells into blood in mice Blood 1997 89: 3186–3191

    CAS  PubMed  Google Scholar 

  10. Molineux G, McCrea C, Yan XQ et al. 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

    CAS  PubMed  Google Scholar 

  11. Laterveer L, Lindley I, Hamilton M et al. Interleukin-8 induces rapid mobilization of hematopoietic stem cells with radioprotective capacity and long-term myelolymphoid repopulating ability Blood 1995 85: 2269–2275

    CAS  PubMed  Google Scholar 

  12. Mauch P, Lamont C, Neben TY et al. Hematopoietic stem cells in the blood after stem cell factor and interleukin-11 administration: evidence for different mechanisms of mobilization Blood 1995 86: 4674–4680

    CAS  PubMed  Google Scholar 

  13. de Sauvage FJ, Hass PE, Spencer SD et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand Nature 1994 369: 533–538

    Article  CAS  PubMed  Google Scholar 

  14. Lok S, Kaushansky K, Holly RD et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo Nature 1994 369: 565–568

    Article  CAS  PubMed  Google Scholar 

  15. Kaushansky K, Lok S, Holly RD et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin Nature 1994 369: 568–571

    Article  CAS  PubMed  Google Scholar 

  16. Wendling F, Maraskovsky E, Debili N et al. c-Mpl ligand is a humoral regulator of megakaryocytopoiesis Nature 1994 369: 571–574

    Article  CAS  PubMed  Google Scholar 

  17. Bartley TD, Bogenberger J, Hunt P et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl Cell 1994 77: 1117–1124

    Article  CAS  PubMed  Google Scholar 

  18. Kobayashi M, Laver JH, Kato T et al. Recombinant human thrombopoietin (Mpl ligand) enhances proliferation of erythroid progenitors Blood 1995 86: 2494–2499

    CAS  PubMed  Google Scholar 

  19. Papayannopoulou T, Brice M, Farrer D, Kaushansky K . Insights into the cellular mechanisms of erythropoietin–thrombopoietin synergy Exp Hematol 1996 24: 660–669

    CAS  PubMed  Google Scholar 

  20. Sitnicka E, Lin N, Priestley GV et al. The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells Blood 1996 87: 4998–5005

    CAS  PubMed  Google Scholar 

  21. Kobayashi M, Laver JH, Kato T et al. Thrombopoietin supports proliferation of human primitive hematopoietic cells in synergy with Steel factor and/or interleukin-3 Blood 1996 88: 429–436

    CAS  PubMed  Google Scholar 

  22. Hokom MM, Lacey D, Kinstler OB et al. Pegylated megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice Blood 1995 86: 4486–4492

    CAS  PubMed  Google Scholar 

  23. Farese A, Hunt P, Boone T, MacVittie T . Combined administration of recombinant human megakaryocyte growth and development factor and granulocyte colony-stimulating factor enhances multilineage hematopoietic reconstitution in nonhuman primates after radiation-induced marrow aplasia J Clin Invest 1996 97: 2145–2151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Akahori H, Shibuya K, Obuchi M et al. Effect of recombinant human thrombopoietin in nonhuman primates with chemotherapy-induced thrombocytopenia Br J Haematol 1996 94: 722–728

    Article  CAS  PubMed  Google Scholar 

  25. Grossmann A, Lenox J, Ren HP et al. Thrombopoietin accelerates platelet, red blood cell, and neutrophil recovery in myelosuppressed mice Exp Hematol 1996 24: 1238–1246

    CAS  PubMed  Google Scholar 

  26. Basser RL, Rasko JEJ, Clarke K et al. Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer Blood 1997 89: 3118–3128

    CAS  PubMed  Google Scholar 

  27. Fanucchi M, Glaspy J, Crawford J et al. Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer New Engl J Med 1997 336: 404–409

    Article  CAS  PubMed  Google Scholar 

  28. Molineux G, Hartley C, McElroy P et al. Megakaryocyte growth and development factor accelerates platelet recovery in peripheral blood progenitor cell transplant recipients Blood 1996 88: 366–376

    CAS  PubMed  Google Scholar 

  29. Carver-Moore K, Broxmeyer HE, Luoh SM et al. Low levels of erythroid and myeloid progenitors in thrombopoietin- and c-mpl-deficient mice Blood 1996 88: 803–808

    CAS  PubMed  Google Scholar 

  30. Torii Y, Nitta Y, Akahori H et al. Mobilization of primitive haemopoietic progenitor cells and stem cells with long-term repopulating ability into peripheral blood in mice by pegylated recombinant human megakaryocyte growth and development factor Br J Haematol 1998 103: 1172–1180

    Article  CAS  PubMed  Google Scholar 

  31. Vadhan-Raj S, Murray LJ, Bueso-Ramos C et al. Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer Ann Intern Med 1997 126: 673–681

    Article  CAS  PubMed  Google Scholar 

  32. Rasko JEJ, Basser RL, Boyd J et al. Multilineage mobilization of peripheral blood progenitor cells in humans following administration of PEG-rHuMGDF Br J Haematol 1997 97: 871–880

    Article  CAS  PubMed  Google Scholar 

  33. Basser RL, Rasko JEJ, Clarke K et al. Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer Lancet 1996 348: 1279–1281

    Article  CAS  PubMed  Google Scholar 

  34. Till JE, McCulloch EA . A direct measurement of the radiation sensitivity of normal mouse bone marrow cells Radiat Res 1961 14: 213–222

    Article  CAS  PubMed  Google Scholar 

  35. Magli MC, Iscove NN, Odartchenko N . Transient nature of early haematopoietic spleen colonies Nature 1982 295: 527–529

    Article  CAS  PubMed  Google Scholar 

  36. Hodgson GS, Bradley TR . Properties of haematopoietic stem cells surviving 5-fluorouracil treatment: evidence for a pre-CFU-S cell? Nature 1979 281: 381–382

    Article  CAS  PubMed  Google Scholar 

  37. Yano T, Katayama Y, Sunami K et al. G-CSF-induced mobilization of peripheral blood stem cells for allografting: comparative study of daily single versus divided dose of G-CSF Int J Hematol 1997 66: 169–178

    Article  CAS  PubMed  Google Scholar 

  38. Roberts AW, Metcalf D . Granulocyte colony-stimulating factor induces selective elevations of progenitor cells in the peripheral blood of mice Exp Hematol 1994 22: 1156–1163

    CAS  PubMed  Google Scholar 

  39. Kabaya K, Akahori H, Shibuya K et al. In vivo effects of pegylated recombinant human megakaryocyte growth and development factor on hematopoiesis in normal mice Stem Cells 1996 14: 651–660

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Honda, K., Takenaka, K., Shinagawa, K. et al. Synergistic effects of pegylated recombinant human megakaryocyte growth and development factor and granulocyte colony-stimulating factor on mobilization of hematopoietic progenitor and stem cells with long-term repopulating ability into peripheral blood in mice. Bone Marrow Transplant 28, 329–334 (2001). https://doi.org/10.1038/sj.bmt.1703140

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1703140

Keywords

This article is cited by

Search

Quick links