Effect of Cytokines on the Development of Megakaryocytes and Platelets

An Ultrastructural Analysis
  • Dorothea Zucker-Franklin


Megakaryocytes have intrigued investigators for more than a century, an interest spurred enormously by the availability of newer methods of analysis during the past 25 years. More recently, the discovery of hemopoietic cytokines culminating in the identification, purification, and manufacture of recombinant human thrombopoietins (rHuTPOs) has driven research on megakaryocytes and thrombocytopoiesis to an unprecedented level.


Leukemia Inhibitory Factor Platelet Production Normal Platelet Count Human Megakaryocyte Megakaryocyte Progenitor 
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  1. 1.
    Zucker-Franklin D. The ultrastructure of megakaryocytes and platelets. In: Gordon AS (ed). Regulation of Hematopoiesis. New York: Appleton-Century-Crofts; 1970: 1553–1586.Google Scholar
  2. 2.
    Zucker-Franklin D. Megakaryocytes and platelets. In: Zucker-Franklin D, Greaves MF, Grossi CE, Marmont AM (eds). Atlas of Blood Cells, Function and Pathology. Philadelphia: Edi Ermes Milan & Febiger; 1989: 623–693.Google Scholar
  3. 3.
    Zucker-Franklin D. Platelet morphology and function. In: Williams WJ, Beutler E, Erslev AJ, Lichtman MA (eds). Hematology. New York: McGraw Hill; 1990: 1172–1181.Google Scholar
  4. 4.
    Zucker-Franklin D, Stahl C, Hyde P. Antigenic dissimilarity between platelet and megakaryocyte surface membranes. In: Levine RF, Williams N, Levin J, Evatt BL (eds). Megakaryocyte Development and Function. Progress in Clinical and Biological Research. New York: Alan R. Liss; 1986: 215: 259–264.Google Scholar
  5. 5.
    Metcalf D. Hematopoietic Colonies: In Vitro Cloning of Normal and Leukemia Cells. New York: Springer Verlag; 1977.Google Scholar
  6. 6.
    Metcalf D, MacDonald HR, Odartchenko N, Sordat B. Growth of mouse megakaryocyte colonies in vitro. Proc Natl Acad Sci USA. 1975; 72: 1744–1748.PubMedCrossRefGoogle Scholar
  7. 7.
    Nakeff A, van Noord MJ, Blansjaar N. Electron microscopy of megakaryocytes in thin-layer agar cultures of mouse bone marrow. J Ultrastruct Res. 1974; 49: 1–10.PubMedCrossRefGoogle Scholar
  8. 8.
    Mazur EM, Hoffman R, Chasis J, Marchesi S, Bruno E. Immunofluorescent identification of human megakaryocyte colonies using an antiplatelet glycoprotein antiserum. Blood. 1981; 57: 277–286.PubMedGoogle Scholar
  9. 9.
    Fauser M, Messner HA. Identification of megakaryocytes, macrophages, and eosinophils in colonies of human bone marrow containing neutrophilic granulocytes and erythroblasts. Blood. 1979; 53: 1023–1027.PubMedGoogle Scholar
  10. 10.
    McLeod DL, Shreve MM, Axelrad AA. Induction of megakaryocyte colonies with platelet formation in vitro. Nature. 1976; 261: 492–494.PubMedCrossRefGoogle Scholar
  11. 11.
    Geissler D, Konwalinka G, Peschel C, Grunewald K, Odavic R, Braunsteiner H. A regulatory role of activated T lymphocytes on human megakaryocytopoiesis in vitro. Br J Haematol. 1985; 60: 233–238.PubMedCrossRefGoogle Scholar
  12. 12.
    Quesenberry PJ, Ihle JN, McGrath E. The effect of Interleukin-3 and GM-CSA-2 on megakaryocyte and myeloid clonal colony formation. Blood. 1985; 65: 214–217.PubMedGoogle Scholar
  13. 13.
    Williams N, Eger RR, Jackson HM, Nelson DJ. Two factor requirement for murine megakaryocyte colony formation. J Cell Physiol. 1982; 110: 101–104.PubMedCrossRefGoogle Scholar
  14. 14.
    Sakaguchi M, Kawakita M, Matsushita J, Shibuya K, Koishihara Y, Takatsuki K. Human erythropoietin stimulates murine megakaryopoiesis in serum-free culture. Exp Hematol. 1987; 15: 1028–1034.PubMedGoogle Scholar
  15. 15.
    Williams N, Jackson H, Iscove NN, Dukes PP. The role of erythropoietin, thrombopoietic stimulating factor, and myeloid colony-stimulating factors on murine megakaryocyte colony formation. Exp Hematol. 1984; 12: 734–740.PubMedGoogle Scholar
  16. 16.
    McDonald TP, Shadduck RK. Comparative effects of thrombopoietin and colony-stimulating factors. Exp Hematol. 1982; 10: 544–550.PubMedGoogle Scholar
  17. 17.
    Evatt BL, Kellar KL, Ramsey RB. Thrombopoietin: past, present and future. In: Levine RF, Williams N, Levin J, Evatt BL (eds). Megakaryocyte Development and Function. Progress in Clinical and Biological Research. New York: Alan R. Liss; 1986; 215: 143–155.Google Scholar
  18. 18.
    Mazur EM, Hoffman R, Bruno E. Regulation of human megakaryocytopoiesis. An in vitro analysis. J Clin Invest. 1981; 68: 733–741.PubMedCrossRefGoogle Scholar
  19. 19.
    McLeod DL, Shreeve MM, Axelrad AA. Improved plasma culture system for production of erythrocytic colonies in vitro: quantitative assay method for CFU-E. Blood. 1974; 44: 517–534.PubMedGoogle Scholar
  20. 20.
    Dexter TM, Allen TD, Lajtha LG. Conditions controlling the proliferation of haematopoietic stem cells in vitro. J Cell Physiol. 1977; 91: 335–344.PubMedCrossRefGoogle Scholar
  21. 21.
    Zucker-Franklin D, Petursson S. Thrombocytopoiesis—analysis by membrane tracer and freeze-fracture studies on fresh human and cultured mouse megakaryocytes. J Cell Biol. 1984; 99: 390–402.PubMedCrossRefGoogle Scholar
  22. 22.
    Mayer P, Geissler K, Ward M, Metcalf D. Recombinant human leukemia inhibitory factor induces acute phase proteins and raises the blood platelet counts in nonhuman primates. Blood. 1993;81:3226–3233.PubMedGoogle Scholar
  23. 23.
    Briddell RA, Bruno E, Cooper RJ, Brandt JE, Hoffman R. Effect of c-kit ligand on in vitro human megakaryocytopoiesis. Blood. 1991; 78: 2854–2859.PubMedGoogle Scholar
  24. 24.
    McNiece IK, McGrath HE, Quesenberry PJ. Granulocyte colony-stimulating factor augments in vitro megakaryocyte colony formation by Interleukin-3. Exp Hematol. 1988; 16: 807–810.PubMedGoogle Scholar
  25. 25.
    Debili N, Masse JM, Katz A, Guichard J, Breton-Gorius J, Vainchenker W. Effects of the recombinant hematopoietic growth factors interleukin-3, interleukin-6, stem cell factor, leukemia inhibitory factor, on the megakaryocytic differentiation of CD34+ cells. Blood. 1993; 82: 84–95.PubMedGoogle Scholar
  26. 26.
    Ishibashi T, Burstein SA. Interleukin-3 promotes the differentiation of isolated single megakaryocytes. Blood. 1986; 67: 1512–1514.PubMedGoogle Scholar
  27. 27.
    Williams N, Sparrow R, Gill K, Yasmeen D, McNiece I. Murine megakaryocyte colony stimulating factor: its relationship to Interleukin-3. Leukemia Res. 1985; 9: 1487–1496.CrossRefGoogle Scholar
  28. 28.
    Ganser A, Lindemann A, Seipelt G, et al. Effects of recombinant human interleukin-3 in patients with normal hematopoiesis and in patients with bone marrow failure. Blood. 1990; 76: 666–676.PubMedGoogle Scholar
  29. 29.
    Carrington PA, Hill RJ, Stenberg PE, et al. Multiple in vivo effects of interleukin-3 and interleukin-6 on murine megakaryocytopoiesis. Blood. 1991; 77: 34–41.PubMedGoogle Scholar
  30. 30.
    Guinan EC, Lee YS, Lopez KD, et al. Effects of Interleukin-3 and granulocyte-macrophage colony-stimulating factor on thrombopoiesis in congenital amegakaryocytic thrombocytopenia. Blood. 1993; 81: 1691–1698.PubMedGoogle Scholar
  31. 31.
    Kaushansky K, Broudy VC, Lin N, et al. Thrombopoietin, the Mpl ligand, is essential for full megakaryocyte development. Proc Natl Acad Sci USA 1995; 92: 3234–3238.PubMedCrossRefGoogle Scholar
  32. 32.
    Murray LJ, Bruno E, Zucker-Franklin D, et al. Thrombopoietin induction of megakaryocytopoiesis from purified subpopulations of human CD34+ cells including primitive CD34+ Thy-1+ Lin- cells. Exper Hematol. (in press).Google Scholar
  33. 33.
    Bruno E, Murray LJ, Zucker-Franklin D, et al. Further definition of the cellular target of human thrombopoietin. Blood. 1995; 86: 365a (abstract no 1449).Google Scholar
  34. 34.
    Robinson BE, McGrath HE, Quesenberry PJ. Recombinant murine granulocyte macrophage colony-stimulating factor has megakaryocyte colony-stimulating activity and augments megakaryocyte colony stimulation by Interleukin 3. J Clin Invest. 1987; 79: 1648–1652.PubMedCrossRefGoogle Scholar
  35. 35.
    Bruno E, Briddell R, Hoffman R. Effect of recombinant and purified hematopoietic growth factors on human megakaryocyte colony formation. Exp Hematol. 1988; 16: 371–377.PubMedGoogle Scholar
  36. 36.
    Stahl CP, Winton EF, Monroe MC, et al. Recombinant human granulocyte-macrophage colony-stimulating factor promotes megakaryocyte maturation in nonhuman primates. Exp Hematol. 1991; 19:810–816.PubMedGoogle Scholar
  37. 37.
    Stahl CP, Winton EF, Monroe MC, et al. Differential effects of sequential, simultaneous, and single agent interleukin-3 and granulocyte-macrophage colony-stimulating factor on megakaryocyte maturation and platelet response in primates. Blood. 1992; 80: 2479–2485.PubMedGoogle Scholar
  38. 38.
    Ishibashi T, Kimura H, Shikama Y, et al. Interleukin 6 is a potent thrombopoietic factor in vivo in mice. Blood. 1989; 74: 1241–1244.PubMedGoogle Scholar
  39. 39.
    Bruno E, Hoffman R. Effect of interleukin 6 on in vitro human megakaryocytopoiesis: its interaction with other cytokines. Exp Hematol. 1989; 17: 1038–1043.PubMedGoogle Scholar
  40. 40.
    Koike K, Nakahata T, Kubo T, et al. Interleukin-6 enhances murine megakaryocytopoiesis in serum-free culture. Blood. 1990; 75: 2286–2291.PubMedGoogle Scholar
  41. 41.
    Kimura H, Ishibashi T, Ushida T, Maruyama Y, Friese P, Burstein SA. Interleukin-6 is a differentiation factor for human megakaryocytes in vitro. Eur J Immunol. 1990; 20: 1927–1931.PubMedCrossRefGoogle Scholar
  42. 42.
    Hill RJ, Warren MK, Stenberg P, et al. Stimulation of megakaryocytopoiesis in mice by human recombinant interleukin-6. Blood. 1991; 77: 42–48.PubMedGoogle Scholar
  43. 43.
    Imai T, Koike K, Kubo T, et al. Interleukin-6 supports human megakaryocyte proliferation and differentiation in vitro. Blood. 1991; 78: 1969–1974.PubMedGoogle Scholar
  44. 44.
    Leven RM, Rodriguez A. Immunomagnetic bead isolation of megakaryocytes from guinea-pig bone marrow: effect of recombinant interleukin-6 on size, ploidy and cytoplasmic fragmentation. Br J Haematol. 1991; 77: 267–273.PubMedCrossRefGoogle Scholar
  45. 45.
    Burstein SA, Downs T, Friese P, et al. Thrombocytopoiesis in normal and sublethally irradiated dogs: response to human interleukin-6. Blood. 1992; 80: 420–428.PubMedGoogle Scholar
  46. 46.
    Kishimoto T. The biology of Interleukin-6. Blood. 1989; 74: 1–10.PubMedGoogle Scholar
  47. 47.
    Navarro S, Debili N, Le Couedic JP, et al. Interleukin-6 and its receptor are expressed by human megakaryocytes: in vitro effects on proliferation and endoreduplication. Blood. 1991; 77: 461–471.PubMedGoogle Scholar
  48. 48.
    Stahl CP, Zucker-Franklin D, Evatt BL, Winton EF. Effects of human interleukin-6 on megakaryocyte development and thrombocytopoiesis in primates. Blood. 1991; 78: 1467–1475.PubMedGoogle Scholar
  49. 49.
    Peng J, Friese P, George JN, Dale GL, Burstein SA. Alteration of platelet function in dogs mediated by interleukin-6. Blood. 1994; 83: 398–403.PubMedGoogle Scholar
  50. 50.
    Du XX, Williams DA. Interleukin-11: a multifunctional growth factor derived from the hematopoietic environment. Blood. 1994; 83: 2023–2030.PubMedGoogle Scholar
  51. 51.
    Paul SR, Bennet F, Calvetti JA, et al. Molecular cloning of a cDNA encoding interleukin-11, a stromal cell-derived lymphopoietic and hematopoietic cytokine. Proc Natl Acad Sci USA. 1990; 87:7512–7516.PubMedCrossRefGoogle Scholar
  52. 52.
    Yonemura Y, Kawakita M, Masuda T, Fujimoto K, Takastuki K. Effect of recombinant human interleukin-11 on rat megakaryopoiesis and thrombopoiesis in vivo: comparative study with interleukin-6. Br J Haematol. 1993; 84: 16–23.PubMedCrossRefGoogle Scholar
  53. 53.
    Teramura M, Kobayashi S, Hoshino S, et al. Interleukin-11 enhances human mega-karyocytopoiesis in vitro. Blood. 1992; 79: 327–331.PubMedGoogle Scholar
  54. 54.
    Burstein SA, Mei-RL, Henthorn J, et al. Leukemia inhibitory factor and interleukin-11 promote maturation of murine and human megakaryocytes in vitro. J Cell Physiol. 1992; 153: 305–312.PubMedCrossRefGoogle Scholar
  55. 55.
    Zucker-Franklin D, Kaushansky K. The effect of thrombopoietin on the development of megakaryocytes and platelets: an ultrastructural analysis. Blood. 1996; 88: 1632–1638.PubMedGoogle Scholar
  56. 56.
    Bruno E, Briddell RA, Cooper RJ, Hoffman R. Effects of recombinant interleukin-11 on human megakaryocyte progenitor cells. Exp Hematol. 1991; 19:378–381.PubMedGoogle Scholar
  57. 57.
    Neben TY, Loebelenz J, Hayes L, et al. Recombinant human interleukin-11 stimulates megakaryocytopoiesis and increases peripheral platelets in normal and splenectomized mice. Blood 1993;81:901–908.PubMedGoogle Scholar
  58. 58.
    Leonard JP, Quinto CM, Kozitza MK, Neben TY, Goldman S J. Recombinant human IL-11 stimulates multilineage hematopoietic recovery in mice after a myelosuppressive regimen of sublethal irradiation and carboplatin. Blood. 1994; 83: 1499–1506.PubMedGoogle Scholar
  59. 59.
    Nash RA, Seidel K, Storb R, et al. Effects of rhIL-11 on normal dogs and after sublethal radiation. Exp Hematol. 1995; 23: 389–396.PubMedGoogle Scholar
  60. 60.
    Gurney Al, Carver Moore K, de Sauvage FJ, Moore MW. Thrombocytopenia in c-mpl-deficient mice. Science. 1994; 265: 1445–1447.PubMedCrossRefGoogle Scholar
  61. 61.
    Methia N, Louache F, Vainchenker W, Wendung F. Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood. 1993; 82:1395–1401.PubMedGoogle Scholar

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© Humana Press Inc. 1997

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  • Dorothea Zucker-Franklin

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