Role of thrombopoietin in hematopoietic stem cell and progenitor regulation

Current Opinion in Hematology

Volumn 7, Issue 3, 2000, Pages 183-190

  Drachman, Jonathan G ^a  

^a PUGET SOUND BLOOD CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 AMINO 3 METHOXYPHENYL)CHROMONE; CELL SURFACE RECEPTOR; JANUS KINASE; MITOGEN ACTIVATED PROTEIN KINASE; THROMBOPOIETIN;

CELL MATURATION; GENE THERAPY; GENETIC TRANSDUCTION; HEMATOPOIETIC STEM CELL; KNOCKOUT MOUSE; MEGAKARYOCYTE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY MECHANISM; REVIEW; STEM CELL; THROMBOCYTE; THROMBOCYTOPENIA; THROMBOCYTOPOIESIS;

ANIMALS; CELL DIFFERENTIATION; CELL DIVISION; HEMATOPOIETIC STEM CELLS; HUMANS; MEGAKARYOCYTES; NEOPLASM PROTEINS; PROTO-ONCOGENE PROTEINS; RECEPTORS, CYTOKINE; RECEPTORS, IMMUNOLOGIC; RECEPTORS, THROMBOPOIETIN; THROMBOPOIETIN;

EID: 0033997149     PISSN: 10656251     EISSN: None     Source Type: Journal    
DOI: 10.1097/00062752-200005000-00010     Document Type: Review

References (82)

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27. 27 Kimura S, Roberts AW, Metcalf D, Alexander WS: Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc Natl Acad Sci U S A 1998, 95:1195-1200. This paper convincingly demonstrates that mpl-nullizygous mice have an intrinsic stem cell defect resulting in markedly reduced primitive hematopoietic progenitors. Hematopoietic cells derived from mpl -/-donors were unable to compete with cells from normal mice during repopulation assays or serial transplantation experiments.
28. + cells from Mpl-nullizygous mice have one seventh the repopulating capacity of similar cells from normal mice. Together with the paper by Kimura et al. (Proc Natl Acad Sci U S A 1998, 95:1195-1200), this paper establishes unequivocally the nonredundant role of thrombopoietin and Mpl on hematopoietic stem cells in vivo.
29. 29 Muraoka K, Ishii E, Tsuji K, Yamamoto S, Yamaguchi H, Hara T, et al.: Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia. Br J Haematol 1997, 96:287-292.
30. 30 Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, Good RA, Hara T: Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci U S A 1999, 96:3132-3136. This report is the first example of a human disorder caused by separate mutations in each of the two mpl alleles, effectively replicating the phenotype of mp/-nullizygous mice. It is not yet clear what percentage of patients with congenital amegakaryocytic thrombocytopenia will have the same molecular defect. Other mutations in similar patients have recently been reported.
31. 31 van den Oudenrijn S, Bruin M, Folman CC, Peters M, Faulkner LB, de Haas M, von dem Borne AE: Mutations in the thrombopoietin receptor gene, c-mpl, may cause congenital amegakaryocytic thrombocytopenia [abstract]. Blood 1999, 94:679.
32. 32 Freedman MH, Estrov Z: Congenital amegakaryocytic thrombocytopenia: an intrinsic hematopoietic stem cell defect. Am J Pediatr Hematol Oncol 1990, 12:225-230.
33. 33 Hokom MM, Lacey D, Kinstler OB, Choi E, Kaufman S, Faust J, et al.: Pegylated megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice. Blood 1995, 86:4486-4492.
34. 34 Mouthon MA, Van der Meeren A, Gaugier MH, Visser TP, Squiban C, Gourmelon P, Wagemaker G: Thrombopoietin promotes hematopoietic recovery and survival after high-dose whole body irradiation. Int J Radiat Oncol Biol Phys 1999, 43:867-875. Thrombopoietin given immediately after total body irradiation (8 Gy) Improved survival as well as improving the platelet nadir and accelerating recovery of platelet, erythrocytes, and neutrophils in mice. A single dose was as effective as daily thrombopoietin administration for 7 days.
35. 35 Zhou W, Toombs CF, Zou T, Guo J, Robinson MO: Transgenic mice overexpressing human c-mpl ligand exhibit chronic thrombocytosis and display enhanced recovery from 5-fluorouracil or antiplatelet serum treatment. Blood 1997, 89:1551-1559.
36. 36 Kaushansky K, Broudy VC, Grossmann A, Humes J, Lin N, Ren HP, et al.: Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy. J Clin Invest 1995, 96:1683-1687.
37. 37 Kaushansky K, Lin N, Grossmann A, Humes J, Sprugel KH, Broudy VC: Thrombopoietin expands erythroid, granulocyte-macrophage, and megakaryocytic progenitor cells in normal and myelosuppressed mice. Exp Hematol 1996,24:265-269.
38. 38 Farese AM, Hunt P, Boone T, MacVittie Tj: Recombinant human megakaryocyte growth and development factor stimulates thrombocytopoiesis in normal nonhuman primates. Blood 1995, 86:54-59.
39. 39 Neelis KJ, Visser TP, Dimjati W, Thomas GR, Fielder PJ, Bloedow D, et al.: A single dose of thrombopoietin shortly after myelosuppressive total body irradiation prevents pancytopenia in mice by promoting short-term multilineage spleen-repopulating cells at the transient expense of bone marrow-repopulating cells. Blood 1998, 92:1586-1597. Careful study of the timing of thrombopoietin administration after irradiation shows that there is a narrow window immediately after treatment during which thrombopoietin can stimulate the appearance of multilineage progenitors. Furthermore, assays of colony-forming units-spleen versus repopulating cells suggest that thrombopoietin results in a transient decrease in repopulating cells whereas colony-forming units-spleen and multilineage progenitors increase.
40. + cells in rhesus monkeys after treatment with marrow-suppressive total body irradiation (5 Gy). However, no significant effect of thrombopoietin was seen after a higher dose of irradiation (8 Gy) and autologous stem cell transplantation. This underscores several of the clinical trials in humans that demonstrated a lower efficacy of thrombopoietin when the degree of myelosuppression was greater.
41. 41 Vadhan-Raj S, Murray LJ, Bueso-Ramos C, Patel S, Reddy SP, Hoots WK, 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.
42. 42 Van XQ, Lacey DL, Saris C, Mu S, Hill D, Hawley RG, Fetcher FA: Ectopic overexpression of c-mpl by retroviral-mediated gene transfer suppressed megakaryopoiesis but enhanced erythropoiesis in mice. Exp Hematol 1999, 27:1409-1417. Forced expression of Mpl on all hematopoietic cells resulted in mice with low platelet counts and diminished hematopoietic progenitors. Presumably, this is due to increased degradation of plasma thrombopoietin (via receptor binding and internalization). Erythropoiesis in these mice was increased despite decreased colony forming unit-erythroid and burst forming unit-erythroid, suggesting a direct effect of thrombopoietin on Mpl-expressing erythrocytes. Of note, Mpl-overexpressing mice died several months after transplantation. Although the cause of death is not known, this could represent aplastic anemia due to exhaustion of stem cells.
43. 43 Torii Y, Nitta Y, Akahori H, Tawara T, Kuwaki T, Ogami K, 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.
44. + cell subsets into peripheral blood and expands multilineage progenitors in bone marrow of cancer patients with normal hematopoiesis. Exp Hematol 1998, 26:207-216.
45. + cells, resulting in fewer apheresis procedures. After high-dose chemotherapy, breast cancer patients receiving the peripheral progenitor cells mobilized by thrombopoietin/G-CSF experienced somewhat faster hematopoietic recovery and received statistically fewer erythrocyte and platelet transfusions than those receiving progenitors mobilized by G-CSF alone.
46. 46 Yang C, Xia Y, Li J, Kuter DJ: The appearance of anti-thrombopoietin antibody and circulating thrombopoietin-IgG complexes in a patient developing thrombocytopenia after the injection of PEG-rHuMGDF [abstract]. Blood 1999, 94:681.
47. 47 Cwirla SE, Balasubramanian P, Duffin DJ, Wagstrom CR, Gates CM, Singer SC, et al.: Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science 1997, 276:1696-1699.
48. 48 Kimura T, Kaburaki H, Miyamoto S, Katayama J, Watanabe Y: Discovery of a novel thrombopoietin mimic agonist peptide. J Biochem 1997, 122:1046-1051.
49. 49 de Serres M, Ellis B, Dillberger JE, Rudolph SK, Hutchins JT, Boytos CM, et al.: immunogenicity of thrombopoietin mimetic peptide GW395058 in BALB/c mice and New Zealand white rabbits: evaluation of the potential for thrombopoietin neutralizing antibody production in man. Stem Cells 1999, 17:203-209. Preclinical studies using a small peptide agonist of Mpl did not reveal any immune response against native thrombopoietin, nor did the molecule crossreact with antithrombopoietin antibodies.
50. 50 Borge OJ, Ramsfjell V, Veiby OP, Murphy MJ Jr, Lok S, Jacobsen SE: Thrombopoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro. Blood 1996, 88:2859-2870.
51. 51 Borge OJ, Ramsfjell V, Cui L, Jacobsen SE: Ability of early acting cytokines to directly promote survival and suppress apoptosis of human primitive CD34+CD38-bone marrow cells with multilineage potential at the single-cell level: key role of thrombopoietin. Blood 1997, 90:2282-2292.
52. 52 Young JC, Bruno E, Luens KM, Wu S, Backer M, Murray LJ: Thrombopoietin stimulates megakaryocytopoiesis, myelopoiesis, and expansion of CD34+ progenitor cells from single CD34+Thy-1+Lin-primitive progenitor cells. Blood 1996, 88:1619-1631.
53. 53 Ramsfjell V, Borge OJ, Veiby OP, Cardier J, Murphy MJ Jr, Lyman SD, et al.: Thrombopoietin, but not erythropoietin, directly stimulates multilineage growth of primitive murine bone marrow progenitor cells in synergy with early acting cytokines: distinct interactions with the ligands for c-kit and FLT3. Blood 1996, 88:4481-4492.
54. 54 Ramsfjell V, Borge OJ, Cui L, Jacobsen SE: Thrombopoietin directly and potently stimulates multilineage growth and progenitor cell expansion from primitive (CD34+ CD38-) human bone marrow progenitor cells: distinct and key interactions with the ligands for c-kit and flt3, and inhibitory effects of TGF-β and TNF-α J Immunol 1997, 158:5169-5177.
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56. 56 Piacibello W, Sanavio F, Garetto L, Severine A, Bergandi D, Ferrario J, et al.: Extensive amplification and self-renewal of human primitive hematopoietic stem cells from cord blood. Blood 1997, 89:2644-2653.
57. 57 Piacibello W, Sanavio F, Garetto L, Severino A, Dane A, Gammaitoni L, Aglietta M: Differential growth factor requirement of primitive cord blood hematopoietic stem cell for self-renewal and amplification versus proliferation and differentiation. Leukemia 1998, 12:718-727.
58. 58 Murray LJ, Young JC, Osborne LJ, Luens KM, Scollay R, Hill BL: Thrombopoietin, flt3, and kit ligands together suppress apoptosis of human mobilized CD34+ cells and recruit primitive CD34+ Thy-1+ cells into rapid division. Exp Hematol 1999, 27:1019-1028.
59. 59 Piacibello W, Sanavio F, Severino A, Dane A, Gammaitoni L, Fagioli F, et al.: Engraftment in nonobese diabetic severe combined immunodeficient mice of human CD34(+) cord blood cells after ex vivo expansion: evidence for the amplification and self-renewal of repopulating stem cells. Blood 1999, 93:3736-3749. This paper demonstrates that human hematopoietic stem cells can be expanded in vitro using a combination of cytokines i0ncluding thrombopoietin (MGDF), Flk2/Flt3 ligand, and SCF ± interleukin-6. After 10 weeks, the expanded cells are capable of engrafting NOD-SCID mice, and dilution experiments indicate that the SRCs are increased more than 70-fold.
60. 60 Liu J, Li K, Yuen PM, Fok TF, Yau FW, Yang M, Li CK: Ex vivo expansion of enriched CD34+ cells from neonatal blood in the presence of thrombopoietin, a comparison with cord blood and bone marrow. Bone Marrow Transplant 1999, 24:247-252.
61. + cell decline and ex vivo expansion capacity. Br J Haematol 1999, 104:178-185.
62. + cells after 2 weeks in vitro. This result highlights the role for precise combinations of cytokines (and probably concentrations) skewing the content of expanded hematopoietic cultures. The omission of Flk2/Flt3 ligand and presence of granulocyte-macrophage colony-stimulating factor results in much lower CD34 expansion than seen with thrombopoietin and Flk2/Flt3 ligand (Piacibello et al., Blood 1997, 89:2644-2653 and Piacibello et al., Blood 1999, 93:3736-3749).
63. 63 Ramsfjell V, Bryder D, Bjorgvinsdottir H, Kornfalt S, Nilsson L, Borge OJ, Jacobsen SE: Distinct requirements for optimal growth and in vitro expansion of human CD34(+)CD38(-) bone marrow long-term culture-initiating cells (LTC-IC), extended LTC-IC, and murine in vivo long-term reconstituting stem cells. Blood 1999, 94:4093-4102. This paper demonstrates that thrombopoietin (MGDF), in combination with SCF and Flk2/Flt3 ligand, is necessary for expansion of extended LTC-IC (12 weeks) whereas standard LTC-IC could be expanded in the absence of thrombopoietin.
64. 64 Kawada H, Ando K, Tsuji T, Shimakura Y, Nakamura Y, Chargui J, et al.: Rapid ex vivo expansion of human umbilical cord hematopoietic progenitors using a novel culture system. Exp Hematol 1999, 27:904-915. Results demonstrate that human cord blood progenitors can be expanded in 5 days using coculture conditions with a murine stromal cell line (HESS-5) in addition to thrombopoietin and Flk2/Flt3 ligand. LTC-ICs and SRCs are both shown to be increased. Under these conditions, cell-to-cell contact between hematopoietic cells and stromal cells appears to accelerate and enhance expansion of primitive progenitors.
65. 65 Yagi M, Ritchie KA, Sitnicka E, Storey C, Roth GJ, Bartelmez S: Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin. Proc Natl Acad Sci U S A 1999, 96:8126-8131. In this study, thrombopoietin was sufficient to expand murine hematopoietic repopulating cells ex vivo up to 4 months in the absence of other cytokines. It is still possible that the horse serum or accessory marrow cells provided additional requirements for stem cell expansion and survival.
66. 66 Murray L, Luens K, Tushinski R, Jin L, Burton M, Chen J, et al.: Optimization of retroviral gene transduction of mobilized primitive hematopoietic progenitors by using thrombopoietin, Flt3, and Kit ligands and RetroNectin culture. Hum Gene Ther 1999, 10:1743-1752. The same combination of thrombopoietin, Flk2/Flt3 ligand, and SCF that promotes stem cell expansion appears to be effective in improving efficiency of retroviral gene transduction of human primitive hematopoietic progenitors.
67. 67 Novelli EM, Cheng L, Yang Y, Leung W, Ramirez M, Tanavde V, et al.: Ex vivo culture of cord blood CD34+ cells expands progenitor cell numbers, preserves engraftment capacity in nonobese diabetic/severe combined immunodeficient mice, and enhances retroviral transduction efficiency. Hum Gene Ther 1999, 10:2927-2940.
68. 68 Hennemann B, Conneally E, Pawliuk R, Leboulch P, Rose-John S, Reid D, et al.: Optimization of retroviral-mediated gene transfer to human NOD/SCID mouse repopulating cord blood cells through a systematic analysis of protocol variables. Exp Hematol 1999, 27:817-825.
69. 69 Jin L, Siritanaratkul N, Emery DW, Richard RE, Kaushansky K, Papayannopoulou T, Blau CA: Targeted expansion of genetically modified bone marrow cells. Proc Natl Acad Sci U S A 1998, 95:8093-8097. Chemically induced dimerization of the Mpl cytoplasmic domain results in long-term sustained proliferation of transfected murine bone marrow cells. This technique may potentially allow selective amplification of transduced hematopoietic cells in vivo.
70. 70 Jin L, Zeng H, Otto KG, Emery DW, Blau CA: Selective amplification of genetically modified hemopoietic cells in vivo using a cell growth switch [abstract]. Blood 1999, 94:669.
71. 71 Stoffel R, Ziegler S. Ghilardi N, Ledermann B, de Sauvage FJ, Skoda RC: Permissive role of thrombopoietin and granulocyte colony-stimulating factor receptors in hematopoietic cell fate decisions in vivo. Proc Natl Acad Sci U SA 1999, 96:698-702. Homologous recombination was used to substitute the G-CSF receptor cytoplasmic domain for that of the native thrombopoietin receptor, creating mice with a chimeric Mpl/G-CSF receptor. In mice that were homozygous for the chimeric receptor, platelet counts and other hematopoietic parameters were normal, suggesting that specific Mpl signaling pathways are not essential for megakaryocytopoiesis.
72. 72 Miller CP, Liu ZY, Noguchi CT, Wojchowski DM: A minimal cytoplasmic subdomain of the erythropoietin receptor mediates erythroid and megakaryocytic cell development. Blood 1999, 94:3381-3387. Further evidence for a permissive role of cytokines in lineage-specific maturation is presented. When expressed in transgenic mice, a truncated form of the erythropoietin receptor cytoplasmic domain is shown to support megakaryocyte development similar to thrombopoietin in vitro.
73. 73 Yang FC, Watanabe S, Tsuji K, Xu MJ, Kaneko A, Ebihara Y, Nakahata T: Human granulocyte colony-stimulating factor (G-CSF) stimulates the in vitro and in vivo development but not commitment of primitive multipotential progenitors from transgenic mice expressing the human G-CSF receptor. Blood 1998, 92:4632-4640.
74. 74 Yang FC, Tsuji K, Oda A, Ebihara Y, Xu MJ, Kaneko A, et al.: Differential effects of human granulocyte colony-stimulating factor (hG-CSF) and thrombopoietin on megakaryopoiesis and platelet function in hG-CSF receptor-transgenic mice. Blood 1999, 94:950-958. Bone marrow cells from transgenic mice that express the human G-CSF receptor demonstrate megakaryocyte development in vitro in response to G-CSF. However, G-CSF is not as potent as thrombopoietin, nor is it capable of activating all of the same signaling molecules or enhancing ADP-induced aggregation of platelets. This demonstrates that many but not all of the functions of Mpl can be accomplished by the G-CSF receptor.
75. 75 Melemed AS, Ryder JW, Vik TA: Activation of the mitogen-activated protein kinase pathway is involved in and sufficient for megakaryocytic differentiation of CMK cells. Blood 1997, 90:3462-3470.
76. 76 Rouyez MC, Boucheron C, Gisselbrecht S, Dusanter-Fourt I, Porteu F: Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway. Mol Cell Biol 1997, 17:4991-5000.
77. + cell from umbilical cord blood, inhibition of MAPK resulted in increased proliferation and cellularity of cultures as well as in a greater percentage of immature progenitors and blast cells. This suggests that MAPK activation may be important in thrombopoietin-induced differentiation, and MAPK inhibition may be important for thrombopoietin-induced stem cell expansion.
78. 78 Rojnuckarin P, Drachman JG, Kaushansky K: Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. Blood 1999, 94:1273-1282. In this paper, murine bone marrow was cultured with thrombopoietin in the presence or absence of the MAPK inhibitor PD98059. Inhibition of MAPK was associated with megakaryocytes of lower ploidy classes, demonstrating a role for MAPK in endomitosis.
79. 79 Dorsch M, Fan PD, Danial NN, Rothman PB, Goff SP: The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway. J Exp Med 1997, 186:1947-1955.
80. 80 Dorsch M, Danial NN, Rothman PB, Goff SP: A thrombopoietin receptor mutant deficient in Jak-STAT activation mediates proliferation but not differentiation in UT-7 cells. Blood 1999, 94:2676-2685. In this study, deletion of the first seven cytoplasmic residues of Mpl created a mutant receptor that can support thrombopoietin-induced proliferation but not differentiation of UT-7 cells. Because the mutant receptor fails to activate Jak2, it suggests that the signaling mechanisms that promote terminal differentiation lie downstream of Jak2 in this in vitro model of megakaryocyte development.
81. 81 Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, et al.: Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998,93:385-395.
82. 82 Ritchie A, Braun SE, He J, Broxmeyer HE: Thrombopoietin-induced conformational change in p53 lies downstream of the p44/p42 mitogen activated protein kinase cascade in the human growth factor-dependent cell line M07e. Oncogene 1999, 18:1465-1477.