Experimental Hematology
Volume 37, Issue 11 , Pages 1364-1377.e4 , November 2009

Ex vivo expansion of human hematopoietic stem cells by a small-molecule agonist of c-MPL

  • Taito Nishino

      Affiliations

    • Research Promotion and Coordination Department, Nissan Chemical Industries, Tokyo, Japan
    • ,
  • Katsuaki Miyaji

      Affiliations

    • Synthesis Research Department, Chemical Research Laboratories, Nissan Chemical Industries, Chiba, Japan
    • ,
  • Norihisa Ishiwata

      Affiliations

    • Pharmaceutical Research Department, Biological Research Laboratories, Nissan Chemical Industries, Saitama, Japan
    • ,
  • Kazutaka Arai

      Affiliations

    • Research Promotion and Coordination Department, Nissan Chemical Industries, Tokyo, Japan
    • ,
  • Makiko Yui

      Affiliations

    • ReproCELL Inc., Tokyo, Japan
    • Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
    • ,
  • Yasuyuki Asai

      Affiliations

    • ReproCELL Inc., Tokyo, Japan
    • ,
  • Hiromitsu Nakauchi

      Affiliations

    • Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Japan
    • ,
  • Atsushi Iwama

      Affiliations

    • Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
    • Corresponding Author InformationOffprint requests to: Atsushi Iwama, M.D., Ph.D., Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670 Japan

Received 13 July 2009 ,Revised 31 August 2009 ,Accepted 2 September 2009.

References 

  1. de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994;369:533–538
  2. 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
  3. 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
  4. Wendling F, Maraskovsky E, Debili N, et al. c-Mpl ligand is a humoral regulator of megakaryocytopoiesis. Nature. 1994;369:571–574
  5. 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
  6. Sasaki K, Odai H, Hanazono Y, et al. TPO/c-mpl ligand induces tyrosine phosphorylation of multiple cellular proteins including proto-oncogene products, Vav and c-Cbl, and Ras signaling molecules. Biochem Biophys Res Commun. 1995;216:338–347
  7. Drachman JG, Griffin JD, Kaushansky K. The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl. J Biol Chem. 1995;270:4979–4982
  8. Ezumi Y, Takayama H, OkumaThrombopoietin M. c-Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists-induced aggregation in platelets in vitro. FEBS Lett. 1995;374:48–52
  9. Bacon CM, Tortolani PJ, Shimosaka A, et al. Thrombopoietin (TPO) induces tyrosine phosphorylation and activation of STAT5 and STAT3. FEBS Lett. 1995;370:63–68
  10. 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
  11. Miyakawa Y, Rojnuckarin P, Habib T, Kaushansky K. Thrombopoietin induces phosphoinositol 3-kinase activation through SHP2, Gab, and insulin receptor substrate proteins in BAF3 cells and primary murine megakaryocytes. J Biol Chem. 2001;276:2494–2502
  12. Sattler M, Salgia R, Durstin MA, Prasad KV, Griffin JD. Thrombopoietin induces activation of the phosphatidylinositol-3′ kinase pathway and formation of a complex containing p85PI3K and the protooncoprotein p120CBL. J Cell Physiol. 1997;171:28–33
  13. Solar GP, Kerr WG, Zeigler FC, et al. Role of c-mpl in early hematopoiesis. Blood. 1998;92:4–10
  14. 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
  15. Kaushansky K. Thrombopoietin: accumulating evidence for an important biological effect on the hematopoietic stem cell. Ann N Y Acad Sci. 2003;996:39–43
  16. Buza-Vidas N, Antonchuk J, Qian H, et al. Cytokines regulate postnatal hematopoietic stem cell expansion: opposing roles of thrombopoietin and LNK. Genes Dev. 2006;20:2018–2023
  17. Yoshihara H, Arai F, Hosokawa K, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007;1:685–697
  18. Qian H, Buza-Vidas N, Hyland CD, et al. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell. 2007;1:671–684
  19. 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
  20. Fox N, Priestley G, Papayannopoulou T, Kaushansky K. Thrombopoietin expands hematopoietic stem cells after transplantation. J Clin Invest. 2002;110:389–394
  21. Seita J, Ema H, Ooehara J, et al. Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction. Proc Natl Acad Sci U S A. 2007;104:2349–2354
  22. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993;81:2844–2853
  23. Kondo M, Wagers AJ, Manz MG, et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol. 2003;21:759–806
  24. Shizuru JA, Negrin RS, Weissman IL. Hematopoietic stem and progenitor cells Clinical and preclinical regeneration of the hematolymphoid system. Annu Rev Med. 2005;56:509–538
  25. Verma IM, Weitzman MD. Gene therapy: twenty-first century medicine. Annu Rev Biochem. 2005;74:711–738
  26. Sauvageau G, Iscove NN, Humphries RK. In vitro and in vivo expansion of hematopoietic stem cells. Oncogene. 2004;23:7223–7232
  27. Sorrentino BP. Clinical strategies for expansion of haematopoietic stem cells. Nat Rev Immunol. 2004;4:878–888
  28. Hofmeister CC, Zhang J, Knight KL, Le P, Stiff PJ. Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche. Bone Marrow Transplant. 2007;39:11–23
  29. Piacibello W, Sanavio F, Garetto L, et al. Extensive amplification and self-renewal of human primitive hematopoietic stem cells from cord blood. Blood. 1997;89:2644–2653
  30. Blank U, Karlsson G, Karlsson S. Signaling pathways governing stem-cell fate. Blood. 2008;111:492–503
  31. Oostendorp RA, Audet J, Miller C, Eaves CJ. Cell division tracking and expansion of hematopoietic long-term repopulating cells. Leukemia. 1999;13:499–501
  32. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241–3248
  33. Basser RL, O'Flaherty E, Green M, et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood. 2002;99:2599–2602
  34. Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109:4607–4616
  35. Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinical activity of Eltrombopag (SB-497115), an oral, non-peptide thrombopoietin receptor agonist. Stem Cells. 2009;27:424–430
  36. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:641–648
  37. Fukushima-Shintani M, Suzuki K, Iwatsuki Y, et al. AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist. Eur J Haematol. 2009;82:247–254
  38. Nakamura T, Miyakawa Y, Miyamura A, et al. A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis. Blood. 2006;107:4300–4307
  39. Nogami W, Yoshida H, Koizumi K, et al. The effect of a novel, small non-peptidyl molecule butyzamide on human thrombopoietin receptor and megakaryopoiesis. Haematologica. 2008;93:1495–1504
  40. Komatsu N, Kunitama M, Yamada M, et al. Establishment and characterization of the thrombopoietin-dependent megakaryocytic cell line, UT-7/TPO. Blood. 1996;87:4552–4460
  41. Komatsu N, Nakauchi H, Miwa A, et al. Establishment and characterization of a human leukemic cell line with megakaryocytic features: dependency on granulocyte-macrophage colony-stimulating factor, interleukin 3, or erythropoietin for growth and survival. Cancer Research. 1991;51:341–348
  42. Komatsu N, Yamamoto M, Fujita H, et al. Establishment and characterization of an erythropoietin-dependent subline, UT-7/Epo, derived from human leukemia cell line, UT-7. Blood. 1993;82:456–464
  43. Dao MA, Nolta JA. Cytokine and integrin stimulation synergize to promote higher levels of GATA-2, c-myb, and CD34 protein in primary human hematopoietic progenitors from bone marrow. Blood. 2007;109:2373–2379
  44. Francoeur A, Assalian A. Microcat: a novel cell proliferation and cytotoxicity assay based on WST-1. Biochemica. 1996;3:19–25
  45. Kato Y, Iwama A, Tadokoro Y, et al. Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis. J Exp Med. 2005;202:169–179
  46. Larochelle A, Vormoor J, Hanenberg H, et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy. Nat Med. 1996;2:1329–1337
  47. Pflumio F, Izac B, Katz A, et al. Phenotype and function of human hematopoietic cells engrafting immune-deficient CB17-severe combined immunodeficiency mice and nonobese diabetic-severe combined immunodeficiency mice after transplantation of human cord blood mononuclear cells. Blood. 1996;88:3731–3740
  48. Bhatia M, Wang JC, Kapp U, Bonnet D, Dick JE. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci U S A. 1997;94:5320–5325
  49. Ueda T, Tsuji K, Yoshino H, et al. Expansion of human NOD/SCID-repopulating cells by stem cell factor, Flk2/Flt3 ligand, thromb-opoietin, IL-6, and soluble IL-6 receptor. J Clin Invest. 2000;105:1013–1021
  50. Vainchenker W, Deschamps JF, Bastin JM, Breton-Gorius TJ, McMichael AJ. Two monoclonal antiplatelet antibodies as markers of human megakaryocyte maturation: immunofluorescent staining and platelet peroxidase detection in megakaryocyte colonies and in in vivo cells from normal and leukemic patients. Blood. 1982;59:514–521
  51. Ohmizono Y, Sakabe H, Kimura T, et al. Thrombopoietin augments ex vivo expansion of human cord blood-derived hematopoietic progenitors in combination with stem cell factor and flt3 ligand. Leukemia. 1997;11:524–530
  52. McNiece IK, Stewart DM, Deacon DM, et al. Detection of a human CFC with a high proliferative potential. Blood. 1989;74:609–612
  53. Danet GH, Pan Y, Luongo JL, Bonnet DA, Simon MC. Expansion of human SCID-repopulating cells under hypoxic conditions. J Clin Invest. 2003;112:126–135
  54. Kirito K, Fox N, Komatsu N, Kaushansky K. Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1alpha. Blood. 2005;105:4258–4263
  55. Kirito K, Kaushansky K. Thrombopoietin stimulates vascular endothelial cell growth factor (VEGF) production in hematopoietic stem cells. Cell Cycle. 2005;4:1729–1731
  56. Zhou J, Brüne B. Cytokines and hormones in the regulation of hypoxia inducible factor-1alpha (HIF-1alpha). Cardiovasc Hematol Agents Med Chem. 2006;4:189–197
  57. Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A. 1993;90:4304–4308
  58. Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance. J Biol Chem. 2003;278:19575–19578
  59. Suzuki T, Yokoyama Y, Kumano K, et al. Highly efficient ex vivo expansion of human hematopoietic stem cells using Delta1-Fc chimeric protein. Stem Cells. 2006;24:2456–2465
  60. Zhang CC, Kaba M, Iizuka S, Huynh H, Lodish HF. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood. 2008;111:3415–3423
  61. Chute JP, Muramoto GG, Whitesides J, et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci U S A. 2006;103:11707–11712
  62. Wagner W, Ansorge A, Wirkner U, et al. Molecular evidence for stem cell function of the slow-dividing fraction among human hematopoietic progenitor cells by genome-wide analysis. Blood. 2004;104:675–686
  63. Mahmud N, Devine SM, Weller KP, et al. The relative quiescence of hematopoietic stem cells in nonhuman primates. Blood. 2001;97:3061–3068
  64. Shima H, Takubo K, Iwasaki H, et al. Reconstitution activity of hypoxic cultured human cord blood CD34-positive cells in NOG mice. Biochem Biophys Res Commun. 2009;378:467–472
  65. Gerber HP, Malik AK, Solar GP, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417:954–958
  66. Kondoh H. Cellular life span and the Warburg effect. Exp Cell Res. 2008;314:1923–1928
  67. Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007;129:465–472
  68. Araki H, Mahmud N, Milhem M, et al. Expansion of human umbilical cord blood SCID-repopulating cells using chromatin-modifying agents. Exp Hematol. 2006;34:140–149

PII: S0301-472X(09)00360-9

doi: 10.1016/j.exphem.2009.09.001

Experimental Hematology
Volume 37, Issue 11 , Pages 1364-1377.e4 , November 2009

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