Skip to main content

Advertisement

SpringerLink
Log in

The secret life of a megakaryocyte: emerging roles in bone marrow homeostasis control

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Megakaryocytes are rare cells found in the bone marrow, responsible for the everyday production and release of millions of platelets into the bloodstream. Since the discovery and cloning, in 1994, of their principal humoral factor, thrombopoietin, and its receptor c-Mpl, many efforts have been directed to define the mechanisms underlying an efficient platelet production. However, more recently different studies have pointed out new roles for megakaryocytes as regulators of bone marrow homeostasis and physiology. In this review we discuss the interaction and the reciprocal regulation of megakaryocytes with the different cellular and extracellular components of the bone marrow environment. Finally, we provide evidence that these processes may concur to the reconstitution of the bone marrow environment after injury and their deregulation may lead to the development of a series of inherited or acquired pathologies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Fliedner TM et al (1985) Bone marrow structure and its possible significance for hematopoietic cell renewal. Ann N Y Acad Sci 459:73–84

    CAS  PubMed  Google Scholar 

  2. Li XM, Hu Z, Jorgenson ML, Slayton WB (2009) High levels of acetylated low-density lipoprotein uptake and low tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (Tie2) promoter activity distinguish sinusoids from other vessel types in murine bone marrow. Circulation 120(19):1910–1918

    CAS  PubMed  Google Scholar 

  3. Smaniotto S et al (2013) Mouse basophils reside in extracellular matrix-enriched bone marrow niches which control their motility. PLoS One 8(9):e70292

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Nilsson SK et al (1998) Immunofluorescence characterization of key extracellular matrix proteins in murine bone marrow in situ. J Histochem Cytochem 46(3):371–377

    CAS  PubMed  Google Scholar 

  5. Malara A et al (2014) Megakaryocytes contribute to the bone marrow-matrix environment by expressing fibronectin, type IV collagen, and laminin. Stem Cells 32(4):926–937

    CAS  PubMed  Google Scholar 

  6. Lo Celso C et al (2009) Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457(7225):92–96

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Arai F et al (2004) Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118(2):149–161

    CAS  PubMed  Google Scholar 

  8. Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ (2005) SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121(7):1109–1121

    CAS  PubMed  Google Scholar 

  9. Mendez-Ferrer S et al (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466(7308):829–834

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Calvi LM et al (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425(6960):841–846

    CAS  PubMed  Google Scholar 

  11. Greenbaum A et al (2013) CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495(7440):227–230

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Kunisaki Y et al (2013) Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502(7473):637–643

    CAS  PubMed  Google Scholar 

  13. Hanoun M, Frenette PS (2013) This niche is a maze; an amazing niche. Cell Stem Cell 12(4):391–392

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Hartwig J, Italiano J (2003) The birth of the platelet. J Thromb Haemost 1(7):1580–1586

    CAS  PubMed  Google Scholar 

  15. Pallotta I, Lovett M, Rice W, Kaplan DL, Balduini A (2009) Bone marrow osteoblastic niche: a new model to study physiological regulation of megakaryopoiesis. PLoS One 4(12):e8359

    PubMed Central  PubMed  Google Scholar 

  16. Becker RP, De Bruyn PP (1976) The transmural passage of blood cells into myeloid sinusoids and the entry of platelets into the sinusoidal circulation; a scanning electron microscopic investigation. Am J Anat 145(2):183–205

    CAS  PubMed  Google Scholar 

  17. Junt T et al (2007) Dynamic visualization of thrombopoiesis within bone marrow. Science 317(5845):1767–1770

    CAS  PubMed  Google Scholar 

  18. Kowata S et al (2014) Platelet demand modulates the type of intravascular protrusion of megakaryocytes in bone marrow. Thromb Haemost 112(4):743–756

    PubMed  Google Scholar 

  19. Heazlewood SY et al (2013) Megakaryocytes co-localise with hemopoietic stem cells and release cytokines that up-regulate stem cell proliferation. Stem Cell Res 11(2):782–792

    CAS  PubMed  Google Scholar 

  20. Thon JN et al (2010) Cytoskeletal mechanics of proplatelet maturation and platelet release. J Cell Biol 191(4):861–874

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Leven RM (1987) Megakaryocyte motility and platelet formation. Scanning Microsc 1(4):1701–1709

    CAS  PubMed  Google Scholar 

  22. Tablin F, Castro M, Leven RM (1990) Blood platelet formation in vitro. The role of the cytoskeleton in megakaryocyte fragmentation. J Cell Sci 97((Pt 1)):59–70

    PubMed  Google Scholar 

  23. Hamada T et al (1998) Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. J Exp Med 188(3):539–548

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Wang JF, Liu ZY, Groopman JE (1998) The alpha-chemokine receptor CXCR4 is expressed on the megakaryocytic lineage from progenitor to platelets and modulates migration and adhesion. Blood 92(3):756–764

    CAS  PubMed  Google Scholar 

  25. Avecilla ST et al (2004) Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med 10(1):64–71

    CAS  PubMed  Google Scholar 

  26. Niswander LM, Fegan KH, Kingsley PD, McGrath KE, Palis J (2014) SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady-state and following radiation injury. Blood 124(2):277–286

    CAS  PubMed  Google Scholar 

  27. Pitchford SC, Lodie T, Rankin SM (2012) VEGFR1 stimulates a CXCR4-dependent translocation of megakaryocytes to the vascular niche, enhancing platelet production in mice. Blood 120(14):2787–2795

    CAS  PubMed  Google Scholar 

  28. Pittenger MF et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147

    CAS  PubMed  Google Scholar 

  29. Sacchetti B et al (2007) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131(2):324–336

    CAS  PubMed  Google Scholar 

  30. Haynesworth SE, Baber MA, Caplan AI (1996) Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol 166(3):585–592

    CAS  PubMed  Google Scholar 

  31. Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL (1998) Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 176(1):57–66

    CAS  PubMed  Google Scholar 

  32. Broudy VC, Lin NL, Kaushansky K (1995) Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro. Blood 85(7):1719–1726

    CAS  PubMed  Google Scholar 

  33. Navarro S et al (1991) Interleukin-6 and its receptor are expressed by human megakaryocytes: in vitro effects on proliferation and endoreplication. Blood 77(3):461–471

    CAS  PubMed  Google Scholar 

  34. Ishibashi T et al (1989) Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA 86(15):5953–5957

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Metcalf D, Hilton D, Nicola NA (1991) Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro. Blood 77(10):2150–2153

    CAS  PubMed  Google Scholar 

  36. Cheng L, Qasba P, Vanguri P, Thiede MA (2000) Human mesenchymal stem cells support megakaryocyte and pro-platelet formation from CD34 + hematopoietic progenitor cells. JCP 184(1):58–69

    CAS  Google Scholar 

  37. Majumdar MK et al (2003) Characterization and functionality of cell surface molecules on human mesenchymal stem cells. J Biomed Sci 10(2):228–241

    CAS  PubMed  Google Scholar 

  38. Angelopoulou M et al (2003) Cotransplantation of human mesenchymal stem cells enhances human myelopoiesis and megakaryocytopoiesis in NOD/SCID mice. Exp Hematol 31:413–420

    CAS  PubMed  Google Scholar 

  39. Sugiyama T, Kohara H, Noda M, Nagasawa T (2006) Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25(6):977–988

    CAS  PubMed  Google Scholar 

  40. Frey BM, Rafii S, Crystal RG, Moore MA (1998) Adenovirus long-term expression of thrombopoietin in vivo: a new model for myeloproliferative syndrome and osteomyelofibrosis. Schweiz Med Wochenschr 128(42):1587–1592

    CAS  PubMed  Google Scholar 

  41. Frey BM et al (1998) Adenovector-mediated expression of human thrombopoietin cDNA in immune-compromised mice: insights into the pathophysiology of osteomyelofibrosis. J Immunol 160(2):691–699

    CAS  PubMed  Google Scholar 

  42. Yan XQ et al (1995) Chronic exposure to retroviral vector encoded MGDF (mpl-ligand) induces lineage-specific growth and differentiation of megakaryocytes in mice. Blood 86(11):4025–4033

    CAS  PubMed  Google Scholar 

  43. Yan XQ et al (1996) A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation. Blood 88(2):402–409

    CAS  PubMed  Google Scholar 

  44. Villeval JL et al (1997) High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice. Blood 90(11):4369–4383

    CAS  PubMed  Google Scholar 

  45. Shivdasani RA et al (1995) Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 81(5):695–704

    CAS  PubMed  Google Scholar 

  46. Shivdasani RA, Fujiwara Y, McDevitt MA, Orkin SH (1997) A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J 16(13):3965–3973

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Kacena MA et al (2004) Megakaryocyte-osteoblast interaction revealed in mice deficient in transcription factors GATA-1 and NF-E2. J Bone Miner Res 19(4):652–660

    CAS  PubMed  Google Scholar 

  48. Suva LJ et al (2008) Platelet dysfunction and a high bone mass phenotype in a murine model of platelet-type von Willebrand disease. Am J Pathol 172(2):430–439

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Wickenhauser C et al (1995) Detection and quantification of transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF) release by normal human megakaryocytes. Leukemia 9(2):310–315

    CAS  PubMed  Google Scholar 

  50. Bord S et al (2005) Megakaryocytes modulate osteoblast synthesis of type-l collagen, osteoprotegerin, and RANKL. Bone 36(5):812–819

    CAS  PubMed  Google Scholar 

  51. Bord S et al (2004) Synthesis of osteoprotegerin and RANKL by megakaryocytes is modulated by oestrogen. Br J Haematol 126(2):244–251

    CAS  PubMed  Google Scholar 

  52. Bord S, Ireland DC, Beavan SR, Compston JE (2003) The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts. Bone 32(2):136–141

    CAS  PubMed  Google Scholar 

  53. Pearse RN et al (2001) Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci USA 98(20):11581–11586

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Chagraoui H et al (2003) Expression of osteoprotegerin mRNA and protein in murine megakaryocytes. Exp Hematol 31(11):1081–1088

    CAS  PubMed  Google Scholar 

  55. Kacena MA et al (2006) Megakaryocyte-mediated inhibition of osteoclast development. Bone 39(5):991–999

    CAS  PubMed  Google Scholar 

  56. Jiang S et al (1994) Cytokine production by primary bone marrow megakaryocytes. Blood 84(12):4151–4156

    CAS  PubMed  Google Scholar 

  57. Soslau G, Morgan DA, Jaffe JS, Brodsky I, Wang Y (1997) Cytokine mRNA expression in human platelets and a megakaryocytic cell line and cytokine modulation of platelet function. Cytokine 9(6):405–411

    CAS  PubMed  Google Scholar 

  58. Wickenhauser C et al (1995) Secretion of cytokines (interleukins-1 alpha, -3, and -6 and granulocyte-macrophage colony-stimulating factor) by normal human bone marrow megakaryocytes. Blood 85(3):685–691

    CAS  PubMed  Google Scholar 

  59. Vannucchi AM et al (2002) Development of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1(low) mice). Blood 100(4):1123–1132

    CAS  PubMed  Google Scholar 

  60. Sipe JB et al (2004) Localization of bone morphogenetic proteins (BMPs)-2, -4, and -6 within megakaryocytes and platelets. Bone 35(6):1316–1322

    CAS  PubMed  Google Scholar 

  61. Ciovacco WA et al (2009) The role of gap junctions in megakaryocyte-mediated osteoblast proliferation and differentiation. Bone 44(1):80–86

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Lemieux JM, Horowitz MC, Kacena MA (2010) Involvement of integrins alpha(3)beta(1) and alpha(5)beta(1) and glycoprotein IIb in megakaryocyte-induced osteoblast proliferation. J Cell Biochem 109(5):927–932

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Cheng YH et al (2013) Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation. J Bone Miner Res 28(6):1434–1445

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Cheng YH et al (2014) Signaling pathways involved in megakaryocyte-mediated proliferation of osteoblast lineage cells. J Cell Physiol 230(3):578–586

    Google Scholar 

  65. Ciovacco WA, Cheng YH, Horowitz MC, Kacena MA (2010) Immature and mature megakaryocytes enhance osteoblast proliferation and inhibit osteoclast formation. J Cell Biochem 109(4):774–781

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Chagraoui H et al (2002) Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. Blood 100(10):3495–3503

    CAS  PubMed  Google Scholar 

  67. Chagraoui H et al (2003) Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO. Blood 101(8):2983–2989

    CAS  PubMed  Google Scholar 

  68. Dominici M et al (2009) Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation. Blood 114(11):2333–2343

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Olson TS et al (2013) Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning. Blood 121(26):5238–5249

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Kacena MA, Gundberg CM, Nelson T, Horowitz MC (2005) Loss of the transcription factor p45 NF-E2 results in a developmental arrest of megakaryocyte differentiation and the onset of a high bone mass phenotype. Bone 36(2):215–223

    CAS  PubMed  Google Scholar 

  71. Shivdasani RA, Fielder P, Keller GA, Orkin SH, de Sauvage FJ (1997) Regulation of the serum concentration of thrombopoietin in thrombocytopenic NF-E2 knockout mice. Blood 90(5):1821–1827

    CAS  PubMed  Google Scholar 

  72. Meijome TE et al (2014) GATA-1 Deficiency rescues trabecular but not cortical bone in opg deficient mice. J Cell Physiol 230(4):783–790

    Google Scholar 

  73. Naveiras O et al (2009) Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460(7252):259–263

    PubMed Central  CAS  PubMed  Google Scholar 

  74. Kato H et al (2006) Adiponectin acts as an endogenous antithrombotic factor. Arterioscler Thromb Vasc Biol 26(1):224–230

    CAS  PubMed  Google Scholar 

  75. Sun S et al (2013) Expression of plasma membrane receptor genes during megakaryocyte development. Physiol Genomics 45(6):217–227

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Nakata M, Yada T, Soejima N, Maruyama I (1999) Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes 48(2):426–429

    CAS  PubMed  Google Scholar 

  77. Nakata M, Maruyama I, Yada T (2005) Leptin potentiates ADP-induced [Ca(2 +)](i) increase via JAK2 and tyrosine kinases in a megakaryoblast cell line. Diabetes Res Clin Pract 70(3):209–216

    CAS  PubMed  Google Scholar 

  78. Gerrits AJ et al (2012) Induction of insulin resistance by the adipokines resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 in human megakaryocytes. Haematologica 97(8):1149–1157

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Hooper AT et al (2009) Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4(3):263–274

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Rafii S et al (1995) Human bone marrow microvascular endothelial cells support long-term proliferation and differentiation of myeloid and megakaryocytic progenitors. Blood 86(9):3353–3363

    CAS  PubMed  Google Scholar 

  81. Rafii S, Mohle R, Shapiro F, Frey BM, Moore MA (1997) Regulation of hematopoiesis by microvascular endothelium. Leuk Lymphoma 27(5–6):375–386

    CAS  PubMed  Google Scholar 

  82. Irie S, Tavassoli M (1986) Purification and characterization of rat bone marrow endothelial cells. Exp Hematol 14(10):912–918

    CAS  PubMed  Google Scholar 

  83. Fei RG, Penn PE, Wolf NS (1990) A method to establish pure fibroblast and endothelial cell colony cultures from murine bone marrow. Exp Hematol 18(8):953–957

    CAS  PubMed  Google Scholar 

  84. Masek LC, Sweetenham JW (1994) Isolation and culture of endothelial cells from human bone marrow. Br J Haematol 88(4):855–865

    CAS  PubMed  Google Scholar 

  85. Delia D et al (1993) CD34 expression is regulated reciprocally with adhesion molecules in vascular endothelial cells in vitro. Blood 81(4):1001–1008

    CAS  PubMed  Google Scholar 

  86. Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G (1998) A common precursor for hematopoietic and endothelial cells. Development 125(4):725–732

    CAS  PubMed  Google Scholar 

  87. Möhle R, Green D, Moore MA, Nachman RL, Rafii S (1997) Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 94(2):663–668

    PubMed Central  PubMed  Google Scholar 

  88. Bobik R, Hong Y, Breier G, Martin JF, Erusalimsky JD (1998) Thrombopoietin stimulates VEGF release from c-Mpl-expressing cell lines and haematopoietic progenitors. FEBS Lett 423(1):10–14

    CAS  PubMed  Google Scholar 

  89. Kwon SM et al (2014) Cross Talk with Hematopoietic cells regulates the endothelial progenitor cell differentiation of cd34 positive cells. PLoS One 9(8):e106310

    PubMed Central  PubMed  Google Scholar 

  90. Kopp HG et al (2006) Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization. J Clin Invest 116(12):3277–3291

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Kong Y et al (2014) Association between an impaired bone marrow vascular microenvironment and prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 20(8):1190–1197

    PubMed  Google Scholar 

  92. Yamazaki S et al (2011) Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147(5):1146–1158

    CAS  PubMed  Google Scholar 

  93. Suzuki C et al (1989) Continuous perfusion with interleukin 6 (IL-6) enhances production of hematopoietic stem cells (CFU-S). Biochem Biophys Res Commun 159(3):933–938

    CAS  PubMed  Google Scholar 

  94. Kirouac DC et al (2010) Dynamic interaction networks in a hierarchically organized tissue. Mol Syst Biol 6:417

    PubMed Central  PubMed  Google Scholar 

  95. Zhao M et al (2014) Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med 20(11):1321–1326

    CAS  PubMed  Google Scholar 

  96. Bruns I et al (2014) Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med 20(11):1315–1320

    CAS  PubMed  Google Scholar 

  97. Tew JG et al (1992) Germinal centers and antibody production in bone marrow. Immunol Rev 126:99–112

    CAS  PubMed  Google Scholar 

  98. Kallies A et al (2004) Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med 200(8):967–977

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Sze DM, Toellner KM, García de Vinuesa C, Taylor DR, MacLennan IC (2000) Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J Exp Med 192(6):813–821

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Tokoyoda K, Egawa T, Sugiyama T, Choi BI, Nagasawa T (2004) Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20(6):707–718

    CAS  PubMed  Google Scholar 

  101. Belnoue E et al (2008) APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 111(5):2755–2764

    CAS  PubMed  Google Scholar 

  102. Winter O et al (2010) Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood 116(11):1867–1875

    CAS  PubMed  Google Scholar 

  103. Landoni VI (2004) Macrophage derived signalling regulates negatively the megakaryocyte compartment. Cell Mol Biol (Noisy-le-grand) 50:OL667–OL675

    CAS  Google Scholar 

  104. D’Atri LP et al (2011) Paracrine regulation of megakaryo/thrombopoiesis by macrophages. Exp Hematol 39(7):763–772

    PubMed  Google Scholar 

  105. Clark BR, Keating A (1995) Biology of bone marrow stroma. Ann N Y Acad Sci 770:70–78

    CAS  PubMed  Google Scholar 

  106. Moore KA (2004) Recent advances in defining the hematopoietic stem cell niche. Curr Opin Hematol 11(2):107–111

    CAS  PubMed  Google Scholar 

  107. Coppinger JA, Maguire PB (2007) Insights into the platelet releasate. Curr Pharm Des 13(26):2640–2646

    CAS  PubMed  Google Scholar 

  108. Zufferey A et al (2014) Characterization of the platelet granule proteome: evidence of the presence of MHC1 in alpha-granules. J Proteomics 101:130–140

    CAS  PubMed  Google Scholar 

  109. Italiano JE et al (2008) Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111(3):1227–1233

    PubMed Central  CAS  PubMed  Google Scholar 

  110. Sehgal S, Storrie B (2007) Evidence that differential packaging of the major platelet granule proteins von Willebrand factor and fibrinogen can support their differential release. J Thromb Haemost 5(10):2009–2016

    CAS  PubMed  Google Scholar 

  111. Villeneuve J et al (2009) Tissue inhibitors of matrix metalloproteinases in platelets and megakaryocytes: a novel organization for these secreted proteins. Exp Hematol 37(7):849–856

    CAS  PubMed  Google Scholar 

  112. Balduini A et al (2008) Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes. J Thromb Haemost 6(11):1900–1907

    CAS  PubMed  Google Scholar 

  113. Lane WJ et al (2000) Stromal-derived factor 1-induced megakaryocyte migration and platelet production is dependent on matrix metalloproteinases. Blood 96(13):4152–4159

    CAS  PubMed  Google Scholar 

  114. Schachtner H et al (2013) Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane. Blood 121(13):2542–2552

    CAS  PubMed  Google Scholar 

  115. Schick PK, Wojensk CM, Bennett V, Denisova L (1996) Fibronectin isoforms in megakaryocytes. Stem Cells 14(Suppl 1):212–219

    PubMed  Google Scholar 

  116. Nigatu A et al (2006) Megakaryocytic cells synthesize and platelets secrete alpha5-laminins, and the endothelial laminin isoform laminin 10 (alpha5beta1gamma1) strongly promotes adhesion but not activation of platelets. Thromb Haemost 95(1):85–93

    CAS  PubMed  Google Scholar 

  117. Bentley SA, Alabaster O, Foidart JM (1981) Collagen heterogeneity in normal human bone marrow. Br J Haematol 48(2):287–291

    CAS  PubMed  Google Scholar 

  118. Reilly JT, Nash JR, Mackie MJ, McVerry BA (1985) Immuno-enzymatic detection of fibronectin in normal and pathological haematopoietic tissue. Br J Haematol 59(3):497–504

    CAS  PubMed  Google Scholar 

  119. Cattoretti G, Schiró R, Orazi A, Soligo D, Colombo MP (1993) Bone marrow stroma in humans: anti-nerve growth factor receptor antibodies selectively stain reticular cells in vivo and in vitro. Blood 81(7):1726–1738

    CAS  PubMed  Google Scholar 

  120. Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP (2007) Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol 139(3):351–362

    CAS  PubMed  Google Scholar 

  121. Bauermeister DE (1971) Quantitation of bone marrow reticulin–a normal range. Am J Clin Pathol 56(1):24–31

    CAS  PubMed  Google Scholar 

  122. Thiele J et al (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90(8):1128–1132

    PubMed  Google Scholar 

  123. Eliades A et al (2011) Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase. J Biol Chem 286(31):27630–27638

    PubMed Central  CAS  PubMed  Google Scholar 

  124. Kagan HM, Li W (2003) Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 88(4):660–672

    CAS  PubMed  Google Scholar 

  125. Balduini CL, Pecci A, Noris P (2013) Diagnosis and management of inherited thrombocytopenias. Semin Thromb Hemost 39(2):161–171

    CAS  PubMed  Google Scholar 

  126. Balduini CL, Savoia A, Seri M (2013) Inherited thrombocytopenias frequently diagnosed in adults. J Thromb Haemost 11(6):1006–1019

    CAS  PubMed  Google Scholar 

  127. Pecci A et al (2009) Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation. Thromb Haemost 102(1):90–96

    CAS  PubMed  Google Scholar 

  128. Chen Z et al (2007) The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway. Blood 110(1):171–179

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Balduini A et al (2009) Proplatelet formation in heterozygous Bernard-Soulier syndrome type Bolzano. J Thromb Haemost 7(3):478–484

    CAS  PubMed  Google Scholar 

  130. Balduini A, Malara A, Balduini CL, Noris P (2011) Megakaryocytes derived from patients with the classical form of Bernard-Soulier syndrome show no ability to extend proplatelets in vitro. Platelets 22(4):308–311

    CAS  PubMed  Google Scholar 

  131. Bury L, Malara A, Gresele P, Balduini A (2012) Outside-in signalling generated by a constitutively activated integrin αIIbβ3 impairs proplatelet formation in human megakaryocytes. PLoS One 7(4):e34449

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Kunishima S et al (2013) ACTN1 mutations cause congenital macrothrombocytopenia. Am J Hum Genet 92(3):431–438

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Guéguen P et al (2013) A missense mutation in the alpha-actinin 1 gene (ACTN1) is the cause of autosomal dominant macrothrombocytopenia in a large French family. PLoS One 8(9):e74728

    PubMed Central  PubMed  Google Scholar 

  134. Bluteau D et al (2014) Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. J Clin Invest 124(2):580–591

    PubMed Central  CAS  PubMed  Google Scholar 

  135. Necchi V et al (2013) Ubiquitin/proteasome-rich particulate cytoplasmic structures (PaCSs) in the platelets and megakaryocytes of ANKRD26-related thrombo-cytopenia. Thromb Haemost 109(2):263–271

    CAS  PubMed  Google Scholar 

  136. Bottega R et al (2013) Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency. Haematologica 98(6):868–874

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Nurden AT, Nurden P (2007) The gray platelet syndrome: clinical spectrum of the disease. Blood Rev 21(1):21–36

    CAS  PubMed  Google Scholar 

  138. Breton-Gorius J, Vainchenker W, Nurden A, Levy-Toledano S, Caen J (1981) Defective alpha-granule production in megakaryocytes from gray platelet syndrome: ultrastructural studies of bone marrow cells and megakaryocytes growing in culture from blood precursors. Am J Pathol 102(1):10–19

    PubMed Central  CAS  PubMed  Google Scholar 

  139. Guerrero JA, et al. (2014) Gray Platelet Syndrome: Pro-inflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer resistance to cancer metastasis in mice. Blood

  140. Barosi G, Lupo L, Rosti V (2012) Management of myeloproliferative neoplasms: from academic guidelines to clinical practice. Curr Hematol Malig Rep 7(1):50–56

    PubMed  Google Scholar 

  141. Malinge S et al (2008) Activating mutations in human acute megakaryoblastic leukemia. Blood 112(10):4220–4226

    CAS  PubMed  Google Scholar 

  142. Thiele J et al. (2008) Primary myelofibrosis. (Swerdlow SH, Campo E, Harris NL, Jaffee ES, Pileri SA, Stein H, Thiele J, Vardiman JW, ed., Lyon: IARC Press), pp 44–47

  143. Michiels JJ (1997) Diagnostic criteria of the myeloproliferative disorders (MPD): essential thrombocythaemia, polycythaemia vera and chronic megakaryocytic granulocytic metaplasia. Neth J Med 51(2):57–64

    CAS  PubMed  Google Scholar 

  144. Michiels JJ, Berneman Z, Schroyens W, De Raeve H (2014) Changing Concepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: from dameshek 1950 to vainchenker 2005 and beyond. Acta Haematol 133(1):36–51

    PubMed  Google Scholar 

  145. Alvarez-Larrán A et al (2014) WHO-histological criteria for myeloproliferative neoplasms: reproducibility, diagnostic accuracy and correlation with gene mutations and clinical outcomes. Br J Haematol 166(6):911–919

    PubMed  Google Scholar 

  146. Balduini A et al (2011) In vitro megakaryocyte differentiation and proplatelet formation in Ph-negative classical myeloproliferative neoplasms: distinct patterns in the different clinical phenotypes. PLoS One 6(6):e21015

    PubMed Central  CAS  PubMed  Google Scholar 

  147. Tefferi A et al (2014) CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 28(7):1472–1477

    CAS  PubMed  Google Scholar 

  148. Barosi G (2014) Essential thrombocythemia vs. early/prefibrotic myelofibrosis: why does it matter. Best Pract Res Clin Haematol 27(2):129–140

    PubMed  Google Scholar 

  149. Kralovics R et al (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352(17):1779–1790

    CAS  PubMed  Google Scholar 

  150. Baxter EJ et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365(9464):1054–1061

    CAS  PubMed  Google Scholar 

  151. Kaushansky K (2009) Molecular mechanisms of thrombopoietin signaling. J Thromb Haemost 7(Suppl 1):235–238

    CAS  PubMed  Google Scholar 

  152. Hitchcock IS, Kaushansky K (2014) Thrombopoietin from beginning to end. Br J Haematol 165(2):259–268

    CAS  PubMed  Google Scholar 

  153. Seita J et al (2007) Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction. Proc Natl Acad Sci USA 104(7):2349–2354

    PubMed Central  CAS  PubMed  Google Scholar 

  154. James C et al (2008) The hematopoietic stem cell compartment of JAK2V617F-positive myeloproliferative disorders is a reflection of disease heterogeneity. Blood 112(6):2429–2438

    CAS  PubMed  Google Scholar 

  155. Anand S et al (2011) Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood 118(1):177–181

    CAS  PubMed  Google Scholar 

  156. Tiedt R et al (2008) Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 111(8):3931–3940

    CAS  PubMed  Google Scholar 

  157. Sangkhae V, Etheridge SL, Kaushansky K, Hitchcock IS (2014) The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm. Blood 124(26):3956–3963

    CAS  PubMed  Google Scholar 

  158. Lasho TL, Pardanani A, Tefferi A (2010) LNK mutations in JAK2 mutation-negative erythrocytosis. N Engl J Med 363(12):1189–1190

    CAS  PubMed  Google Scholar 

  159. Oh ST et al (2010) Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood 116(6):988–992

    PubMed Central  CAS  PubMed  Google Scholar 

  160. Pardanani A et al (2010) LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia 24(10):1713–1718

    CAS  PubMed  Google Scholar 

  161. Lasho TL, Tefferi A, Finke C, Pardanani A (2011) Clonal hierarchy and allelic mutation segregation in a myelofibrosis patient with two distinct LNK mutations. Leukemia 25(6):1056–1058

    CAS  PubMed  Google Scholar 

  162. Velazquez L et al (2002) Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. J Exp Med 195(12):1599–1611

    PubMed Central  CAS  PubMed  Google Scholar 

  163. Takaki S, Morita H, Tezuka Y, Takatsu K (2002) Enhanced hematopoiesis by hematopoietic progenitor cells lacking intracellular adaptor protein. Lnk. J Exp Med 195(2):151–160

    CAS  Google Scholar 

  164. Tong W, Lodish HF (2004) Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. J Exp Med 200(5):569–580

    PubMed Central  PubMed  Google Scholar 

  165. Bersenev A et al (2010) Lnk constrains myeloproliferative diseases in mice. J Clin Invest 120(6):2058–2069

    PubMed Central  CAS  PubMed  Google Scholar 

  166. Pardanani AD et al (2006) MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108(10):3472–3476

    CAS  PubMed  Google Scholar 

  167. Pikman Y et al (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 3(7):e270

    PubMed Central  PubMed  Google Scholar 

  168. Chaligné R et al (2008) New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition. Leukemia 22(8):1557–1566

    PubMed  Google Scholar 

  169. Vannucchi AM et al (2008) Characteristics and clinical correlates of MPL 515 W > L/K mutation in essential thrombocythemia. Blood 112(3):844–847

    CAS  PubMed  Google Scholar 

  170. Beer PA et al (2008) MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 112(1):141–149

    CAS  PubMed  Google Scholar 

  171. Guglielmelli P et al (2007) Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. Br J Haematol 137(3):244–247

    CAS  PubMed  Google Scholar 

  172. Chaligné R et al (2007) Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis. Blood 110(10):3735–3743

    PubMed  Google Scholar 

  173. Li Y et al (1996) Proto-oncogene c-mpl is involved in spontaneous megakaryocytopoiesis in myeloproliferative disorders. Br J Haematol 92(1):60–66

    CAS  PubMed  Google Scholar 

  174. Ulich TR et al (1996) Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice. Blood 87(12):5006–5015

    CAS  PubMed  Google Scholar 

  175. Yanagida M et al (1997) The role of transforming growth factor-beta in PEG-rHuMGDF-induced reversible myelofibrosis in rats. Br J Haematol 99(4):739–745

    CAS  PubMed  Google Scholar 

  176. Kuter DJ et al (2009) Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood 114(18):3748–3756

    CAS  PubMed  Google Scholar 

  177. Kuter DJ (2009) Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med 60:193–206

    CAS  PubMed  Google Scholar 

  178. Klampfl T et al (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369(25):2379–2390

    CAS  PubMed  Google Scholar 

  179. Nangalia J et al (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369(25):2391–2405

    PubMed Central  CAS  PubMed  Google Scholar 

  180. Broséus J, Park JH, Carillo S, Hermouet S, Girodon F (2014) Presence of calreticulin mutations in JAK2-negative polycythemia vera. Blood

  181. Smith MJ, Koch GL (1989) Multiple zones in the sequence of calreticulin (CRP55, calregulin, HACBP), a major calcium binding ER/SR protein. EMBO J 8(12):3581–3586

    PubMed Central  CAS  PubMed  Google Scholar 

  182. Di Buduo CA et al (2014) The importance of calcium in the regulation of megakaryocyte function. Haematologica 99(4):769–778

    PubMed  Google Scholar 

  183. Vannucchi AM et al (2014) Calreticulin mutation-specific immunostaining in myeloproliferative neoplasms: pathogenetic insight and diagnostic value. Leukemia 28(9):1811–1818

    PubMed Central  CAS  PubMed  Google Scholar 

  184. Llewelyn Roderick H, Llewellyn DH, Campbell AK, Kendall JM (1998) Role of calreticulin in regulating intracellular Ca2 + storage and capacitative Ca2 + entry in HeLa cells. Cell Calcium 24(4):253–262

    CAS  PubMed  Google Scholar 

  185. Ma J, Pan Z (2003) Retrograde activation of store-operated calcium channel. Cell Calcium 33(5–6):375–384

    CAS  PubMed  Google Scholar 

  186. Grosse J et al (2007) An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice. J Clin Invest 117(11):3540–3550

    PubMed Central  CAS  PubMed  Google Scholar 

  187. Dragoni S et al (2014) Enhanced expression of Stim, Orai, and TRPC transcripts and proteins in endothelial progenitor cells isolated from patients with primary myelofibrosis. PLoS ONE 9(3):e91099

    PubMed Central  PubMed  Google Scholar 

  188. Rampal R et al (2014) Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood 123(22):e123–e133

    PubMed  Google Scholar 

  189. Barnard DR et al (2007) Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: report from the Children’s Oncology Group. Pediatr Blood Cancer 49(1):17–22

    PubMed  Google Scholar 

  190. Malinge S, Izraeli S, Crispino JD (2009) Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 113(12):2619–2628

    PubMed Central  CAS  PubMed  Google Scholar 

  191. Wickrema A, Crispino JD (2007) Erythroid and megakaryocytic transformation. Oncogene 26(47):6803–6815

    CAS  PubMed  Google Scholar 

  192. Fröhling S et al (2007) Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell 12(6):501–513

    PubMed  Google Scholar 

  193. Fröhling S, Scholl C, Gilliland DG, Levine RL (2005) Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol 23(26):6285–6295

    PubMed  Google Scholar 

  194. Khan I, Malinge S, Crispino J (2011) Myeloid leukemia in Down syndrome. Crit Rev Oncog 16(1–2):25–36

    PubMed Central  PubMed  Google Scholar 

  195. Walters DK et al (2006) Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10(1):65–75

    CAS  PubMed  Google Scholar 

  196. Wechsler J et al (2002) Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32(1):148–152

    CAS  PubMed  Google Scholar 

  197. Li Z et al (2005) Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet 37(6):613–619

    CAS  PubMed  Google Scholar 

  198. Kuhl C et al (2005) GATA1-mediated megakaryocyte differentiation and growth control can be uncoupled and mapped to different domains in GATA1. Mol Cell Biol 25(19):8592–8606

    PubMed Central  CAS  PubMed  Google Scholar 

  199. Shivdasani R (2002) An animal model for myelofibrosis. Blood 100(4):1109

    CAS  Google Scholar 

  200. Vyas P, Ault K, Jackson CW, Orkin SH, Shivdasani RA (1999) Consequences of GATA-1 deficiency in megakaryocytes and platelets. Blood 93(9):2867–2875

    CAS  PubMed  Google Scholar 

  201. Vannucchi AM et al (2005) A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF-beta1 in the development of myelofibrosis. Blood 105(9):3493–3501

    CAS  PubMed  Google Scholar 

  202. Hollanda LM et al (2006) An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nat Genet 38(7):807–812

    CAS  PubMed  Google Scholar 

  203. Hoeller S et al (2014) Morphologic and GATA1 sequencing analysis of hematopoiesis in fetuses with trisomy 21. Hum Pathol 45(5):1003–1009

    CAS  PubMed  Google Scholar 

  204. Stankiewicz MJ, Crispino JD (2013) AKT collaborates with ERG and Gata1 s to dysregulate megakaryopoiesis and promote AMKL. Leukemia 27(6):1339–1347

    PubMed Central  CAS  PubMed  Google Scholar 

  205. Balduini A et al (2012) Constitutively released adenosine diphosphate regulates proplatelet formation by human megakaryocytes. Haematologica 97(11):1657–1665

    PubMed Central  CAS  PubMed  Google Scholar 

  206. Currao M, Balduini CL, Balduini A (2013) High doses of romiplostim induce proliferation and reduce proplatelet formation by human megakaryocytes. PLoS One 8(1):e54723

    PubMed Central  CAS  PubMed  Google Scholar 

  207. Bonner JC (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 15(4):255–273

    CAS  PubMed  Google Scholar 

  208. Pohlers D et al (2009) TGF-beta and fibrosis in different organs-molecular pathway imprints. Biochim Biophys Acta 1792(8):746–756

    CAS  PubMed  Google Scholar 

  209. Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342(18):1350–1358

    CAS  PubMed  Google Scholar 

  210. Zingariello M et al (2013) Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis. Blood 121(17):3345–3363

    PubMed Central  CAS  PubMed  Google Scholar 

  211. Ciurea SO et al (2007) Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. Blood 110(3):986–993

    PubMed Central  CAS  PubMed  Google Scholar 

  212. Badalucco S et al (2013) Involvement of TGFβ1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis. Haematologica 98(4):514–517

    PubMed Central  CAS  PubMed  Google Scholar 

  213. Ponce CC, de Lourdes F, Chauffaille M, Ihara SS, Silva MR (2012) The relationship of the active and latent forms of TGF-β1 with marrow fibrosis in essential thrombocythemia and primary myelofibrosis. Med Oncol 29(4):2337–2344

    CAS  PubMed  Google Scholar 

  214. Terui T et al (1990) The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis. Blood 75(7):1540–1548

    CAS  PubMed  Google Scholar 

  215. Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79(4):1283–1316

    CAS  PubMed  Google Scholar 

  216. Biernacka A, Dobaczewski M, Frangogiannis NG (2011) TGF-β signaling in fibrosis. Growth Factors 29(5):196–202

    CAS  PubMed  Google Scholar 

  217. Katoh O, Kimura A, Itoh T, Kuramoto A (1990) Platelet derived growth factor messenger RNA is increased in bone marrow megakaryocytes in patients with myeloproliferative disorders. Am J Hematol 35(3):145–150

    CAS  PubMed  Google Scholar 

  218. Bock O et al (2005) Aberrant expression of platelet-derived growth factor (PDGF) and PDGF receptor-alpha is associated with advanced bone marrow fibrosis in idiopathic myelofibrosis. Haematologica 90(1):133–134

    CAS  PubMed  Google Scholar 

  219. Niino D, Tsuchiya T, Tomonaga M, Miyazaki Y, Ohshima K (2013) Clinicopathological features of acute megakaryoblastic leukaemia: relationship between fibrosis and platelet-derived growth factor. Pathol Int 63(3):141–149

    CAS  PubMed  Google Scholar 

  220. Fava RA et al (1990) Synthesis of transforming growth factor-beta 1 by megakaryocytes and its localization to megakaryocyte and platelet alpha-granules. Blood 76(10):1946–1955

    CAS  PubMed  Google Scholar 

  221. Janssens K, ten Dijke P, Janssens S, Van Hul W (2005) Transforming growth factor-beta1 to the bone. Endocr Rev 26(6):743–774

    CAS  PubMed  Google Scholar 

  222. Yang M, Chesterman CN, Chong BH (1995) Recombinant PDGF enhances megakaryocytopoiesis in vitro. Br J Haematol 91(2):285–289

    CAS  PubMed  Google Scholar 

  223. Su RJ et al (2001) Platelet-derived growth factor enhances ex vivo expansion of megakaryocytic progenitors from human cord blood. Bone Marrow Transplant 27(10):1075–1080

    CAS  PubMed  Google Scholar 

  224. Tibbles HE, Navara CS, Hupke MA, Vassilev AO, Uckun FM (2002) Thrombopoietin induces p-selectin expression on platelets and subsequent platelet/leukocyte interactions. Biochem Biophys Res Commun 292(4):987–991

    CAS  PubMed  Google Scholar 

  225. Malara A et al (2011) Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A. Blood 117(8):2476–2483

    CAS  PubMed  Google Scholar 

  226. Abbonante V et al (2013) Discoidin domain receptor 1 protein is a novel modulator of megakaryocyte-collagen interactions. J Biol Chem 288(23):16738–16746

    PubMed Central  CAS  PubMed  Google Scholar 

  227. Chang Y et al (2007) Proplatelet formation is regulated by the Rho/ROCK pathway. Blood 109(10):4229–4236

    CAS  PubMed  Google Scholar 

  228. Malara A et al (2011) Extracellular matrix structure and nano-mechanics determine megakaryocyte function. Blood 118(16):4449–4453

    PubMed Central  CAS  PubMed  Google Scholar 

  229. Shin JW, Swift J, Spinler KR, Discher DE (2011) Myosin-II inhibition and soft 2D matrix maximize multinucleation and cellular projections typical of platelet-producing megakaryocytes. Proc Natl Acad Sci USA 108(28):11458–11463

    PubMed Central  CAS  PubMed  Google Scholar 

  230. Richardson JL, Shivdasani RA, Boers C, Hartwig JH, Italiano JE (2005) Mechanisms of organelle transport and capture along proplatelets during platelet production. Blood 106(13):4066–4075

    PubMed Central  CAS  PubMed  Google Scholar 

  231. Pallotta I, Lovett M, Kaplan DL, Balduini A (2011) Three-dimensional system for the in vitro study of megakaryocytes and functional platelet production using silk-based vascular tubes. Tissue Eng Part C Methods 17(12):1223–1232

    PubMed Central  PubMed  Google Scholar 

  232. Omenetto FG, Kaplan DL (2010) New opportunities for an ancient material. Science 329(5991):528–531

    PubMed Central  CAS  PubMed  Google Scholar 

  233. Zhang J et al (2012) Stabilization of vaccines and antibiotics in silk and eliminating the cold chain. Proc Natl Acad Sci USA 109(30):11981–11986

    PubMed Central  CAS  PubMed  Google Scholar 

  234. Matsunaga T et al (2006) Ex vivo large-scale generation of human platelets from cord blood CD34 + cells. Stem Cells 24(12):2877–2887

    CAS  PubMed  Google Scholar 

  235. de Barros AP et al (2010) Osteoblasts and bone marrow mesenchymal stromal cells control hematopoietic stem cell migration and proliferation in 3D in vitro model. PLoS One 5(2):e9093

    PubMed Central  PubMed  Google Scholar 

  236. Sullenbarger B, Bahng JH, Gruner R, Kotov N, Lasky LC (2009) Prolonged continuous in vitro human platelet production using three-dimensional scaffolds. Exp Hematol 37(1):101–110

    PubMed Central  CAS  PubMed  Google Scholar 

  237. Torisawa YS et al (2014) Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. Nat Methods 11(6):663–669

    CAS  PubMed  Google Scholar 

  238. Thon JN et al (2014) Platelet bioreactor-on-a-chip. Blood [Epub ahead of print]

Download references

Acknowledgments

This review was made possible through research support by Cariplo Foundation (2010-0807), Italian Ministry of Health (grant RF-2009-1550218), Italian Ministry of University and Research FIRB (RBFR1299KO) and a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano) “Special Program Molecular Clinical Oncology 5 × 1000” to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative) and US National Institutes of Health (grant EB016041-01).

Conflict of interests

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, University of Pavia, Via Forlanini 6, 27100, Pavia, Italy

    Alessandro Malara, Vittorio Abbonante, Christian A. Di Buduo, Lorenzo Tozzi, Manuela Currao & Alessandra Balduini

  2. Laboratory of Biotechnology, IRCCS San Matteo Foundation, Pavia, Italy

    Alessandro Malara, Vittorio Abbonante, Christian A. Di Buduo, Manuela Currao & Alessandra Balduini

  3. Department of Biomedical Engineering, Tufts University, Medford, MA, USA

    Lorenzo Tozzi & Alessandra Balduini

Authors
  1. Alessandro Malara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vittorio Abbonante
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian A. Di Buduo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lorenzo Tozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manuela Currao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alessandra Balduini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandra Balduini.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Malara, A., Abbonante, V., Di Buduo, C.A. et al. The secret life of a megakaryocyte: emerging roles in bone marrow homeostasis control. Cell. Mol. Life Sci. 72, 1517–1536 (2015). https://doi.org/10.1007/s00018-014-1813-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-014-1813-y

Keywords

Search

Navigation