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.
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References
Fliedner TM et al (1985) Bone marrow structure and its possible significance for hematopoietic cell renewal. Ann N Y Acad Sci 459:73–84
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
Smaniotto S et al (2013) Mouse basophils reside in extracellular matrix-enriched bone marrow niches which control their motility. PLoS One 8(9):e70292
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
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
Lo Celso C et al (2009) Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457(7225):92–96
Arai F et al (2004) Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118(2):149–161
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
Mendez-Ferrer S et al (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466(7308):829–834
Calvi LM et al (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425(6960):841–846
Greenbaum A et al (2013) CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495(7440):227–230
Kunisaki Y et al (2013) Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502(7473):637–643
Hanoun M, Frenette PS (2013) This niche is a maze; an amazing niche. Cell Stem Cell 12(4):391–392
Hartwig J, Italiano J (2003) The birth of the platelet. J Thromb Haemost 1(7):1580–1586
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
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
Junt T et al (2007) Dynamic visualization of thrombopoiesis within bone marrow. Science 317(5845):1767–1770
Kowata S et al (2014) Platelet demand modulates the type of intravascular protrusion of megakaryocytes in bone marrow. Thromb Haemost 112(4):743–756
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
Thon JN et al (2010) Cytoskeletal mechanics of proplatelet maturation and platelet release. J Cell Biol 191(4):861–874
Leven RM (1987) Megakaryocyte motility and platelet formation. Scanning Microsc 1(4):1701–1709
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
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
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
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
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
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
Pittenger MF et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147
Sacchetti B et al (2007) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131(2):324–336
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
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
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
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
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
Metcalf D, Hilton D, Nicola NA (1991) Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro. Blood 77(10):2150–2153
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
Majumdar MK et al (2003) Characterization and functionality of cell surface molecules on human mesenchymal stem cells. J Biomed Sci 10(2):228–241
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
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
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
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
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
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
Villeval JL et al (1997) High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice. Blood 90(11):4369–4383
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
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
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
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
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
Bord S et al (2005) Megakaryocytes modulate osteoblast synthesis of type-l collagen, osteoprotegerin, and RANKL. Bone 36(5):812–819
Bord S et al (2004) Synthesis of osteoprotegerin and RANKL by megakaryocytes is modulated by oestrogen. Br J Haematol 126(2):244–251
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
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
Chagraoui H et al (2003) Expression of osteoprotegerin mRNA and protein in murine megakaryocytes. Exp Hematol 31(11):1081–1088
Kacena MA et al (2006) Megakaryocyte-mediated inhibition of osteoclast development. Bone 39(5):991–999
Jiang S et al (1994) Cytokine production by primary bone marrow megakaryocytes. Blood 84(12):4151–4156
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
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
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
Sipe JB et al (2004) Localization of bone morphogenetic proteins (BMPs)-2, -4, and -6 within megakaryocytes and platelets. Bone 35(6):1316–1322
Ciovacco WA et al (2009) The role of gap junctions in megakaryocyte-mediated osteoblast proliferation and differentiation. Bone 44(1):80–86
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
Cheng YH et al (2013) Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation. J Bone Miner Res 28(6):1434–1445
Cheng YH et al (2014) Signaling pathways involved in megakaryocyte-mediated proliferation of osteoblast lineage cells. J Cell Physiol 230(3):578–586
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
Chagraoui H et al (2002) Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. Blood 100(10):3495–3503
Chagraoui H et al (2003) Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO. Blood 101(8):2983–2989
Dominici M et al (2009) Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation. Blood 114(11):2333–2343
Olson TS et al (2013) Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning. Blood 121(26):5238–5249
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
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
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
Naveiras O et al (2009) Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460(7252):259–263
Kato H et al (2006) Adiponectin acts as an endogenous antithrombotic factor. Arterioscler Thromb Vasc Biol 26(1):224–230
Sun S et al (2013) Expression of plasma membrane receptor genes during megakaryocyte development. Physiol Genomics 45(6):217–227
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
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
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
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
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
Rafii S, Mohle R, Shapiro F, Frey BM, Moore MA (1997) Regulation of hematopoiesis by microvascular endothelium. Leuk Lymphoma 27(5–6):375–386
Irie S, Tavassoli M (1986) Purification and characterization of rat bone marrow endothelial cells. Exp Hematol 14(10):912–918
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
Masek LC, Sweetenham JW (1994) Isolation and culture of endothelial cells from human bone marrow. Br J Haematol 88(4):855–865
Delia D et al (1993) CD34 expression is regulated reciprocally with adhesion molecules in vascular endothelial cells in vitro. Blood 81(4):1001–1008
Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G (1998) A common precursor for hematopoietic and endothelial cells. Development 125(4):725–732
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
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
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
Kopp HG et al (2006) Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization. J Clin Invest 116(12):3277–3291
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
Yamazaki S et al (2011) Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147(5):1146–1158
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
Kirouac DC et al (2010) Dynamic interaction networks in a hierarchically organized tissue. Mol Syst Biol 6:417
Zhao M et al (2014) Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med 20(11):1321–1326
Bruns I et al (2014) Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med 20(11):1315–1320
Tew JG et al (1992) Germinal centers and antibody production in bone marrow. Immunol Rev 126:99–112
Kallies A et al (2004) Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med 200(8):967–977
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
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
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
Winter O et al (2010) Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood 116(11):1867–1875
Landoni VI (2004) Macrophage derived signalling regulates negatively the megakaryocyte compartment. Cell Mol Biol (Noisy-le-grand) 50:OL667–OL675
D’Atri LP et al (2011) Paracrine regulation of megakaryo/thrombopoiesis by macrophages. Exp Hematol 39(7):763–772
Clark BR, Keating A (1995) Biology of bone marrow stroma. Ann N Y Acad Sci 770:70–78
Moore KA (2004) Recent advances in defining the hematopoietic stem cell niche. Curr Opin Hematol 11(2):107–111
Coppinger JA, Maguire PB (2007) Insights into the platelet releasate. Curr Pharm Des 13(26):2640–2646
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
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
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
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
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
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
Schachtner H et al (2013) Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane. Blood 121(13):2542–2552
Schick PK, Wojensk CM, Bennett V, Denisova L (1996) Fibronectin isoforms in megakaryocytes. Stem Cells 14(Suppl 1):212–219
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
Bentley SA, Alabaster O, Foidart JM (1981) Collagen heterogeneity in normal human bone marrow. Br J Haematol 48(2):287–291
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
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
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
Bauermeister DE (1971) Quantitation of bone marrow reticulin–a normal range. Am J Clin Pathol 56(1):24–31
Thiele J et al (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90(8):1128–1132
Eliades A et al (2011) Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase. J Biol Chem 286(31):27630–27638
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
Balduini CL, Pecci A, Noris P (2013) Diagnosis and management of inherited thrombocytopenias. Semin Thromb Hemost 39(2):161–171
Balduini CL, Savoia A, Seri M (2013) Inherited thrombocytopenias frequently diagnosed in adults. J Thromb Haemost 11(6):1006–1019
Pecci A et al (2009) Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation. Thromb Haemost 102(1):90–96
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
Balduini A et al (2009) Proplatelet formation in heterozygous Bernard-Soulier syndrome type Bolzano. J Thromb Haemost 7(3):478–484
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
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
Kunishima S et al (2013) ACTN1 mutations cause congenital macrothrombocytopenia. Am J Hum Genet 92(3):431–438
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
Bluteau D et al (2014) Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. J Clin Invest 124(2):580–591
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
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
Nurden AT, Nurden P (2007) The gray platelet syndrome: clinical spectrum of the disease. Blood Rev 21(1):21–36
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
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
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
Malinge S et al (2008) Activating mutations in human acute megakaryoblastic leukemia. Blood 112(10):4220–4226
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
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
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
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
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
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
Barosi G (2014) Essential thrombocythemia vs. early/prefibrotic myelofibrosis: why does it matter. Best Pract Res Clin Haematol 27(2):129–140
Kralovics R et al (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352(17):1779–1790
Baxter EJ et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365(9464):1054–1061
Kaushansky K (2009) Molecular mechanisms of thrombopoietin signaling. J Thromb Haemost 7(Suppl 1):235–238
Hitchcock IS, Kaushansky K (2014) Thrombopoietin from beginning to end. Br J Haematol 165(2):259–268
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
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
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
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
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
Lasho TL, Pardanani A, Tefferi A (2010) LNK mutations in JAK2 mutation-negative erythrocytosis. N Engl J Med 363(12):1189–1190
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
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
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
Velazquez L et al (2002) Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. J Exp Med 195(12):1599–1611
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
Tong W, Lodish HF (2004) Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. J Exp Med 200(5):569–580
Bersenev A et al (2010) Lnk constrains myeloproliferative diseases in mice. J Clin Invest 120(6):2058–2069
Pardanani AD et al (2006) MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108(10):3472–3476
Pikman Y et al (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 3(7):e270
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
Vannucchi AM et al (2008) Characteristics and clinical correlates of MPL 515 W > L/K mutation in essential thrombocythemia. Blood 112(3):844–847
Beer PA et al (2008) MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 112(1):141–149
Guglielmelli P et al (2007) Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. Br J Haematol 137(3):244–247
Chaligné R et al (2007) Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis. Blood 110(10):3735–3743
Li Y et al (1996) Proto-oncogene c-mpl is involved in spontaneous megakaryocytopoiesis in myeloproliferative disorders. Br J Haematol 92(1):60–66
Ulich TR et al (1996) Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice. Blood 87(12):5006–5015
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
Kuter DJ et al (2009) Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood 114(18):3748–3756
Kuter DJ (2009) Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med 60:193–206
Klampfl T et al (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369(25):2379–2390
Nangalia J et al (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369(25):2391–2405
Broséus J, Park JH, Carillo S, Hermouet S, Girodon F (2014) Presence of calreticulin mutations in JAK2-negative polycythemia vera. Blood
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
Di Buduo CA et al (2014) The importance of calcium in the regulation of megakaryocyte function. Haematologica 99(4):769–778
Vannucchi AM et al (2014) Calreticulin mutation-specific immunostaining in myeloproliferative neoplasms: pathogenetic insight and diagnostic value. Leukemia 28(9):1811–1818
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
Ma J, Pan Z (2003) Retrograde activation of store-operated calcium channel. Cell Calcium 33(5–6):375–384
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
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
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
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
Malinge S, Izraeli S, Crispino JD (2009) Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 113(12):2619–2628
Wickrema A, Crispino JD (2007) Erythroid and megakaryocytic transformation. Oncogene 26(47):6803–6815
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
Fröhling S, Scholl C, Gilliland DG, Levine RL (2005) Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol 23(26):6285–6295
Khan I, Malinge S, Crispino J (2011) Myeloid leukemia in Down syndrome. Crit Rev Oncog 16(1–2):25–36
Walters DK et al (2006) Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10(1):65–75
Wechsler J et al (2002) Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32(1):148–152
Li Z et al (2005) Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet 37(6):613–619
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
Shivdasani R (2002) An animal model for myelofibrosis. Blood 100(4):1109
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
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
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
Hoeller S et al (2014) Morphologic and GATA1 sequencing analysis of hematopoiesis in fetuses with trisomy 21. Hum Pathol 45(5):1003–1009
Stankiewicz MJ, Crispino JD (2013) AKT collaborates with ERG and Gata1 s to dysregulate megakaryopoiesis and promote AMKL. Leukemia 27(6):1339–1347
Balduini A et al (2012) Constitutively released adenosine diphosphate regulates proplatelet formation by human megakaryocytes. Haematologica 97(11):1657–1665
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
Bonner JC (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 15(4):255–273
Pohlers D et al (2009) TGF-beta and fibrosis in different organs-molecular pathway imprints. Biochim Biophys Acta 1792(8):746–756
Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342(18):1350–1358
Zingariello M et al (2013) Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis. Blood 121(17):3345–3363
Ciurea SO et al (2007) Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. Blood 110(3):986–993
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
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
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
Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79(4):1283–1316
Biernacka A, Dobaczewski M, Frangogiannis NG (2011) TGF-β signaling in fibrosis. Growth Factors 29(5):196–202
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
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
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
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
Janssens K, ten Dijke P, Janssens S, Van Hul W (2005) Transforming growth factor-beta1 to the bone. Endocr Rev 26(6):743–774
Yang M, Chesterman CN, Chong BH (1995) Recombinant PDGF enhances megakaryocytopoiesis in vitro. Br J Haematol 91(2):285–289
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
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
Malara A et al (2011) Megakaryocyte-matrix interaction within bone marrow: new roles for fibronectin and factor XIII-A. Blood 117(8):2476–2483
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
Chang Y et al (2007) Proplatelet formation is regulated by the Rho/ROCK pathway. Blood 109(10):4229–4236
Malara A et al (2011) Extracellular matrix structure and nano-mechanics determine megakaryocyte function. Blood 118(16):4449–4453
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
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
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
Omenetto FG, Kaplan DL (2010) New opportunities for an ancient material. Science 329(5991):528–531
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
Matsunaga T et al (2006) Ex vivo large-scale generation of human platelets from cord blood CD34 + cells. Stem Cells 24(12):2877–2887
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
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
Torisawa YS et al (2014) Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. Nat Methods 11(6):663–669
Thon JN et al (2014) Platelet bioreactor-on-a-chip. Blood [Epub ahead of print]
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).
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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
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DOI: https://doi.org/10.1007/s00018-014-1813-y