Unraveling Mechanisms that Control Platelet Production

Abstract

Platelets are formed by giant precursor cells called megakaryocytes that reside within the bone marrow. The generation of platelets, and their release into the bloodstream by megakaryocytes, requires a complex series of remodeling events powered by the cytoskeleton to result in the release of many platelets from a single megakaryocyte. Abnormalities in this process can result in thrombocytopenia (low platelet count) and can lead to increased risk of bleeding. This review describes the process of platelet production in detail and discusses new insights into novel platelet biology.

Keywords

megakaryocyte - platelet - proplatelet - thrombopoiesis - cytoskeleton

• References

• 1 Hartwig JH, DeSisto M. The cytoskeleton of the resting human blood platelet: structure of the membrane skeleton and its attachment to actin filaments. J Cell Biol 1991; 112 (3) 407-425
• 2 White JG. Effects of colchicine and vinca alkaloids on human platelets. I. Influence on platelet microtubules and contractile function. Am J Pathol 1968; 53 (2) 281-291
• 3 Schwer HD, Lecine P, Tiwari S, Italiano Jr JE, Hartwig JH, Shivdasani RA. A lineage-restricted and divergent beta-tubulin isoform is essential for the biogenesis, structure and function of blood platelets. Curr Biol 2001; 11 (8) 579-586
• 4 Nakamura F, Pudas R, Heikkinen O , et al. The structure of the GPIb-filamin A complex. Blood 2006; 107 (5) 1925-1932
• 5 Andrews RK, Fox JE. Identification of a region in the cytoplasmic domain of the platelet membrane glycoprotein Ib-IX complex that binds to purified actin-binding protein. J Biol Chem 1992; 267 (26) 18605-18611
• 6 López JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier syndrome. Blood 1998; 91 (12) 4397-4418
• 7 Ware J, Russell S, Ruggeri ZM. Generation and rescue of a murine model of platelet dysfunction: the Bernard-Soulier syndrome. Proc Natl Acad Sci USA 2000; 97 (6) 2803-2808
• 8 Kaushansky K, Drachman JG. The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production. Oncogene 2002; 21 (21) 3359-3367
• 9 Becker RP, De Bruyn PP. 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 1976; 145 (2) 183-205
• 10 Radley J. Ultrastructural aspects of platelet production. Megakaryocyte development and function. Prog Clin Biol Res 1986; 215: 387-398
• 11 Choi ES, Nichol JL, Hokom MM, Hornkohl AC, Hunt P. Platelets generated in vitro from proplatelet-displaying human megakaryocytes are functional. Blood 1995; 85 (2) 402-413
• 12 Shivdasani RA, Rosenblatt MF, Zucker-Franklin D , et al. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 1995; 81 (5) 695-704
• 13 Zucker-Franklin D, Petursson S. Thrombocytopoiesis—analysis by membrane tracer and freeze-fracture studies on fresh human and cultured mouse megakaryocytes. J Cell Biol 1984; 99 (2) 390-402
• 14 Radley JM, Haller CJ. The demarcation membrane system of the megakaryocyte: a misnomer?. Blood 1982; 60 (1) 213-219
• 15 Schulze H, Korpal M, Hurov J , et al. Characterization of the megakaryocyte demarcation membrane system and its role in thrombopoiesis. Blood 2006; 107 (10) 3868-3875
• 16 Yamada E. The fine structure of the megakaryocyte in the mouse spleen. Acta Anat (Basel) 1957; 29 (3) 267-290
• 17 Cramer EM, Norol F, Guichard J , et al. Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand. Blood 1997; 89 (7) 2336-2346
• 18 Italiano Jr JE, Lecine P, Shivdasani RA, Hartwig JH. Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes. J Cell Biol 1999; 147 (6) 1299-1312
• 19 Tablin F, Castro M, Leven RM. Blood platelet formation in vitro. The role of the cytoskeleton in megakaryocyte fragmentation. J Cell Sci 1990; 97 (Pt 1) 59-70
• 20 Patel SR, Richardson JL, Schulze H , et al. Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes. Blood 2005; 106 (13) 4076-4085
• 21 Richardson JL, Shivdasani RA, Boers C, Hartwig JH, Italiano Jr JE. Mechanisms of organelle transport and capture along proplatelets during platelet production. Blood 2005; 106 (13) 4066-4075
• 22 Patel-Hett S, Wang H, Begonja AJ , et al. The spectrin-based membrane skeleton stabilizes mouse megakaryocyte membrane systems and is essential for proplatelet and platelet formation. Blood 2011; 118 (6) 1641-1652
• 23 Junt T, Schulze H, Chen Z , et al. Dynamic visualization of thrombopoiesis within bone marrow. Science 2007; 317 (5845) 1767-1770
• 24 Thon JN, Montalvo A, Patel-Hett S , et al. Cytoskeletal mechanics of proplatelet maturation and platelet release. J Cell Biol 2010; 191 (4) 861-874
• 25 Thon JN, Macleod H, Begonja AJ , et al. Microtubule and cortical forces determine platelet size during vascular platelet production. Nat Commun 2012; 3: 852
• 26 Schwertz H, Köster S, Kahr WH , et al. Anucleate platelets generate progeny. Blood 2010; 115 (18) 3801-3809
• 27 Kaushansky K, Lok S, Holly RD , et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature 1994; 369 (6481) 568-571
• 28 Lu SJ, Li F, Yin H , et al. Platelets generated from human embryonic stem cells are functional in vitro and in the microcirculation of living mice. Cell Res 2011; 21 (3) 530-545
• 29 Takayama N, Nishimura S, Nakamura S , et al. Transient activation of c-MYC expression is critical for efficient platelet generation from human induced pluripotent stem cells. J Exp Med 2010; 207 (13) 2817-2830
• 30 Sullenbarger B, Bahng JH, Gruner R, Kotov N, Lasky LC. Prolonged continuous in vitro human platelet production using three-dimensional scaffolds. Exp Hematol 2009; 37 (1) 101-110
• 31 Lasky LC, Sullenbarger B. Manipulation of oxygenation and flow-induced shear stress can increase the in vitro yield of platelets from cord blood. Tissue Eng Part C Methods 2011; 17 (11) 1081-1088
• 32 Pallotta I, Lovett M, Kaplan DL, Balduini A. Three-dimensional system for the in vitro study of megakaryocytes and functional platelet production using silk-based vascular tubes. Tissue Eng Part C Methods 2011; 17 (12) 1223-1232
• 33 Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science 2010; 328 (5978) 562-564
• 34 Pinedo HM, Verheul HM, D'Amato RJ, Folkman J. Involvement of platelets in tumour angiogenesis?. Lancet 1998; 352 (9142) 1775-1777
• 35 Verheul HM, Hoekman K, Luykx-de Bakker S , et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1997; 3 (12 Pt 1) 2187-2190
• 36 Gimbrone Jr MA, Aster RH, Cotran RS, Corkery J, Jandl JH, Folkman J. Preservation of vascular integrity in organs perfused in vitro with a platelet-rich medium. Nature 1969; 222 (5188) 33-36
• 37 Möhle R, Green D, Moore MA, Nachman RL, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 1997; 94 (2) 663-668
• 38 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis. J Biol Chem 2000; 275 (3) 1521-1524
• 39 Klement GL, Yip TT, Cassiola F , et al. Platelets actively sequester angiogenesis regulators. Blood 2009; 113 (12) 2835-2842
• 40 Cervi D, Yip TT, Bhattacharya N , et al. Platelet-associated PF-4 as a biomarker of early tumor growth. Blood 2008; 111 (3) 1201-1207
• 41 Italiano Jr JE, Richardson JL, Patel-Hett S , et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111 (3) 1227-1233
• 42 Ma L, Perini R, McKnight W , et al. Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc Natl Acad Sci USA 2005; 102 (1) 216-220
• 43 Battinelli EM, Markens BA, Italiano Jr JE. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood 2011; 118 (5) 1359-1369
• 44 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11 (4) 264-274
• 45 Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P. Platelets express functional toll-like receptor-4. Blood 2005; 106 (7) 2417-2423
• 46 Aslam R, Speck ER, Kim M , et al. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 2006; 107 (2) 637-641
• 47 Clark SR, Ma AC, Tavener SA , et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13 (4) 463-469
• 48 Thon JN, Peters CG, Machlus KR , et al. T granules in human platelets function in TLR9 organization and signaling. J Cell Biol 2012; 198 (4) 561-574