Semin Thromb Hemost 2016; 42(03): 215-222
DOI: 10.1055/s-0035-1570077
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

MicroRNAs in Platelet Physiology and Function

Cory R. Lindsay
1   The Cardeza Foundation for Hematologic Research and the Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
,
Leonard C. Edelstein
1   The Cardeza Foundation for Hematologic Research and the Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
› Author Affiliations
Further Information

Publication History

Publication Date:
07 March 2016 (online)

Abstract

Platelets are anucleate blood cells that are best known for their role in hemostasis and thrombosis. Perhaps due to the necessity of maintaining a proteome over an 8- to 9-day lifespan or the need to adapt to environmental situations, platelets retain many of the RNA metabolic processes of nucleated cells such as the ability to splice, translate, and regulate RNA levels through posttranscriptional mechanisms. In fact, in the absence of transcription, the dependence on posttranscriptional mechanisms to regulate gene expression may have resulted in microRNAs (miRNAs) making up a greater proportion of the platelet transcriptome than observed in other cells. miRNAs are ∼22 nucleotide RNA molecules that regulate gene expression through messenger RNA (mRNA) degradation or inhibition of translation. miRNAs regulate differentiation of the platelet precursor, the megakaryocyte. Identification of miRNA:mRNA pairs that are associated with platelet phenotypes has led to the discovery of novel regulators of platelet function in healthy and diseased subjects. Circulating miRNAs may originate from platelets and can serve as biomarkers for platelet function. Platelet microparticles have been demonstrated to have the ability to deliver miRNAs of extracellular targets and alter gene expression in those targets. This review summarizes the current state of knowledge of miRNAs in megakaryocytes, platelets, and platelet microparticles.

 
  • References

  • 1 Hangauer MJ, Vaughn IW, McManus MT. Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. PLoS Genet 2013; 9 (6) e1003569
  • 2 Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones. Cell 2014; 157 (1) 77-94
  • 3 Bray PF, McKenzie SE, Edelstein LC , et al. The complex transcriptional landscape of the anucleate human platelet. BMC Genomics 2013; 14: 1
  • 4 Teruel-Montoya R, Kong X, Abraham S , et al. MicroRNA expression differences in human hematopoietic cell lineages enable regulated transgene expression. PLoS ONE 2014; 9 (7) e102259
  • 5 Weyrich AS, Dixon DA, Pabla R , et al. Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets. Proc Natl Acad Sci USA 1998; 95 (10) 5556-5561
  • 6 Denis MM, Tolley ND, Bunting M , et al. Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 2005; 122 (3) 379-391
  • 7 Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol 2009; 16 (9) 961-966
  • 8 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116 (2) 281-297
  • 9 Londin E, Loher P, Telonis AG , et al. Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc Natl Acad Sci USA 2015; 112 (10) E1106-E1115
  • 10 Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19 (1) 92-105
  • 11 Wienholds E, Kloosterman WP, Miska E , et al. MicroRNA expression in zebrafish embryonic development. Science 2005; 309 (5732) 310-311
  • 12 Chen C, Ridzon DA, Broomer AJ , et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 2005; 33 (20) e179
  • 13 Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010; 11 (9) 597-610
  • 14 Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 2010; 466 (7308) 835-840
  • 15 Bazzini AA, Lee MT, Giraldez AJ. Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish. Science 2012; 336 (6078) 233-237
  • 16 Djuranovic S, Nahvi A, Green R. miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science 2012; 336 (6078) 237-240
  • 17 Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature 2008; 455 (7209) 58-63
  • 18 Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature 2008; 455 (7209) 64-71
  • 19 Schmiedel JM, Klemm SL, Zheng Y , et al. Gene expression. MicroRNA control of protein expression noise. Science 2015; 348 (6230) 128-132
  • 20 Alimonti A, Carracedo A, Clohessy JG , et al. Subtle variations in Pten dose determine cancer susceptibility. Nat Genet 2010; 42 (5) 454-458
  • 21 Rigoutsos I, Tsirigos A. MicroRNA target prediction. In: Slack FJ, , ed. MicroRNAs in Development and Cancer. Hackensack, NJ: Imperial College Press; 2011: 237-264
  • 22 Loeb GB, Khan AA, Canner D , et al. Transcriptome-wide miR-155 binding map reveals widespread noncanonical microRNA targeting. Mol Cell 2012; 48 (5) 760-770
  • 23 Edelstein LC, McKenzie SE, Shaw C, Holinstat MA, Kunapuli SP, Bray PF. MicroRNAs in platelet production and activation. J Thromb Haemost 2013; 11 (Suppl. 01) 340-350
  • 24 Edelstein LC, Bray PF. Small RNAs as potential platelet therapeutics. Handb Exp Pharmacol 2012; (210) 435-445
  • 25 Edelstein LC, Bray PF. MicroRNAs in platelet production and activation. Blood 2011; 117 (20) 5289-5296
  • 26 Zhai PF, Wang F, Su R , et al. The regulatory roles of microRNA-146b-5p and its target platelet-derived growth factor receptor α (PDGFRA) in erythropoiesis and megakaryocytopoiesis. J Biol Chem 2014; 289 (33) 22600-22613
  • 27 Kamat V, Paluru P, Myint M, French DL, Gadue P, Diamond SL. MicroRNA screen of human embryonic stem cell differentiation reveals miR-105 as an enhancer of megakaryopoiesis from adult CD34+ cells. Stem Cells 2014; 32 (5) 1337-1346
  • 28 Chapnik E, Rivkin N, Mildner A , et al. miR-142 orchestrates a network of actin cytoskeleton regulators during megakaryopoiesis. eLife 2014; 3: e01964
  • 29 Metcalf D, Carpinelli MR, Hyland C , et al. Anomalous megakaryocytopoiesis in mice with mutations in the c-Myb gene. Blood 2005; 105 (9) 3480-3487
  • 30 Bianchi E, Bulgarelli J, Ruberti S , et al. MYB controls erythroid versus megakaryocyte lineage fate decision through the miR-486-3p-mediated downregulation of MAF. Cell Death Differ 2015; 22 (12) 1906-1921
  • 31 Sportoletti P, Varasano E, Rossi R , et al. The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model. Blood 2013; 121 (17) 3447-3458
  • 32 Garzon R, Pichiorri F, Palumbo T , et al. MicroRNA fingerprints during human megakaryocytopoiesis. Proc Natl Acad Sci USA 2015; 22 (12) 1906-1921
  • 33 Wang Y, Huang R, Song C, Hu H, Zhang M. Some viral microRNAs were up-regulated in megakaryocytes incubated with immune thrombocytopenia plasma. Eur J Haematol 2013; 90 (3) 220-227
  • 34 Norfo R, Zini R, Pennucci V , et al; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. miRNA-mRNA integrative analysis in primary myelofibrosis CD34+ cells: role of miR-155/JARID2 axis in abnormal megakaryopoiesis. Blood 2014; 124 (13) e21-e32
  • 35 Warshaw AL, Laster L, Shulman NR. The stimulation by thrombin of glucose oxidation in human platelets. J Clin Invest 1966; 45 (12) 1923-1934
  • 36 Weyrich AS, Schwertz H, Kraiss LW, Zimmerman GA. Protein synthesis by platelets: historical and new perspectives. J Thromb Haemost 2009; 7 (2) 241-246
  • 37 Thon JN, Devine DV. Translation of glycoprotein IIIa in stored blood platelets. Transfusion 2007; 47 (12) 2260-2270
  • 38 Corduan A, Plé H, Laffont B , et al. Dissociation of SERPINE1 mRNA from the translational repressor proteins Ago2 and TIA-1 upon platelet activation. Thromb Haemost 2015; 113 (5) 1046-1059
  • 39 Londin ER, Hatzimichael E, Loher P , et al. The human platelet: strong transcriptome correlations among individuals associate weakly with the platelet proteome. Biol Direct 2014; 9: 3
  • 40 Edelstein LC, Simon LM, Montoya RT , et al. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med 2013; 19 (12) 1609-1616
  • 41 Simon LM, Edelstein LC, Nagalla S , et al. Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics. Blood 2014; 123 (16) e37-e45
  • 42 Kondkar AA, Bray MS, Leal SM , et al. VAMP8/endobrevin is overexpressed in hyperreactive human platelets: suggested role for platelet microRNA. J Thromb Haemost 2010; 8 (2) 369-378
  • 43 Nagalla S, Shaw C, Kong X , et al. Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood 2011; 117 (19) 5189-5197
  • 44 Mozaffarian D, Benjamin EJ, Go AS , et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 2015; 131 (4) e29-e322
  • 45 Thomas KL, Honeycutt E, Shaw LK, Peterson ED. Racial differences in long-term survival among patients with coronary artery disease. Am Heart J 2010; 160 (4) 744-751
  • 46 Bruchova H, Merkerova M, Prchal JT. Aberrant expression of microRNA in polycythemia vera. Haematologica 2008; 93 (7) 1009-1016
  • 47 Xu X, Gnatenko DV, Ju J , et al. Systematic analysis of microRNA fingerprints in thrombocythemic platelets using integrated platforms. Blood 2012; 120 (17) 3575-3585
  • 48 Elgheznawy A, Shi L, Hu J , et al. Dicer cleavage by calpain determines platelet microRNA levels and function in diabetes. Circ Res 2015; 117 (2) 157-165
  • 49 Stratz C, Nührenberg T, Fiebich BL , et al. Controlled type II diabetes mellitus has no major influence on platelet micro-RNA expression. Results from micro-array profiling in a cohort of 60 patients. Thromb Haemost 2014; 111 (5) 902-911
  • 50 Leierseder S, Petzold T, Zhang L, Loyer X, Massberg S, Engelhardt S. MiR-223 is dispensable for platelet production and function in mice. Thromb Haemost 2013; 110 (6) 1207-1214
  • 51 Shi R, Ge L, Zhou X , et al. Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity. Thromb Res 2013; 131 (6) 508-513
  • 52 Shrivastava M. The platelet storage lesion. Transfus Apheresis Sci 2009; 41 (2) 105-113
  • 53 Osman A, Hitzler WE, Meyer CU , et al. Effects of pathogen reduction systems on platelet microRNAs, mRNAs, activation, and function. Platelets 2015; 26 (2) 154-163
  • 54 Yu S, Deng G, Qian D , et al. Detection of apoptosis-associated microRNA in human apheresis platelets during storage by quantitative real-time polymerase chain reaction analysis. Blood Transfus 2014; 12 (4) 541-547
  • 55 Yu S, Huang H, Deng G , et al. miR-326 targets antiapoptotic Bcl-xL and mediates apoptosis in human platelets. PLoS ONE 2015; 10 (4) e0122784
  • 56 Pontes TB, Moreira-Nunes CdeF, Maués JH , et al. The miRNA profile of platelets stored in a blood bank and its relation to cellular damage from storage. PLoS ONE 2015; 10 (6) e0129399
  • 57 Kai ZS, Pasquinelli AE. MicroRNA assassins: factors that regulate the disappearance of miRNAs. Nat Struct Mol Biol 2010; 17 (1) 5-10
  • 58 Schöler N, Langer C, Döhner H, Buske C, Kuchenbauer F. Serum microRNAs as a novel class of biomarkers: a comprehensive review of the literature. Exp Hematol 2010; 38 (12) 1126-1130
  • 59 Lu J, Guo S, Ebert BL , et al. MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Dev Cell 2008; 14 (6) 843-853
  • 60 Creemers EE, Tijsen AJ, Pinto YM. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease?. Circ Res 2012; 110 (3) 483-495
  • 61 Berckmans RJ, Nieuwland R, Böing AN, Romijn FP, Hack CE, Sturk A. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 2001; 85 (4) 639-646
  • 62 Badrnya S, Baumgartner R, Assinger A. Smoking alters circulating plasma microvesicle pattern and microRNA signatures. Thromb Haemost 2014; 112 (1) 128-136
  • 63 Duan X, Zhan Q, Song B , et al. Detection of platelet microRNA expression in patients with diabetes mellitus with or without ischemic stroke. J Diabetes Complications 2014; 28 (5) 705-710
  • 64 Zampetaki A, Willeit P, Tilling L , et al. Prospective study on circulating MicroRNAs and risk of myocardial infarction. J Am Coll Cardiol 2012; 60 (4) 290-299
  • 65 Williams Z, Ben-Dov IZ, Elias R , et al. Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. Proc Natl Acad Sci USA 2013; 110 (11) 4255-4260
  • 66 Willeit P, Zampetaki A, Dudek K , et al. Circulating microRNAs as novel biomarkers for platelet activation. Circ Res 2013; 112 (4) 595-600
  • 67 Zhang Y-Y, Zhou X, Ji W-J , et al. Decreased circulating microRNA-223 level predicts high on-treatment platelet reactivity in patients with troponin-negative non-ST elevation acute coronary syndrome. J Thromb Thrombolysis 2014; 38 (1) 65-72
  • 68 Chyrchel B, Toton-Zuranska J, Kruszelnicka O , et al. Association of plasma miR-223 and platelet reactivity in patients with coronary artery disease on dual antiplatelet therapy: A preliminary report. Platelets 2015; 26 (6) 593-597
  • 69 de Boer HC, van Solingen C, Prins J , et al. Aspirin treatment hampers the use of plasma microRNA-126 as a biomarker for the progression of vascular disease. Eur Heart J 2013; 34 (44) 3451-3457
  • 70 Italiano Jr JE, Mairuhu AT, Flaumenhaft R. Clinical relevance of microparticles from platelets and megakaryocytes. Curr Opin Hematol 2010; 17 (6) 578-584
  • 71 Hunter MP, Ismail N, Zhang X , et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS ONE 2008; 3 (11) e3694
  • 72 Yuan A, Farber EL, Rapoport AL , et al. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS ONE 2009; 4 (3) e4722
  • 73 Risitano A, Beaulieu LM, Vitseva O, Freedman JE. Platelets and platelet-like particles mediate intercellular RNA transfer. Blood 2012; 119 (26) 6288-6295
  • 74 Gidlöf O, van der Brug M, Ohman J , et al. Platelets activated during myocardial infarction release functional miRNA, which can be taken up by endothelial cells and regulate ICAM1 expression. Blood 2013; 121 (19) 3908-3917 , S1–S26
  • 75 Laffont B, Corduan A, Plé H , et al. Activated platelets can deliver mRNA regulatory Ago2•microRNA complexes to endothelial cells via microparticles. Blood 2013; 122 (2) 253-261
  • 76 Pan Y, Liang H, Liu H , et al. Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via targeting the insulin-like growth factor 1 receptor. J Immunol 2014; 192 (1) 437-446
  • 77 Duchez AC, Boudreau LH, Bollinger J , et al. Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA. Proc Natl Acad Sci USA 2015; 112 (27) E3564-E3573
  • 78 Shan Z, Qin S, Li W , et al. An endocrine genetic signal between blood cells and vascular smooth muscle cells: role of microRNA-223 in smooth muscle function and atherogenesis. J Am Coll Cardiol 2015; 65 (23) 2526-2537
  • 79 Brogren H, Karlsson L, Andersson M, Wang L, Erlinge D, Jern S. Platelets synthesize large amounts of active plasminogen activator inhibitor 1. Blood 2004; 104 (13) 3943-3948
  • 80 Savini I, Catani MV, Arnone R , et al. Translational control of the ascorbic acid transporter SVCT2 in human platelets. Free Radic Biol Med 2007; 42 (5) 608-616
  • 81 Evangelista V, Manarini S, Di Santo A , et al. De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin. Circ Res 2006; 98 (5) 593-595
  • 82 Schubert S, Weyrich AS, Rowley JW. A tour through the transcriptional landscape of platelets. Blood 2014; 124 (4) 493-502