Review Article
Placenta-Derived Exosomes and Syncytiotrophoblast Microparticles and their Role in Human Reproduction: Immune Modulation for Pregnancy Success
Lucia Mincheva-Nilsson,
Vladimir Baranov,
Corresponding Author
Lucia Mincheva-Nilsson
Department of Clinical Microbiology, Division of Clinical Immunology, Umeå University, Umeå, Sweden
Correspondence
Lucia Mincheva-Nilsson, Department of Clinical Microbiology, Division of Clinical Immunology, Umeå University, S-90185 Umeå, Sweden.
E-mail: [email protected]
Search for more papers by this authorVladimir Baranov
Department of Clinical Microbiology, Division of Clinical Immunology, Umeå University, Umeå, Sweden
Search for more papers by this authorLucia Mincheva-Nilsson,
Vladimir Baranov,
Corresponding Author
Lucia Mincheva-Nilsson
Department of Clinical Microbiology, Division of Clinical Immunology, Umeå University, Umeå, Sweden
Correspondence
Lucia Mincheva-Nilsson, Department of Clinical Microbiology, Division of Clinical Immunology, Umeå University, S-90185 Umeå, Sweden.
E-mail: [email protected]
Search for more papers by this authorVladimir Baranov
Department of Clinical Microbiology, Division of Clinical Immunology, Umeå University, Umeå, Sweden
Search for more papers by this authorAbstract
The syncytiotrophoblast (STB) of human placenta constitutively produces and secretes extracellular vesicles of different size, morphology and function that enter the maternal circulation, and participate in the maternal–fetal cross-talk during pregnancy. Syncytiotrophoblast-derived microvesicles/microparticles (STBM) are larger microvesicles (0.2–2 μm) shed by the apical plasma membrane of the STB as a result of cell activation and turnover. Simultaneously with the STBM shedding, the STB produces and secretes exosomes – nanosized (30–100/150 nm) membrane-bound microvesicles that originate from the endosomal compartment. They convey cell–cell contact ‘by proxy’ transporting signals/packages of information between donor and recipient cells locally or/and at a distance. STBM and exosomes, delivered directly in the maternal blood surrounding the chorionic villi of the placenta, have contrasting biological functions. While the exosomes are immunosuppressive down regulating maternal immunity in pluripotent ways, the main effects of STBM on the maternal immune system are pro-inflammatory, immune activating, and pro-coagulant. Since both STBM and exosomes are present in the maternal circulation throughout normal pregnancy logical questions are what is the net effect of these vesicles on the maternal immune system and is this effect beneficial or detrimental to pregnancy. In this review, the current knowledge about placenta-derived extracellular vesicles with a main focus on exosomes is summarized and discussed. In a concluding remark, a hypothetical proposal on how STBM and exosomes might interact in pregnancy is discussed and a way to evaluate this interaction is suggested.
References
- 1Mincheva-Nilsson L: Immune cells and molecules in pregnancy: friends or foes to the fetus? Expert Rev Clin Immunol 2006; 2: 447–460.
10.1586/1744666X.2.3.457 Google Scholar
- 2Abrahams VM, Straszewski-Chavez SL, Guller S, Mor G: First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol Hum Reprod 2004; 10: 55–63.
- 3Frängsmyr L, Baranov V, Nagaeva O, Stendahl U, Kjellberg L, Mincheva-Nilsson L: Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level. Mol Hum Reprod 2005; 11: 35–41.
- 4Taylor DD, Akyol S, Gercel-Taylor C: Pregnancy-associated exosomes and their modulation of T cell signaling. J Immunol 2006; 176: 1534–1542.
- 5Sabapatha A, Gercel-Taylor C, Taylor DD: Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences. Am J Reprod Immunol 2006; 56: 345–355.
- 6Mincheva-Nilsson L, Nagaeva O, Chen T, Stendahl U, Antsiferova J, Mogren I, Hernestål J, Baranov V: Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: a possible novel immune escape mechanism for fetal survival. J Immunol 2006; 176: 3585–3592.
- 7Hedlund M, Stenqvist A-C, Nagaeva O, Kjellberg L, Wulff M, Baranov V, Mincheva-Nilsson L: Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function. J Immunol 2009; 183: 340–351.
- 8Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L: Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells suggesting exosome-mediated immune privilege of the fetus. J Immunol 2013; 191: 5515–5523.
- 9Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ: Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2006; 20: 847–856.
- 10Rechavi O, Goldstein I, Kloog Y: Intercellular exchange of proteins: the immune cell habit of sharing. FEBS Lett 2009; 583: 1792–1799.
- 11Vlassov A, Magdaleno S, Setterquist R, Conrad R: Exosomes: current knowledge of their composition, biological functions and diagnostic potentials. Biochim Biophys Acta 2012; 1820: 940–948.
- 12Cocucci E, Racchetti G, Meldolesi J: Shedding microvesicles: artefacts no more. Trends Cell Biol 2009; 19: 43–51.
- 13Simak J, Gelderman MP: Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers. Transfus Med Rev 2006; 20: 1–26.
- 14Keller S, Sanderson MP, Stoek A, Altevogt P: Exosomes: from biogenesis to biological function. Immunol Lett 2006; 107: 102–108.
- 15Thery C, Ostrowski M, Segura E: Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009; 9: 581–593.
- 16Witwer KW, Buzas EI, Bemis LT, Bora A, Lässer C, Lötvall J, Nolte-'tHoen EN, Piper M, Sivaraman S, Skog J, Thery C, Wauben MH, Hochberg F: Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles 2013; 2: 20360.
- 17Lakkaraju A, Rodriguez-Boulan E: Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol 2008; 18: 199–209.
- 18Diamant M, Nieuwland R, Pablo RF, Sturk A, Smit JW, Radder JK: Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106: 2442–2447.
- 19Willekens FL, Were JM, Roerdinkholder-Stoelwinder B, Groenen-Döpp YA, van den Bos AG, Bosman GJ, van Berkel TJ: Liver Kuppfer cells rapidly remove red blood cell derived vesicles from the circulation by scavenger receptors. Blood 2005; 105: 2141–2145.
- 20Mincheva-Nilsson L, Baranov V: The role of placental exosomes in reproduction. Am J Reprod Immunol 2010; 63: 520–533.
- 21Mincheva-Nilsson L: Placental exosome-mediated immune protection of the fetus: feeling groovy in a cloud of exosomes. Exp Rev Obstet Gynecol 2010; 5: 619–634.
- 22Babst M: A protein's final ESCRT. Traffic 2005; 6: 2–9.
- 23Babst M: A close-up of the ESCRTs. Dev Cell 2006; 10: 547–548.
- 24Hurley JH: ESCRT complexes and the biogenesis of multivesicular bodies. Curr Opin Cell Biol 2008; 20: 4–11.
- 25Williams RL, Urbé S: The emerging shape of the ESCRT machinery. Nat Rev Mol Cell Biol 2007; 8: 355–368.
- 26Baletti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Verneiren E, Zimmermann P, David G: Syndecan-cyntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol 2012; 14: 667–685.
- 27Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF, Thery C: Rab27a and Rab 27b control different steps of the exosome secretion pathway. Nat Cell Biol 2010; 12: 19–30. Supp. 1–13.
- 28Amzallag N, Passer BJ, Allanic D, Segura E, Thery C, Goud B, Amson R, Telerman A: TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a non-classical pathway. J Biol Chem 2004; 279: 46104–46112.
- 29Savina A, Fader CM, Vidal M, Damiani MT, Colombo MI: Rab 11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic 2005; 6: 131–143.
- 30Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brügger B, Simons M: Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 2008; 319: 1244–1247.
- 31Simpson RJ, Jensen SS, Lim JWE: Proteomic profiling of exosomes: current perspectives. Proteomics 2008; 8: 4083–4099.
- 32Batista BS, Eng WS, Pilobello KT, Hendricks-Muñoz KD, Mahal LK: Identification of a conserved glycan signature for microvesicles. J Proteome Res 2011; 10: 4624–4633.
- 33Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S: Identification of Tim4 as a phospatidylserine receptor. Nature 2007; 450: 435–439.
- 34Matsua H, Chevallier J, Mayran N, Le Blanc I, Ferguson C, Fauré J, Blanc NS, Matile S, Dubochet J, Sadoul R, Parton RG, Vilbois F, Gruenberg J: Role of LBPA and Alix in multivesicular liposome formation and endosomal organization. Science 2004; 303: 531–534.
- 35Denzer K, Kleijmeer MJ, Heijnen HFG, Stoorvogel W, Geuze HJ: Exosome: from internal vesicle of the multivesicular body to intercellular signalling device. J Cell Sci 2000; 113: 3365–3374.
- 36Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO: Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9: 654–659.
- 37Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakfield XO: Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008; 10: 1470–1476.
- 38Mignot G, Roux S, Thery C, Ségura E, Zitvogel L: Prospects for exosomes in immunotherapy of cancer. J Cell Mol Med 2006; 10: 376–388.
- 39Maguire CA, Balaj L, Sivaraman S, Commentuijn MH, Ericsson M, Mincheva-Nilsson L, Baranov V, Gianni D, Tannous BA, Sena-Esteves M, Breakefield XO, Skog J: Microvesicle associated AAV vector as a novel gene delivery system. Mol Ther 2012; 20: 960–971.
- 40Mincheva-Nilsson L, Nagaeva O, Sundqvist KG, Hammarström ML, Hammarström S, Baranov V: γδT cells of human early pregnancy decidua: evidence for cytotoxic potency. Int Immunol 2000; 12: 585–596.
- 41Martinez-Lorenzo MJ, Anel A, Gamen S, Monleon I, Lasierra P, Larrad L, Pineiro A, Alava MA, Naval J: Activated human T cells release bioactive Fas Ligand and APO2 ligand in microvesicles. J Immunol 1999; 163: 1274–1281.
- 42Karlsson M, Lundin S, Dahlgren O, Kahu H, Petersson I, Telemo E: “Tolerosomes” are produced by intestinal epithelial cells. Eur J Immunol 2001; 31: 2892–2900.
10.1002/1521-4141(2001010)31:10<2892::AID-IMMU2892>3.0.CO;2-I CAS PubMed Web of Science® Google Scholar
- 43Clayton A, Mitchel JP, Court J, Mason MD, Tabi Z: Human tumor derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 2007; 67: 7458–7466.
- 44Altevogt P, Brets NP, Ridinger J, Utikal J, Umansky V: Novel insights inro exoso,e-induced tumor-associated inflammation and immunomodulatyion. Semin Cancer Biol 2014; doi:10.1016/j.semcancer.2014.04.008 [Epub ahead of print].
- 45Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L: Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 2007; 67: 2912–2915.
- 46Iero M, Valenti R, Huber V, Fillipazzi P, Parmiani G, Fais S, Rivoltini L: Tumor-released exosomes and their implications in cancer immunity. Cell Death Differ 2008; 15: 80–88.
- 47Mincheva-Nilsson L, Baranov V: Cancer exosomes and NKG2D receptor-ligand interactions: impairing NLG2D mediated cytotoxicity and anti-tumor immune surveillance. Semin Cancer Biol 2014. doi: 10.1016/j.semcancer.2014.02.010 [Epub ahead of print].
- 48Blackburn DG, Taylor JM, Padykula HA: Trophoblast concept as applied to therian mammals. J Morphol 1988; 196: 127–136.
- 49Fuchs R, Ellinger I: Endocytic and transcytic processes in villous: role in nutrient transport to the human fetus. Traffic 2004; 5: 725–738.
- 50Enders AC: Formation of syncytium from cytotrophoblast in the human placenta. Obstet Gynecol 1965; 25: 378–386.
- 51Ramsey EM: What we have learned about placental circulation. J Reprod Med 1985; 30: 312–317.
- 52Culler S: Role of the syncytium in placenta-mediated complications of preeclampsia. Thromb Res 2009; 123: 389–392.
- 53Tooth B, Lok CAR, Böing A, Diamant M, van der Post JAM, Friese K, Nieuwland R: Microparticles and exosomes: impact on normal and complicated pregnancy. Am J Reprod Immunol 2007; 58: 389–402.
- 54Redman CWG, Sargent IL: Microparticles and immunomodulation in pregnancy and pre-eclampsia. J Reprod Immunol 2007; 76: 61–67.
- 55Yano Y, Shiba E, Kambayashi J, Sakon M, Kawasaki T, Fujitani K, Kang J, Mori T: The effect of calpeptin (a calpain specific inhibitor) on agonist induced microparticle formation from the platelet plasma membrane. Thromb Res 1993; 71: 385–396.
- 56Freyssinet JM, Toti F: Formation of procoagulant microparticles and properties. Thromb Res 2010; 125: S46–S48.
- 57Redman CWG, Tanetta DS, Dragovic RA, Gardiner C, Southcombe JH, Collet GP, Sargent IL: Review: does size matter? Placental debris and the pathophysiology of pre-eclampsia. Placenta 2012; 26: S48–S54.
- 58Smith NC, Brush MG, Luckett S: Preparation of human placental villous surface membranes. Nature 1974; 252: 302–303.
- 59Knight M, Redman CW, Linton EA, Sargent IL: Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol 1998; 105: 632–640.
- 60Germain SJ, Sacks GP, Soorana SR, Sargent IL, Redman CW: Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles. J Immunol 2007; 178: 5949–5956.
- 61Sargent IL, Borzychowski AM, Redman CW: Immunoregulation in normal pregnancy and preeclampsia: an overview. Reprod Biomed Online 2006; 13: 680–686.
- 62Gardiner C, Tanetta DS, Simms CA, Harrison P, Redman CW, Sargent IL: Syncytiotrophoblast microvesicles released from pre-eclampsia placentae exhibit increased tissue factor activity. PLoS One 2011; 6: e26313.
- 63Guller S, Tang Z, Ma YY, Di Santo S, Sager R, Schneider H: Protein composition of microparticles shed from human placenta during placenta perfusion: potential role in angiogenesis and fibrinolysis in preeclampsia. Placenta 2011; 32: 63–69.
- 64Holder BS, Tower CL, Jones CJP, Alpin JD, Abrahams VM: Hightened pro-inflammatory effect of pre-eclamptic placental microvesicles on peripheral blood immune cells in humans. Biol Reprod 2012; 86: 1–7.
10.1095/biolreprod.111.097014 Google Scholar
- 65Laude I, Rongieres-Bertrand C, Boyer-Neumann C, Wolf M, Mairovitz V, Hugel B, Greyssinet JM, Frydman R, Mayer D, Eschwege V: Circulating procoagulant microparticles in women with unexplained pregnancy loss: a new insight. Thromb Haemost 2001; 85: 18–21.
- 66Carp H, Dardik R, Lubetsky A, Solomon O, Eskaraev R, Rosenthal E, Inbal A: Prevalence of circulating procoagulant microparticles in women with recurrent miscarriage: a case-controlled study. Hum Reprod 2004; 19: 191–195.
- 67Eagle RA, Jafferji I, Barrow AD: Beyond stressed self: evidence for NKG2D ligand expression on healthy cells. Curr Immunol Rev 2009; 5: 22–34.
- 68Agüera-Gonzalez S, Boutet P, Reyburn HT, Vales-Gomez M: Brief residence at the plasma membrane of the MHC class 1-related chain B is due to clathrin-mediated cholesterol-dependent endocytosis and shedding. J Immunol 2009; 182: 4800–4808.
- 69Cerwenka A: New twist on the regulation of NKG2D ligand expression. J Exp Med 2009; 206: 265–268.
- 70Zuccato E, Blott EJ, Holt O, Sigismund S, Shaw M, Bossi G, Griffiths GM: Sorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitinylation and phosphorylation. J Cell Sci 2007; 120: 191–199.
- 71Eleme K, Taner ST, Önfelt B, Collinson LM, McCann FE, Chalupny NJ, Cosman D, Hopkins C, Magee AI, Davis DM: Cell surface organization of stress-inducible proteins ULBP and MICA that stimulate human NK cells and T cells via NKG2D. J Exp Med 2004; 199: 1005–1010.
- 72Ashiru O, Boutet P, Fernandez-Messina L, Aguiera-Gonzales S, Skepper JN, Vales-Gomez M, Reyburn HT: Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes. Cancer Res 2010; 70: 481–489.
- 73de Gassart A, Geminard C, Fevrier B, Raposo G, Vidal M: Lipid raft-associated protein sorting in exosomes. Blood 2003; 102: 4336–4344.
- 74O'Reilly LA, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, Haynes NM, Tarlinton DM, Zhang JG, Belz GT, Smyth MJ, Bouillet P, Robb L, Strasser A: Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 2009; 461: 659–663.
- 75Apps R, Gardner L, Moffet A: A critical look at HLA-G. Trends Immunol 2009; 29: 313–321.
- 76Kshirsagar SK, Alam SM, Jasti S, Hodes H, Nauser T, Gilliam M, Billstrand C, Hunt JS, Petroff MG: Immunomodulatory molecules are released from the first trimester and term placenta via exosomes. Placenta 2012; 33: 982–990.
- 77Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakfield XO, Widmark A: Prostate cancer derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer 2009; 100: 1603–1607.
- 78Taylor DD, Gercel-Taylor C: MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers for ovarian cancer. Gynecol Oncol 2008; 110: 13–21.
- 79Ouyang Y, Mouillet J-F, Coyne CB, Sadovsky Y: Review: placenta-specific microRNAs in exosomes – good things come in nano-packages. Placenta 2014; 28: S69–S73.
- 80Luo SS, Ishibashi O, Ishikawa G, Ishikawa T, Katayama A, Mishima T, Takizawa I, Shigihara T, Goto T, Izumi A, Ohjuchi A, Matsubara S, Takeshita T, Takizawa T: Human villous trophoblast express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol Reprod 2009; 81: 717–729.
- 81Chim SS, Shing TK, Hung EC, Leung TY, Lau TK, Chiu RW, Lo YM: Detection and characterization of placental micro RNAs in maternal plasma. Clin Chem 2008; 54: 482–490.
- 82Pisitkun T, Shen RF, Knepper MA: Identification and proteomic analysis of exosomes in human urine. Proc Natl Acad Sci USA 2004; 101: 13368–13373.
- 83Keller S, Rupp C, Stoek A, Runz S, Fogel M, Lugert S, Hager H-D, Abdel-Bakky MS, Gutwein P, Altevogt P: CD24 is a marker of exosomes secreted into urine and amniotic fluid. Kidney Int 2007; 72: 1095–1102.
- 84Sacks GP, Studena K, Sargent K, Redman CW: Normal pregnancy and pre-eclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol 1998; 179: 80–86.
- 85Sacks G, Sargent I, Redman C: An innate view of human pregnancy. Immunol Today 1999; 20: 114–118.
- 86Hedlund M, Nagaeva O, Kargl D, Baranov V, Mincheva-Nilsson L: Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PLoS One 2011; 6: e16899.
