Journal of Assisted Reproduction and Genetics

, Volume 36, Issue 2, pp 189–198 | Cite as

Extracellular vesicle mediated embryo-endometrial cross talk during implantation and in pregnancy

  • Noble K. Kurian
  • Deepak ModiEmail author


Extracellular vesicles are lipoproteinaceous membrane-enclosed nanometer-sized structures produced by cells and are thought to mediate cellular communications. Loaded with a specific set of miRNA and protein depending on their tissue of origin, these extracellular vesicles modulate diverse set of biological processes in their target tissues. In recent years, data has gathered on the roles of extracellular vesicles in embryo implantation and pregnancy. Embryo, oviduct, endometrial epithelium and stroma/decidua derived vesicles interact with trophoblast cells and promote their growth and differentiation to aid in embryo implantation. The placental vesicles are detected in maternal circulation that aids in feto-maternal immune tolerance, their levels vary in women with pregnancy-related complications like preeclampsia. Beyond the host, the microbes in the genital tract are also reported to produce extracellular vesicles which are thought to be responsible for inflammation and preterm births. This review focuses on the extracellular vesicular trafficking involved in success of pregnancy.


Extracellular vesicles Exosomes Embryo Implantation Pregnancy Cross talk Infection 


Funding information

The manuscript bears the NIRRH ID:REV/652/07-2017. DM lab and is supported by grants from the Indian Council of Medical Research, Department of Science and Technology, Department of Biotechnology, Government of India. NK is a recipient of the Kerala State Council for Science, Technology & Environment Post-Doctoral Fellowship.


  1. 1.
    Modi DN, Godbole G, Suman P, Gupta SK. Endometrial biology during trophoblast invasion. Front Biosci (Schol Ed). 2012;4:1151–71.Google Scholar
  2. 2.
    Modi DN, Bhartiya P. Physiology of embryo-endometrial cross talk. Biomed Res J. 2015;2(1):83–104.CrossRefGoogle Scholar
  3. 3.
    Ashary N, Tiwari A, Modi D. Embryo implantation: war in times of love. Endocrinology. 2018;159(2):1188–98.PubMedCrossRefGoogle Scholar
  4. 4.
    Bhusane K, Bhutada S, Chaudhari U, Savardekar L, Katkam R, Sachdeva G. Secrets of endometrial receptivity: some are hidden in uterine secretome. Am J Reprod Immunol. 2016;75(3):226–36.PubMedCrossRefGoogle Scholar
  5. 5.
    Evans J, Salamonsen LA, Winship A, Menkhorst E, Nie G, Gargett CE, et al. Fertile ground: human endometrial programming and lessons in health and disease. Nat Rev Endocrinol. 2016;12(11):654–67.PubMedCrossRefGoogle Scholar
  6. 6.
    Shah J, Gangadharan A, Shah V. Effect of intrauterine instillation of granulocyte colony-stimulating factor on endometrial thickness and clinical pregnancy rate in women undergoing in vitro fertilization cycles: an observational cohort study. Int J Infertil Fetal Med. 2014;5(3):100–6.CrossRefGoogle Scholar
  7. 7.
    Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754–67.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Godbole G, Suman P, Malik A, Galvankar M, Joshi N, Fazleabas A, et al. Decrease in expression of HOXA10 in the decidua after embryo implantation promotes trophoblast invasion. Endocrinology. 2017;158(8):2618–33.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Sharma S, Godbole G, Modi D. Decidual control of trophoblast invasion. Am J Reprod Immunol. 2016;75(3):341–50.PubMedCrossRefGoogle Scholar
  10. 10.
    James-Allan LB, Whitley GS, Leslie K, Wallace AE, Cartwright JE. Decidual cell regulation of trophoblast is altered in pregnancies at risk of pre-eclampsia. J Mol Endocrinol. 2018;60(3):239–46.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Garrido-Gomez T, Dominguez F, Quiñonero A, Diaz-Gimeno P, Kapidzic M, Gormley M, et al. Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology. Proc Natl Acad Sci U S A. 2017;114(40):E8468–77.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    MikoŁaj P, Balaj ZL, Breakefield XO, Lai CP. Extracellular vesicles: composition, biological relevance, and methods of study. Bioscience. 2015;65(8):783–97.CrossRefGoogle Scholar
  13. 13.
    Laulagnier K, Motta C, Hamdi S, Sébastien ROY, Fauvelle F, Pageaux JF, et al. Mast cell-and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem J. 2004;380(1):161–71.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Llorente A, Skotland T, Sylvänne T, Kauhanen D, Róg T, Orłowski A, et al. Molecular lipidomics of exosomes released by PC-3 prostate cancer cells. Biochim Biophys Acta. 2013;1831:1302–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Mellisho EA, Velásquez AE, Nuñez MJ, Cabezas JG, Cueto JA, Fader C, et al. Identification and characteristics of extracellular vesicles from bovine blastocysts produced in vitro. PLoS One. 2017;12(5):e0178306.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Giacomini E, Vago R, Sanchez AM, Podini P, Zarovni N, Murdica V, et al. Secretome of in vitro cultured human embryos contains extracellular vesicles that are uptaken by the maternal side. Sci Rep. 2017;7(1):5210.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Qu P, Qing S, Liu R, Qin H, Wang W, Qiao F, et al. Effects of embryo-derived exosomes on the development of bovine cloned embryos. PLoS One. 2017;12(3):e0174535.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Desrochers LM, Bordeleau F, Reinhart-King CA, Cerione RA, Antonyak MA. Microvesicles provide a mechanism for intercellular communication by embryonic stem cells during embryo implantation. Nat Commun. 2016;7:11958.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Burns GW, Brooks KE, Spencer TE. Extracellular vesicles originate from the conceptus and uterus during early pregnancy in sheep. Biol Reprod. 2016;94:56.PubMedCrossRefGoogle Scholar
  20. 20.
    Capalbo A, Ubaldi FM, Cimadomo D, Noli L, Khalaf Y, Farcomeni A, et al. MicroRNAs in spent blastocyst culture medium are derived from trophectoderm cells and can be explored for human embryo reproductive competence assessment. Fertil Steril. 2016;105:225–35.PubMedCrossRefGoogle Scholar
  21. 21.
    Cuman C, Van Sinderen M, Gantier MP, Rainczuk K, Sorby K, Rombauts L, et al. Human blastocyst secreted microRNA regulate endometrial epithelial cell adhesion. EBioMedicine. 2015;2:1528–35.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kropp J, Salih SM, Khatib H. Expression of microRNAs in bovine and human pre-implantation embryo culture media. Front Genet. 2014;5:91.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Noli L, Capalbo A, Dajani Y, Cimadomo D, Bvumbe J, Rienzi L, et al. Human embryos created by embryo splitting secrete significantly lower levels of miRNA-30c. Stem Cells Dev. 2016;25:1853–62.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Rosenbluth EM, Shelton DN, Wells LM, Sparks AE, Van Voorhis BJ. Human embryos secrete microRNAs into culture media–a potential biomarker for implantation. Fertil Steril. 2014;101:1493–500.PubMedCrossRefGoogle Scholar
  25. 25.
    Pérez-Cerezales S, Ramos-Ibeas P, Acuña OS, Avilés M, Coy P, Rizos D, et al. The oviduct: from sperm selection to the epigenetic landscape of the embryo. Biol Reprod. 2017;98(3):262–76.CrossRefGoogle Scholar
  26. 26.
    Al-Dossary AA, Strehler EE, Martin-DeLeon PA. Expression and secretion of plasma membrane Ca2+-ATPase 4a (PMCA4a) during murine estrus: association with oviductal exosomes and uptake in sperm. PLoS One. 2013;8(11):e80181.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Almiñana C, Corbin E, Tsikis G, Alcântara-Neto AS, Labas V, Reynaud K, et al. Oviduct extracellular vesicles protein content and their role during oviduct–embryo cross-talk. Reproduction. 2017;154(3):253–68.CrossRefGoogle Scholar
  28. 28.
    Lopera-Vásquez R, Hamdi M, Fernandez-Fuertes B, Maillo V, Beltrán-Breña P, Calle A, et al. Extracellular vesicles from BOEC in in vitro embryo development and quality. PLoS One. 2016;11(2):e0148083.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Godbole G, Suman P, Gupta SK, Modi D. Decidualized endometrial stromal cell derived factors promote trophoblast invasion. Fertil Steril. 2011;95(4):1278–83.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhu XM, Han T, Sargent IL, Wang YL, Yao YQ. Conditioned medium from human decidual stromal cells has a concentration-dependent effect on trophoblast cell invasion. Placenta. 2009;30(1):74–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Greening DW, Nguyen HP, Elgass K, Simpson RJ, Salamonsen LA. Human endometrial exosomes contain hormone-specific cargo modulating trophoblast adhesive capacity: insights into endometrial-embryo interactions. Biol Reprod. 2016;94:38.PubMedCrossRefGoogle Scholar
  32. 32.
    Ng YH, Rome S, Jalabert A, Forterre A, Singh H, Hincks CL, et al. Endometrial exosomes/microvesicles in the uterine microenvironment: a new paradigm for embryo-endometrial cross talk at implantation. PLoS One. 2013;8:e58502.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Kusama K, Nakamura K, Bai R, Nagaoka K, Sakurai T, Imakawa K. Intrauterine exosomes are required for bovine conceptus implantation. Biochem Biophys Res Commun. 2018;495(1):1370–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Nguyen MA, Karunakaran D, Geoffrion M, Cheng HS, Tandoc K, Matic LP, et al. Extracellular vesicles secreted by atherogenic macrophages transfer microRNA to inhibit cell migration. Arterioscler Thromb Vasc Biol. 2018;38(1):49–63.PubMedCrossRefGoogle Scholar
  35. 35.
    Patil VS, Sachdeva G, Modi DN, Katkam RR, Manjramkar DD, Hinduja I, et al. Rab coupling protein (RCP): a novel target of progesterone action in primate endometrium. J Clin Mol Endocrinol. 2005;35(2):357–72.CrossRefGoogle Scholar
  36. 36.
    Rosas C, Gabler F, Vantman D, Romero C, Vega M. Levels of Rabs and WAVE family proteins associated with translocation of GLUT4 to the cell surface in endometria from hyperinsulinemic PCOS women. Hum Reprod. 2010;25(11):2870–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Koh YQ, Peiris HN, Vaswani K, Reed S, Rice GE, Salomon C, et al. Characterization of exosomal release in bovine endometrial intercaruncular stromal cells. Reprod Biol Endocrinol. 2016;14(1):78.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Harp D, Driss A, Mehrabi S, Chowdhury I, Xu W, Liu D, et al. Exosomes derived from endometriotic stromal cells have enhanced angiogenic effects in vitro. Cell Tissue Res. 2016;365(1):187–96.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Maida Y, Takakura M, Nishiuchi T, Yoshimoto T, Kyo S. Exosomal transfer of functional small RNAs mediates cancer-stroma communication in human endometrium. Cancer Med. 2016;5(2):304–14.PubMedCrossRefGoogle Scholar
  40. 40.
    Zhang J, Li S, Li L, Li M, Guo C, Yao J, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 2015;13(1):17–24.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Burton GJ, Jones CJ. Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol. 2009;48(1):28–37.PubMedCrossRefGoogle Scholar
  42. 42.
    Salomon C, Yee SW, Mitchell MD, Rice GE. The possible role of extravillous trophoblast-derived exosomes on the uterine spiral arterial remodeling under both normal and pathological conditions. Biomed Res Int. 2014;2014:1–10.CrossRefGoogle Scholar
  43. 43.
    Adam S, Elfeky O, Kinhal V, Dutta S, Lai A, Jayabalan N, et al. Fetal-maternal communication via extracellular vesicles–implications for complications of pregnancies. Placenta. 2017;54:83–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Tannetta D, Collett G, Vatish M, Redman C, Sargent I. Syncytiotrophoblast extracellular vesicles–circulating biopsies reflecting placental health. Placenta. 2017a;52:134–8.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Tannetta D, Masliukaite I, Vatish M, Redman C, Sargent I. Update of syncytiotrophoblast derived extracellular vesicles in normal pregnancy and preeclampsia. J Reprod Immunol. 2017b;119:98–106.PubMedCrossRefGoogle Scholar
  46. 46.
    Pillay P, Moodley K, Moodley J, Mackraj I. Placenta-derived exosomes: potential biomarkers of preeclampsia. Int J Nanomedicine. 2017;12:8009–23.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Truong G, Guanzon D, Kinhal V, Elfeky O, Lai A, Longo S, et al. Oxygen tension regulates the miRNA profile and bioactivity of exosomes released from extravillous trophoblast cells–liquid biopsies for monitoring complications of pregnancy. PLoS One. 2017;12(3):e0174514.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Salomon C, Guanzon D, Scholz-Romero K, Longo S, Correa P, Illanes SE, et al. Placental exosomes as early biomarker of preeclampsia: potential role of exosomal microRNAs across gestation. J Clin Endocrinol Metab. 2017;102(9):3182–94.PubMedCrossRefGoogle Scholar
  49. 49.
    Jayabalan N, Nair S, Nuzhat Z, Rice GE, Zuñiga FA, Sobrevia L, et al. Cross talk between adipose tissue and placenta in obese and gestational diabetes mellitus pregnancies via exosomes. Front Endocrinol. 2017;8:239.CrossRefGoogle Scholar
  50. 50.
    Sáez T, Salsoso R, Leiva A, Toledo F, de Vos P, Faas M, et al. Human umbilical vein endothelium-derived exosomes play a role in foetoplacental endothelial dysfunction in gestational diabetes mellitus. Biochim Biophys Acta Mol Basis Dis. 2018;1864(2):499–508.PubMedCrossRefGoogle Scholar
  51. 51.
    Sáez T, de Vos P, Sobrevia L, Faas MM. Is there a role for exosomes in foetoplacental endothelial dysfunction in gestational diabetes mellitus? Placenta. 2018;61:48–54.PubMedCrossRefGoogle Scholar
  52. 52.
    Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB, et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell. 2017;171(2):372–84.PubMedCrossRefGoogle Scholar
  53. 53.
    Zhang Y, Yu M, Tian W. Physiological and pathological impact of exosomes of adipose tissue. Cell Proliferat. 2016;49(1):3–13.CrossRefGoogle Scholar
  54. 54.
    Pelzer ES, Willner D, Buttini M, Hafner LM, Theodoropoulos C, Huygens F. The fallopian tube microbiome: implications for reproductive health. Oncotarget. 2018;9(30):21541.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Champer M, Wong AM, Champer J, Brito IL, Messer PW, Hou JY, et al. The role of the vaginal microbiome in gynecological cancer: a review. BJOG. 2017.Google Scholar
  56. 56.
    Younes JA, Lievens E, Hummelen R, van der Westen R, Reid G, Petrova MI. Women and their microbes: the unexpected friendship. Trends Microbiol. 2017.Google Scholar
  57. 57.
    Vinturache AE, Gyamfi-Bannerman C, Hwang J, Mysorekar IU, Jacobsson B. Maternal microbiome–a pathway to preterm birth. Semin Fetal Neonatal Med. 2016;21(2):94–9.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Ofir-Birin Y, Heidenreich M, Regev-Rudzki N. Pathogen-derived extracellular vesicles coordinate social behaviour and host manipulation. Semin Cell Dev Biol. 2017;67:83–90.PubMedCrossRefGoogle Scholar
  59. 59.
    Nudel K, Massari P, Genco CA. Neisseria gonorrhoeae modulates cell death in human endocervical epithelial cells through export of exosome-associated cIAP2. Infect Immun. 2015;83(9):3410–7.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Bianchi-Jassir F, Seale AC, Kohli-Lynch M, Lawn JE, Baker CJ, Bartlett L, et al. Preterm birth associated with group B Streptococcus maternal colonization worldwide: systematic review and meta-analyses. Clin Infect Dis. 2017;65(suppl_2):S133–42.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Surve MV, Anil A, Kamath KG, Bhutda S, Sthanam LK, Pradhan A, Srivastava R, Basu B, Dutta S, Sen S, Modi D, Banerjee A . Membrane vesicles of group B streptococcus disrupt feto-maternal barrier leading to preterm birth. PLoS Pathog 2016; 12(9): e1005816.Google Scholar
  62. 62.
    Vyas N, Walvekar A, Tate D, Lakshmanan V, Bansal D, Cicero AL, et al. Vertebrate hedgehog is secreted on two types of extracellular vesicles with different signaling properties. Sci Rep. 2014;4:7357.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Molecular and Cellular Biology Laboratory, Indian Council of Medical ResearchNational Institute for Research in Reproductive HealthMumbaiIndia

Personalised recommendations