Extracellular vesicles in follicular fluid: clinical aspects and molecular biology
Recently, extracellular vesicles (EVs), membrane vesicles secreted into the extracellular medium by various cell types of reproductive tissues, have been discovered in human follicular fluid (FF). It was originally thought that EV secretion might be a mechanism used by cells to eliminate intracellular 'debris', but subsequent studies have shown that EVs are used to deliver specific molecular information encapsulated in a double-layered lipid membrane from the donor cell to the recipient cell. EVs contain bioactive molecules, such as mRNA, microRNA, proteins, and lipids, that enable communication and interaction between different cells and tissues, including between the oocyte and somatic cells of the growing follicle. EVs in follicular fluid play an important role in the biological processes of folliculogenesis, oogenesis, and early embryogenesis.Dovgan A.A., Akhmedova Z.F., Sysoeva A.P., Zingerenko B.V., Romanov E.A., Silachev D.N., Makarova N.P., Kalinina E.A.
Conclusion: The reviewed studies provide an opportunity to increase our understanding of the complex mechanisms of reproductive biology and improve the potential for the use of EVs to optimize the embryological stage of in vitro oocyte and embryo culture in assisted reproductive technology programs.
Authors' contributions: Dovgan A.A., Akhmedova Z.F., Sysoeva A.P., Zingerenko B.V., Romanov E.A., Silachev D.N., Makarova N.P., Kalinina E.A. – concept of article, search and review of relevant literature, manuscript drafting, and editing.
Conflicts of interest: The authors have no conflicts of interest to declare.
Funding: This study was funded by state task #12101040600410-7 of the Ministry of Health of the Russian Federation "Addressing infertility in modern conditions by developing a clinical and diagnostic model for infertile couples and using innovative technologies in assisted reproductive programs".
For citation: Dovgan A.A., Akhmedova Z.F., Sysoeva A.P., Zingerenko B.V.,
Romanov E.A., Silachev D.N., Makarova N.P., Kalinina E.A. Extracellular vesicles
in follicular fluid: clinical aspects and molecular biology.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2023; (6): 38-43 (in Russian)
https://dx.doi.org/10.18565/aig.2022.320
Keywords
follicular fluid
extracellular vesicles
exosomes
microvesicles
microRNA
intercellular communication
assisted reproductive technology (ART)
References
- Rodgers R.J., Irving-Rodgers H.F. Formation of the ovarian follicular antrum and follicular fluid. Biol. Reprod. 2010; 82(6): 1021-9. https://dx.doi.org/10.1095/biolreprod.109.082941.
- Hennet M.L., Combelles C.M.H. The antral follicle: a microenvironment for oocyte differentiation. Int. J. Dev. Biol. 2012; 56(10-12): 819-31.https://dx.doi.org/10.1387/ijdb.120133cc.
- Фортыгина Ю.А., Макарова Н.П., Непша О.С., Лобанова Н.Н., Калинина Е.А. Роль липидомных исследований в репродукции человека и исходах программ лечения бесплодия методами вспомогательных репродуктивных технологий. Акушерство и гинекология. 2022; 10: 14-20. [Fortygina Yu.A., Makarova N.P., Nepsha O.S., Lobanova N.N., Kalinina E.A. The role of lipidomic studies in human reproduction and in the outcomes of infertility treatment programs using assisted reproductive technologies. Obstetrics and Gynecology. 2022; (10): 14-20. (in Russian)]. https://dx.doi.org/10.18565/aig.2022.10.14-20.
- Гапоненко А.А., Митюрина Е.В., Франкевич В.Е. Метаболомный профиль фолликулярной жидкости как маркер качества ооцитов в программах вспомогательных репродуктивных технологий. Акушерство и гинекология. 2021; 11: 26-31. [Gaponenko A.A., Mityurina E.V., Frankevich V.E. The follicular fluid metabolomic profile as a marker for oocyte quality in assisted reproductive technology programs. Obstetrics and Gynecology. 2021; (11): 26-31. (in Russian)]. https://dx.doi.org/10.18565/aig.2021.11.26-31.
- Шамина М.А., Тимофеева А.В., Федоров И.С., Калинина Е.А. Оценка уровня экспрессии пивиРНК hsa_piR_020497 в фолликулярной жидкости пациенток с различными исходами программ экстракорпорального оплодотворения. Акушерство и гинекология. 2021; 11: 143-53. [Shamina M.A., Timofeeva A.V., Fedorov I.S., Kalinina E.A. Assessment of the expression level of hsa_pir_020497 piRNA in the follicular fluid of patients with different in vitro fertilization outcomes. Obstetrics and Gynecology. 2021; (11): 143-53.(in Russian)]. https://dx.doi.org/10.18565/aig.2021.11.143-153.
- Zamah A.M., Hassis M.E., Albertolle M.E., Williams K.E. Proteomic analysis of human follicular fluid from fertile women. Clin. Proteomics. 2015; 12(1): 5. https://dx.doi.org/10.1186/s12014-015-9077-6.
- Andersen M.M., Kroll J., Byskov A.G., Faber M. Protein composition in the fluid of individual bovine follicles. Reproduction. 1976; 48(1): 109-18. https://dx.doi.org/10.1530/jrf.0.0480109.
- Ambekar A.S., Nirujogi R.S., Srikanth S.M., Chavan S., Kelkar D.S.,Hinduja I. et al. Proteomic analysis of human follicular fluid: a new perspective towards understanding folliculogenesis. J. Proteomics. 2013; 87: 68-77.https://dx.doi.org/10.1016/j.jprot.2013.05.017.
- György B., Szabó T.G., Pásztói M., Pál Z., Misják P., Aradi B. et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell. Mol. Life Sci. 2011; 68(16): 2667-88. https://dx.doi.org/10.1007/s00018-011-0689-3.
- Raposo G., Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 2013; 200(4): 373-83. https://dx.doi.org/10.1083/jcb.201211138.
- Simpson R.J., Jensen S.S., Lim J.W.E. Proteomic profiling of exosomes: current perspectives. Proteomics. 2008; 8(19): 4083-99. https://dx.doi.org/10.1002/pmic.200800109.
- Valadi H., Ekström K., Bossios A., Sjöstrand M., Lee J.J., Lötvall J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007; 9(6): 654-9.https://dx.doi.org/10.1038/ncb1596.
- EL Andaloussi S., Mäger I., Breakefield X.O., Wood M.J.A. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 2013; 12(5): 347-57. https://dx.doi.org/10.1038/nrd3978.
- Mathivanan S., Ji H., Simpson R.J. Exosomes: extracellular organelles important in intercellular communication. J. Proteomics. 2010; 73(10): 1907-20.https://dx.doi.org/10.1016/j.jprot.2010.06.006.
- Cocucci E., Racchetti G., Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 2009; 19(2): 43-51. https://dx.doi.org/10.1016/j.tcb.2008.11.003.
- Tannetta D., Dragovic R., Alyahyaei Z., Southcombe J. Extracellular vesicles and reproduction–promotion of successful pregnancy. Cell Mol. Immunol. 2014; 11(6): 548-63. https://dx.doi.org/10.1038/cmi.2014.42.
- Théry C., Zitvogel L., Amigorena S. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2002; 2(8): 569-79. https://dx.doi.org/10.1038/nri855.
- Théry C., Ostrowski M., Segura E. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 2009; 9(8): 581-93. https://dx.doi.org/10.1038/nri2567.
- Maas S.L.N., Breakefield X.O., Weaver A.M. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 2017; 27(3): 172-88.https://dx.doi.org/10.1016/j.tcb.2016.11.003.
- Tesfaye D., Hailay T., Salilew-Wondim D., Hoelker M., Bitseha S., Gebremedhn S. Extracellular vesicle mediated molecular signaling in ovarian follicle: Implication for oocyte developmental competence. Theriogenology. 2020; 150: 70-4. https://dx.doi.org/10.1016/j.theriogenology.2020.01.075.
- Pavani K.C., Alminana C., Wydooghe E., Catteeuw M., Ramírez M.A., Mermillod P. et al. Emerging role of extracellular vesicles in communication of preimplantation embryos in vitro. Reprod. Fertil. Dev. 2017; 29(1): 66.https://dx.doi.org/10.1071/RD16318.
- van Engeland M., Kuijpers H.J.H., Ramaekers F.C.S., Reutelingsperger C.P.M., Schutte B. Plasma membrane alterations and cytoskeletal changes in apoptosis. Exp. Cell Res. 1997; 235(2): 421-30. https://dx.doi.org/10.1006/excr.1997.3738.
- Théry C., Witwer K.W., Aikawa E., Alcaraz M.J., Anderson J.D., Andriantsitohaina R. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles. 2018; 7(1): 1535750. https://dx.doi.org/10.1080/20013078.2018.1535750.
- Witwer K.W., Buzás E.I., Bemis L.T., Bora A., Lässer C., Lötvall J. et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles. 2013; 2(1): 20360.https://dx.doi.org/10.3402/jev.v2i0.20360.
- Neyroud A.S., Chiechio R.M., Moulin G., Ducarre S., Heichette C.,Dupont A. et al. Diversity of extracellular vesicles in human follicular fluid: morphological analysis and quantification. Int. J. Mol. Sci. 2022; 23(19): 11676. https://dx.doi.org/10.3390/ijms231911676.
- van der Pol E., Böing A.N., Harrison P., Sturk A., Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol. Rev. 2012; 64(3): 676-705. https://dx.doi.org/10.1124/pr.112.005983.
- Liu Y.J., Wang C. A review of the regulatory mechanisms of extra cellular vesicles-mediated intercellular communication. Cell Commun. Signal. 2023; 21(1): 77. https://dx.doi.org/10.1186/s12964-023-01103-6.
- Ruiz-González I., Xu J., Wang X., Burghardt R.C., Dunlap K.A., Bazer F.W. Exosomes, endogenous retroviruses and toll-like receptors: pregnancy recognition in ewes. Reproduction. 2015; 149(3): 281-91.https://dx.doi.org/10.1530/REP-14-0538.
- Al-Dossary A.A., Strehler E.E., Martin-DeLeon P.A. 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. https://dx.doi.org/10.1371/journal.pone.0080181.
- da Silveira J.C., Veeramachaneni D.N.R., Winger Q.A., Carnevale E.M., Bouma G.J. Cell-secreted vesicles in equine ovarian follicular fluid contain miRNAs and proteins: a possible new form of cell communication within the ovarian follicle. Biol. Reprod. 2012; 86(3): 71. https://dx.doi.org/10.1095/biolreprod.111.093252.
- Machtinger R., Laurent L.C., Baccarelli A.A. Extracellular vesicles: roles in gamete maturation, fertilization and embryo implantation. Hum. Reprod. Update. 2015; dmv055. https://dx.doi.org/10.1093/humupd/dmv055.
- 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. https://dx.doi.org/10.1371/journal.pone.0148083.
- Mellisho E.A., Velásquez A.E., Nuñez M.J., Cabezas J.G., Cueto J.A., Fader C. et al. Identification and characteristics of extracellular vesicles from bovine blastocysts produced in vitro. PLoS One. 2017; 12(5): e0178306.https://dx.doi.org/10.1371/journal.pone.0178306.
- Ng Y.H., Rome S., Jalabert A., Forterre A., Singh H., Hincks C.L., Salamonsen L.A. Endometrial exosomes microvesicles in the uterine microenvironment: a new paradigm for embryo-endometrial cross talk at implantation. PLoS One. 2013; 8(3): e58502. https://dx.doi.org/10.1371/journal.pone.0058502.
- Asea A., Jean-Pierre C., Kaur P., Rao P., Linhares I.M., Skupski D., Witkin S.S. Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J. Reprod. Immunol. 2008; 79(1): 12-7. https://dx.doi.org/10.1016/j.jri.2008.06.001.
- Aalberts M., van Dissel-Emiliani F.M., van Adrichem N.P., van Wijnen M., Wauben M.H., Stout T.A., Stoorvogel W. Identification of distinct populations of prostasomes that differentially express prostate stem cell antigen, annexin A1, and GLIPR2 in humans. Biol. Reprod. 2012; 86(3): 82.https://dx.doi.org/10.1095/biolreprod.111.095760.
- Andronico F., Battaglia R., Ragusa M., Barbagallo D., Purrello M., di Pietro C. Extracellular vesicles in human oogenesis and implantation. Int. J. Mol. Sci. 2019; 20(9): 2162. https://dx.doi.org/10.3390/ijms20092162.
- Diez-Fraile A., Lammens T., Tilleman K., Witkowski W., Verhasselt B., De Sutter P. et al. Age-associated differential microRNA levels in human follicular fluid reveal pathways potentially determining fertility and success of in vitro fertilization. Hum. Fertil. 2014; 17(2): 90-8. https://dx.doi.org/10.3109/14647273.2014.897006.
- Sang Q., Yao Z., Wang H., Feng R., Wang H., Zhao X. et al. Identification of MicroRNAs in human follicular fluid: characterization of MicroRNAs that govern steroidogenesis in vitro and are associated with polycystic ovary syndrome in vivo. J. Clin. Endocrinol. Metab. 2013; 98(7): 3068-79.https://dx.doi.org/10.1210/jc.2013-1715.
- Santonocito M., Vento M., Guglielmino M.R., Battaglia R., Wahlgren J., Ragusa M. et al. Molecular characterization of exosomes and their microRNA cargo in human follicular fluid: bioinformatic analysis reveals that exosomal microRNAs control pathways involved in follicular maturation. Fertil. Steril. 2014; 102(6): 1751-61.e1. https://dx.doi.org/10.1016/j.fertnstert.2014.08.005.
- Sohel M.M.H., Hoelker M., Noferesti S.S., Salilew-Wondim D., Tholen E., Looft C. et al. Exosomal and non-exosomal transport of extra-C+cellular microRNAs in follicular fluid: implications for bovine oocyte developmental competence. PLoS One. 2013; 8(11): e78505. https://dx.doi.org/10.1371/journal.pone.0078505.
- Sohel M.M.H., Hoelker M., Schellander K., Tesfaye D. The extent of the abundance of exosomal and non‐exosomal extracellular miRNAs in the bovine follicular fluid. Reprod. Domest. Anim. 2022; 57(10): 1208-17.https://dx.doi.org/10.1111/rda.14195.
- Rooda I., Hasan M.M., Roos K., Viil J., Andronowska A., Smolander O.P. et al. Cellular, extracellular and extracellular vesicular miRNA profiles of Pre-ovulatory follicles indicate signaling disturbances in polycystic ovaries. Int. J. Mol. Sci. 2020; 21(24): 9550. https://dx.doi.org/10.3390/ijms21249550.
- Navakanitworakul R., Hung W.-T., Gunewardena S., Davis J.S., Chotigeat W., Christenson L.K. Characterization and small RNA content of extracellular vesicles in follicular fluid of developing bovine antral follicles. Sci. Rep. 2016; 6(1): 25486. https://dx.doi.org/10.1038/srep25486.
- Hung W.T., Hong X., Christenson L.K., McGinnis L.K. Extracellular vesicles from bovine follicular fluid support cumulus expansion. Biol. Reprod. 2015; 93(5): 117. https://dx.doi.org/10.1095/biolreprod.115.132977.
- Hung W.T., Navakanitworakul R., Khan T., Zhang P., Davis J.S., McGinnis L.K., Christenson L.K. Stage-specific follicular extracellular vesicle uptake and regulation of bovine granulosa cell proliferation. Biol. Reprod. 2017; 97(4):644-55. https://dx.doi.org/10.1093/biolre/iox106.
- da Silveira J.C., Carnevale E.M., Winger Q.A., Bouma G.J. Regulation of ACVR1 and ID2 by cell-secreted exosomes during follicle maturation in the mare. Reprod. Biol. Endocrinol. 2014; 12(1): 44. https://dx.doi.org/10.1186/1477-7827-12-44.
- da Silveira J.C., Andrade G.M., Del Collado M., Sampaio R.V., Sangalli J.R., Silva L.A. et al. Supplementation with small-extracellular vesicles from ovarian follicular fluid during in vitro production modulates bovine embryo development. PLoS One. 2017; 12(6): e0179451. https://dx.doi.org/10.1371/journal.pone.0179451.
- Sysoeva A.P., Makarova N.P., Silachev D.N., Lobanova N.N., Shevtsova Y.A., Bragina E.E. et al. Influence of extracellular vesicles of the follicular fluid on morphofunctional characteristics of human sperm. Bull. Exp. Biol. Med. 2021; 172(2): 254-62. https://dx.doi.org/10.1007/s10517-021-05372-4.
- Rodrigues T.A., Tuna K.M., Alli A.A., Tribulo P., Hansen P.J., Koh J., Paula-Lopes F.F. Follicular fluid exosomes act on the bovine oocyte to improve oocyte competence to support development and survival to heat shock. Reprod. Fertil. Dev. 2019; 31(5): 888. https://dx.doi.org/10.1071/RD18450.
- Milyutina Yu.P., Korenevskii A.V., Vasilyeva V.V., Bochkovskii S.K., Ishchenko A.M., Simbirtsev A.S. et al. Caspase activation in trophoblast cells after interacting with microparticles produced by natural killer cells in vitro. J. Evol. Biochem.Physiol. 2022; 58(6): 1834-46. https://dx.doi.org/10.1134/S002209302206014X.
- Yuan C., Li Z., Zhao Y., Wang X., Chen L., Zhao Z. et al. Follicular fluid exosomes: important modulator in proliferation and steroid synthesis of porcine granulosa cells. FASEB J. 2021; 35(5): e21610. https://dx.doi.org/10.1096/fj.202100030RR.
Received 30.12.2022
Accepted 27.03.2023
About the Authors
Alina A. Dovgan, MD, PhD, Researcher, Department of Assistive Technologies in Infertility Treatment, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, +7(929)910-46-00, lina.dovgan@gmail.com, https://orcid.org/0000-0002-4927-3590, 117997, Russia, Moscow, Ac. Oparin str., 4.Zumriiat F. Akhmedova, Postgraduate Student, Department of Assistive Technologies in Infertility Treatment, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, +7(926)626-22-24, zyuka-1997@mail.ru, https://orcid.org/0000-0002-4483-8820, 117997, Russia, Moscow, Ac. Oparin str., 4.
Anastasia P. Sysoeva, Clinical Embryologist, Department of Assistive Technologies in Infertility Treatment, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, sysoeva.a.p@gmail.com, https://orcid.org/0000-0002-6502-4498,
117997, Russia, Moscow, Ac. Oparin str., 4.
Boris V. Zingerenko, Junior Researcher, Department of Assistive Technologies in Infertility Treatment, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, b_zingerenko@oparina4.ru, https://orcid.org/0000-0002-8784-5502,
117997, Russia, Moscow, Ac. Oparin str., 4.
Evgeniy A. Romanov, Clinical Embryologist, Department of Assistive Technologies in Infertility Treatment, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, e_romanov@oparina4.ru, 117997, Russia, Moscow, Ac. Oparin str., 4.
Denis N. Silachev, PhD, Chief of the Laboratory of Cellular Technologies, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, d_silachev@oparina4.ru, https://orcid.org/0000-0003-0581-9755, 117997, Russia, Moscow, Ac. Oparin str., 4.
Natalya P. Makarova, PhD, Leading Researcher, Department of Assistive Technologies in Infertility Treatment, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, np_makarova@oparina4.ru, https://orcid.org/0000-0003-8922-2878,
117997, Russia, Moscow, Ac. Oparin str., 4.
Elena A. Kalinina, Dr. Med. Sci., Professor, Head of the Department of Assistive Technologies in Infertility Treatment, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, e_kalinina@oparina4.ru, https://orcid.org/0000-0002-8922-2878,
117997, Russia, Moscow, Ac. Oparin str., 4.