Therapeutic opportunities of extracellular vesicles in reproductive medicine

DOI

https://dx.doi.org/10.18565/aig.2021.7.5-9

Kraevaya E.E., Makarova N.P., Sysoeva A.P., Kalinina E.A., Silachev D.N.
Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow, Russia

Diminished ovarian reserve is an urgent problem of reproductive medicine. Currently, there are no scientifically based and proven methods for solving the problem. One of the promising directions in this area may be the use of extracellular vesicles (EVs) secreted by the cells of structures that have a high biological activity due to different molecules entering into their composition. From the point of view of therapeutic effects, EVs derived from the mesenchymal stromal cells (MSC) of different origins deserve attention. The use of MSC-EVs is currently being actively explored in different fields of regenerative medicine. According to the literature, the administration of MSC-EVs in animal models with ovarian insufficiency could increase the ovarian reserve, reproductive potential, and the effectiveness of assisted reproductive technologies programs. The use of MSC-EVs in medicine is limited by a small number of studies, the insufficient duration of an observation of the models treated with this method, and by the study of possible side effects.
Conclusion. Taking into account the promising results of utilizing MSC-EVs in different fields of regenerative medicine and the data available in the literature on the possibility of increasing the ovarian reserve and improving the reproductive potential with MSC-EVs in the animal models, this method may be a promising treatment in patients with a low reproductive potential and ovarian insufficiency.

extracellular vesicles

mesenchymal stromal cells

assisted reproductive technologies

ovarian reserve

Full text (in Russian)

Keshtkar S., Azarpira N., Ghahremani M.H. Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res. Ther. 2018; 9(1): 63. https://dx.doi.org/10.1186/s13287-018-0791-7.
Simon C., Greening D.W., Bolumar D., Balaguer N., Salamonsen L.A., Vilella F. Extracellular vesicles in human reproduction in health and disease. Endocr. Rev. 2018; 39(3): 292-332. https://dx.doi.org/10.1210/er.2017-00229.
Machtinger R., Laurent L.C., Baccarelli A.A. Extracellular vesicles: roles in gamete maturation, fertilization and embryo implantation. Hum. Reprod. Update. 2016; 22(2): 182-93. https://dx.doi.org/10.1093/humupd/dmv055.
Zaborowski M.P., Balaj L., Breakefield X.O., Lai C.P. Extracellular vesicles: composition, biological relevance, and methods of study. Bioscience. 2015; 65(8): 783-97. https://dx.doi.org/10.1093/biosci/biv084.
Meldolesi J. Exosomes and ectosomes in intercellular communication. Curr. Biol. 2018; 28(8): R435-44. https://dx.doi.org/10.1016/j.cub.2018.01.059.
Silachev D.N., Goryunov K.V., Shpilyuk M.A., Beznoschenko O.S., Morozova N.Y., Kraevaya E.E. et al. Effect of MSCS and MSC- derived extracellular vesicles on human blood coagulation. Cells. 2019; 8(3): 258. https://dx.doi.org/10.3390/cells8030258.
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.
Силачев Д.Н., Головичева В.В., Данилина Т.И., Шевцова Ю.А., Горюнов К.В., Бабенко В.А., Плотников Е.Ю., Туровский Е.А., Зинченко В.П., Зоров Д.Б. Терапевтическое применение стволовых клеток и внеклеточных везикул: можно ли поставить знак равенства? Гены и клетки. 2020; 15 (Спецвыпуск 3): 32. [Silachev D.N., Golovicheva, Danilina T.I., Shevtsova Yu.A., Goryunov K.V. et al. VII Youth School Conference on Molecular and Cellular Biology. Therapeutic Uses of Stem Cells and Extracellular Vesicles: Is It Possible to Equalize? October 12–15, 2020, St. Petersburg. (in Russian)].
Великонивцев Ф.С., Головкин А.С. Терапия внеклеточными везикулами: возможности, механизмы и перспективы применения. Российский кардиологический журнал. 2020; 25(10): 221-31. [Veliconivcev F.C., Golovkin А.С. Extracellular vesicle therapy: possibilities, mechanisms and application prospects. Russian journal of cardiology. 2020; 25(10): 221-21. (in Russian)]. https://dx.doi.org/10.15829/1560-4071-2020-4081.
Yáñez-Mó M., Siljander P.R., Andreu Z., Zavec A.B., Borràs F.E., Buzas E.I. et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles. 2015; 4: 27066. https://dx.doi.org/10.3402/jev.v4.27066.
Силачев Д.Н., Горюнов К.В., Плотников Е.Ю., Шевцова Ю.А., Бабенко В.А., Буров А.А., Рюмина И.И., Подуровская Ю.Л., Зубков В.В. Внеклеточные везикулы мочи как диагностический маркер почечных патологий. Педиатрия. Журнал имени Г.Н. Сперанского. 2020; 99(5): 154-63. [Silachev D.N., Goryunov K.V., Plotnikov E.Yu., Babenko V.A., Burov A.A. et al. Extracellular vesicles of urine as a diagnostic marker of renal pathologies. Pediatrics. 2020; 99(5): 154-63. (in Russian)].
Van Niel G., D'Angelo G., Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 2018; 19(4): 213-28. https://dx.doi.org/10.1038/nrm.2017.125.
Börger V. Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. J. Mol. Sci. 2017; 18(7): 1450. https://dx.doi.org/10.3390/ijms18071450.
Сухих Г.Т., Пекарев О.Г., Пекарева Е.О., Майбородин И.В., Силачев Д.Н., Баранов И.И., Поздняков И.М., Бушуева Н.С., Новиков А.В. Первые результаты клинического применения экстрацеллюлярных микровезикул мезенхимальных стромальных клеток после абдоминального родоразрешения. Акушерство и гинекология. 2021; 1: 52-60. https://dx.doi.org/10.18565/aig.2021.1.52-60. [Sukhikh G.Т., Pekarev O.G., Pekareva G.O., Maiborodin I.V., Silachev D.N. et al. The first results of clinical application of extracellular microvesicles of mesenchymal stromal cells after abdominal delivery. Obstetrics and gynecology. 2021; 1: 52-60. (in Russian)]. https://dx.doi.org/10.18565/aig.2021.1.52-60.
Spees J.L., Lee R.H., Gregory C.A. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res. Ther. 2016; 31(7): 125. https://dx.doi.org/10.1186/s13287-016-0363-7.
Brown C., McKee C., Bakshi S., Walker K., Hakman E., Halassy S. et al. Mesenchymal stem cells: Cell therapy and regeneration potential. J. Tissue Eng. Regen. Med. 2019; 13(9): 1738-55. https://dx.doi.org/10.1002/term.2914.
Sriramulu S., Banerjee A., Di Liddo R., Jothimani G., Gopinath M., Murugesan R. et al. Concise review on clinical applications of conditioned medium derived from human Umbilical Cord-Mesenchymal Stem Cells (UC-MSCs). Int. J. Hematol. Oncol. Stem Cell Res. 2018; 12(3): 230-4.
Phinney D.G., Pittenger M.F. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017; 35(4): 851-8. https://dx.doi.org/10.1002/stem.2575.
Tkach M., Thery D. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016; 164(6): 1226-32. https://dx.doi.org/10.1016/j.cell.2016.01.043.
Zheng G., Huang R., Qiu G., Ge M., Wang J., Shu Q., Xu J. Mesenchymal stromal cell-derived extracellular vesicles: regenerative and immunomodulatory effects and potential applications in sepsis. Cell Tissue Res. 2018; 374(1): 1-15. https://dx.doi.org/10.1007/s00441-018-2871-5.
Matei A.C., Antounians L., Zani A. Extracellular vesicles as a potential therapy for neonatal conditions: state of the art and challenges in clinical translation. Pharmaceutics. 2019; 11(8): 404. 10.3390/pharmaceutics11080404.
Wang Y., Yu D., Liu Z., Zhou F., Dai J., Wu B. et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res. Ther. 2017; 8(1): 189. https://dx.doi.org/10.1186/s13287-017-0632-0.
Kordelas L., Rebmann V., Ludwig A.K., Radtke S., Ruesing J., Doeppner T.R. et al. MSC-derived exosomes: A novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014; 28(4): 970-3. https://dx.doi.org/10.1038/leu.2014.41.
Nassar W., El-Ansary M., Sabry D., Mostafa M.A., Fayad T., Kotb E. et al. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater. Res. 2016; 20: 21. https://dx.doi.org/10.1186/s40824-016-0068-0.
Internet source: ClinicalTrials.gov.
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.
da Silveira J.C., Veeramachaneni D.N., 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.
Liu M., Qiu Y., Xue Z., Wu R., Li J., Niu X. et al. Small extracellular vesicles derived from embryonic stem cells restore ovarian function of premature ovarian failure through PI3K/AKT signaling pathway. Stem Cell Res. Ther. 2020; 11(1): 3. https://dx.doi.org/10.1186/s13287-019-1508-2.
Liu C., Yin H., Jiang H., Du X., Wang C., Liu Y. et al. Extracellular vesicles derived from mesenchymal stem cells recover fertility of premature ovarian insufficiency mice and the effects on their offspring. Сell Transplant. 2020; 29: 963689720923575. https://dx.doi.org/10.1177/0963689720923575.
Marinaro F., Pericuesta E., Sánchez-Margallo F.M., Casado J.G., Álvarez V., Matilla E. et al. Extracellular vesicles derived from endometrial human mesenchymal stem cells improve IVF outcome in an aged murine model. Reprod. Domest. Anim. 2018; 53(Suppl. 2): 46-9. https://dx.doi.org/10.1111/rda.13314.
Lopera-Vasquez R., Hamdi M., Maillo V., Gutierrez-Adan A., Bermejo-Alvarez P., Ramírez M.Á. et al. Effect of bovine oviductal extracellular vesicles on embryo development and quality in vitro. Reproduction. 2017; 153(4): 461-70. https://dx.doi.org/10.1530/REP-16-0384.
Lopera-Vasquez 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.

Received 27.04.2021

Accepted 18.05.2021

Elizaveta E. Kraevaya, Researcher at the Department of Assisted Technologies for the Treatment of Infertility, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia. E-mail: e_kraevaya@oparina4.ru. 117997, Russia, Moscow, Ac. Oparina str., 4.
Natalya P. Makarova, Dr. Bio. Sci., Leading Researcher at the Department of Assisted Reproductive Technologies in the Treatment of Infertility, V.I. Kulakov
NMRC for OG&P, Ministry of Health of Russia. E-mail: np_makarova@oparina4.ru. 117997, Russia, Moscow, Ac. Oparina str., 4.
Anastasia P. Sysoeva, embryologist at the Department of Assisted Reproductive Technologies in the Treatment of Infertility, V.I. Kulakov NMRC for OG&P,
Ministry of Health of Russia. E-mail: a_sysoeva@oparina4.ru. 117997, Russia, Moscow, Ac. Oparina str., 4.
Elena A. Kalinina, Dr. Med. Sci., Professor, Head of the Department of Assisted Technologies for the Treatment of Infertility, Scientific Secretary of the Dissertation Council, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia. E-mail: e_kalinina@oparina4.ru. 117997, Russia, Moscow, Ac. Oparina str., 4.
Denis N. Silachev, Dr. Bio. Sci., Head of the Cell Technologies Laboratory, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia. E-mail: d_silachev@oparina4.ru.
117997, Russia, Moscow, Ac. Oparina str., 4.

For citation: Kraevaya E.E., Makarova N.P., Sysoeva A.P., Kalinina E.A., Silachev D.N. Therapeutic opportunities of extracellular vesicles in reproductive medicine.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 7: 5-9 (in Russian)
https://dx.doi.org/10.18565/aig.2021.7.5-9

Therapeutic opportunities of extracellular vesicles in reproductive medicine

Kraevaya E.E., Makarova N.P., Sysoeva A.P., Kalinina E.A., Silachev D.N.

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