Molecular strategies to enhance the efficiency of in vitro oocyte maturation in a mouse model
REVIEW
Abstract
Introduction. In vivo oocyte maturation occurs within ovarian follicles. Under in vitro conditions, extensive research is being conducted on the cultivation of immature oocytes to achieve full maturity. In vitro oocyte culture is a key technique in reproductive biology, applied in fertility preservation, developmental studies, and assisted reproductive technologies. Aim. To systematize data on growth factors and hormones affecting IVM in mice, aiming to identify optimal strategies for protocol improvement. Materials and methods. An analytical review of 39 scientific publications on mouse IVM was conducted, focusing on morphological maturity criteria, oocyte microenvironment, and signaling pathways. A preliminary quantitative analysis of key modulators’ efficacy was performed. Results. Follicle-stimulating hormone, leukemia inhibitory factor (LIF), bone morphogenetic protein 15 (BMP15), growth differentiation factor 9 (GDF9), epidermal growth factor (EGF), insulin-like growth factors I and II (IGF-I/II), and granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly influence various aspects of maturation: cumulus-oocyte complex expansion, metaphase II attainment, embryo quality, and oxidative stress reduction. Antioxidants (glutathione, atorvastatin) also improve IVM conditions. Conclusion. Combined use of hormones, growth factors, and antioxidants can substantially enhance IVM efficiency. These findings may be extrapolated to human protocol development.
References
1. Шабалов Н.П., Цвелев Ю.В., Кира Е.Ф. Основы перинатологии. Под ред. Н.П. Шабанова, Ю.В. Цвелева. М.: МЕДпресс-информ; 2002. EDN: VXHJOZ.
2. Дробинцева А.О., Фролов В.К., Боголюбова И.О., Савельева О.Е., Кулева С.А. Созревание ооцитов in vitro: биологические основы и перспективы клинического использования. Цитология. 2025;67(2);65–79. https://doi.org/10.31857/S0041377125020015.
3. Доброхотова Ю.Е., Лапина И.А., Малахова А.А., Сорокин Я.А., Чирвон Т.Г. In vitro maturation for fertility preservation in patients with cancer: A review. Гинекология. 2023;25(3):186–192. https://doi.org/10.26442/20795696.2023.
4. Элленбоген А., Шалом-Пац Е., Аншина М.Б., Смирнова А.А. Дозревание ооцитов in vitro. Показания, техника и результаты. Проблемы репродукции. 2015;21(5):32–40.
5. Telfer E.E., Andersen C.Y. In vitro growth and maturation of primordial follicles and immature oocytes. Fertil Steril. 2021;115(5):1116–1125. https://doi.org/10.1016/j.fertnstert.2021.03.004.
6. Edson M.A., Nagaraja A.K., Matzuk M.M. The Mammalian Ovary from Genesis to Revelation. Endocr Rev. 2009;30(6):624–712. https://doi.org/10.1210/er.2008-0041.
7. Monniaux D., editor. Folliculogenesis. Cham: Springer; 2018. https://doi.org/10.1007/978-3-319-75969-3.
8. Pedersen T., Peters H. Proposal for a classification of oocytes and follicles in the mouse ovary. J Reprod Fertil. 1968;17(3):555–557. https://doi.org/10.1530/jrf.0.0170555.
9. Jiang Y., Adhikari D., Li C., Zhou X. Spatiotemporal regulation of maternal m RNAs during vertebrate oocyte meiotic maturation. Biol Rev Camb Philos Soc. 2023;98(3):900–930. https://doi.org/10.1111/brv.12928.
10. Ma J.Y., Li M., Luo Y.B. et al. Maternal factors required for oocyte developmental competence in mice. Transcriptome analysis of non-surrounded nucleolus (NSN) and surrounded nucleolus (SN) oocytes. Cell Cycle. 2013;12(12):1928–1938. https://doi.org/10.4161/cc.24733.
11. Shishova K.V., Lavrentyeva E.A., Khamidullina A.I., Zatsepina O.V. Position of the nucleus in mouse germinal vesicle-stage oocytes with different chromatin configurations. Ontogenez. 2016;47(5):331–338. https://doi.org/10.1134/S009545271605008X.
12. Zuccotti M., Ponce R.H., Boiani M., Guizzardi S., Govoni P. et al. The analysis of chromatin organisation allows selection of mouse antral oocytes competent for development to blastocyst. Zygote. 2002;10(1):73–78. https://doi.org/10.1017/s0967199402001098.
13. Fox C.A., Sheets M.D., Wahle E., Wickens M. Polyadenylation of maternal m RNA during oocyte maturation: poly(A) addition in vitro requires a regulated RNA binding activity and a poly(A) polymerase. EMBO J. 1992;11(13):5021–5032. https://doi.org/10.1002/j.1460-2075.1992.tb05607.x.
14. Reyes J.M., Ross P.J. Cytoplasmic polyadenylation in mammalian oocyte maturation. Wiley Interdisciplinary Reviews: RNA. 2016;7(1):71–89. https://doi.org/10.1002/wrna.1317.
15. Блашкив Т.В., Шепель А.А., Вознесенская Т.Ю. Экспрессия генов клетками кумулюсного окружения ооцита в период овуляции и оплодотворения (обзор литературы). Проблемы репродукции. 2014;20(1):55–58.
16. Strączyńska P., Papis K., Morawiec E., Czerwiński M., Gajewski Z. et al. Signaling mechanisms and their regulation during in vivo or in vitro maturation of mammalian oocytes. Reprod Biol Endocrinol. 2022;20(1):158. https://doi.org/10.1186/s12958-022-01054-1.
17. Thomas F.H., Vanderhyden B.C. Oocyte-granulosa cell interactions during mouse follicular development: regulation of kit ligand expression and its role in oocyte growth. Reprod Biol Endocrinol. 2006;4:19. https://doi.org/10.1186/1477-7827-4-19.
18. Петров И.А., Дмитриева М.Л., Тихоновская О.А., Петрова М.С., Логвинов С.В. Тканевые и молекулярные основы фолликулогенеза. Механизмы раннего фолликулярного роста. Проблемы репродукции. 2017;23(6):33–41.
19. Clarke H.J. Transzonal projections: Essential structures mediating intercellular communication in the mammalian ovarian follicle. Mol Reprod Dev. 2022;89(9):509–525. https://doi.org/10.1002/mrd.23597.
20. Orisaka M., Tajima K., Tsang B.K., Kotsuji F. Oocyte-granulosa-theca cell interactions during preantral follicular development. J Ovarian Res. 2009;2(1):9. https://doi.org/10.1186/1757-2215-2-9.
21. Gurbuz A.S., Gode F., Uzman M.S. et al. Gn RH agonist triggering affects the kinetics of embryo development: a comparative study. J Ovarian Res. 2016;9(1):42. https://doi.org/10.1186/s13048-016-0253-0.
22. Chen L., Russell P.T., Larsen W.J. Sequential effects of follicle-stimulating hormone and luteinizing hormone on mouse cumulus expansion in vitro. Biol Reprod. 1994;51(2):290–295. https://doi.org/10.1095/biolreprod51.2.290.
23. Son Y.B., Jeong Y.I., Hossein M.S., Yu X., Olsson P.O. et al. Influence of PMSG on Super stimulation and Embryo Development Following Somatic Cell Nuclear Transfer in Holstein Cows in the United Arab Emirates. Frontiers in Veterinary Science. 2022;9:895325. https://doi.org/10.3389/fvets.2022.895325.
24. Desroziers E. Unusual suspects: Glial cells in fertility regulation and their suspected role in polycystic ovary syndrome. J Neuroendocrinology. 2022;34(7):e13136. https://doi.org/10.1111/jne.13136.
25. Mesbah F., Zare Shahneh F., Vojdani Z., Mirkhani H. Does metformin improve in vitro maturation and ultrastructure of oocytes retrieved from estradiol valerate polycystic ovary syndrome-induced rats. J Ovarian Res. 2015;8(1):45. https://doi.org/10.1186/s13048-015-0172-3.
26. Sadeghi M., Chegini R., Khafaei M., Sabbagh Ziarani F., Zafari F. Association of Atorvastatin with GDF9 and BMP15 Expression and in vitro Maturation of Mouse Oocytes. Iranian Journal of Pharmaceutical Sciences. 2023;19(3):188–193.
27. Tamura H., Nakamura Y., Korkmaz A. et al. The role of melatonin as an antioxidant in the follicle. J Ovarian Res. 2012;5(1):5. https://doi.org/10.1186/1757-2215-5-5.
28. De Matos D.G., Cervera R.P., Sirard M.A. Leukemia inhibitory factor induces cumulus expansion in immature human and mouse oocytes and improves mouse two-cell rate and delivery rates when it is present during mouse in vitro oocyte maturation. Fertil Steril. 2008;90(6):2367–2375. https://doi.org/10.1016/j.fertnstert.2007.10.020.
29. Zhao T., Pan Y., Li Q., Ding T., Niayale R. et al. Leukemia inhibitory factor enhances the development and subsequent blastocysts quality of yak oocytes in vitro. Frontiers in Veterinary Science. 2022;9:885325. https://doi.org/10.3389/fvets.2022.885325.
30. Budna J., Rybska M., Ciesiółka S. et al. Expression of genes associated with BMP signaling pathway in porcine oocytes before and after IVM — a microarray approach. Reprod Biol Endocrinol. 2017;15(1):43. https://doi.org/10.1186/s12958-017-0259-8.
31. Dimitrakakis C., Zhou J., Bondy C.A. Androgens and mammary growth and neoplasia. Fertil Steril. 2002;77(2 Suppl 2):S26–S33. https://doi.org/10.1016/s0015-0282(01)02965-1.
32. Shekarian A., Sharifi Z.N., Nazarnejad M.M., Saeinia A., Abdi Sh. In Vitro Culture of Mouse Preantral Follicle in Supplemented Medium with Bone Morphogenetic Protein 15 (BMP15). Reprod Biol Endocrinol. 2020;18(1):112. https://doi.org/10.1186/s12958-020-00671-0.
33. Yeo C.X., Gilchrist R.B., Thompson J.G., Lane M. Exogenous growth differentiation factor 9 in oocyte maturation media enhances subsequent embryo development and fetal viability in mice. Hum Reprod. 2008;23(1):67–73. https://doi.org/10.1093/humrep/dem318.
34. Akbartabar Toori M., Mosavi E., Sadeghi M., Chegini R. et al. Influence of Insulin-Like Growth Factor-I on Maturation and Fertilization Rate of Immature Oocyte and Embryo Development in NMRI Mouse with TCM199 and α-MEM Medium. J Clin Diagn Res. 2014;8(12):CC05–CC12. https://doi.org/10.7860/JCDR/2014/10330.5275.
35. Wan Y., Muhammad T., Huang T., Lv Y., Sha Q. et al. IGF2 reduces meiotic defects in oocytes from obese mice and improves embryonic developmental competency. Reprod Biol Endocrinol. 2022;20(1):159. https://doi.org/10.1186/s12958-022-01055-0.
36. Silvia R., Catt S., Pangestu M. The Effects of FSH and Glutathione Supplementation to the in Vitro Maturation Media on Mouse Oocyte Maturation. In: Proceedings of the 1st EAI International Conference on Medical and Health Research. 2019. https://doi.org/10.4108/eai.13-7-2019.2286875.
37. Iyer N. Comparison of two commercial in-vitro maturation culture systems with standard IVM media: what works best for mouse oocytes. MOJ Anatomy & Physiology. 2016;2(4):61–67.
38. Saini A., Mc Pherson N.O., Nottle M. Addition of GM-CSF during in vitro oocyte maturation improves embryo development and implantation and birth rate in mice. Reprod Fertil. 2024;70(4):411–417. https://doi.org/10.1262/jrd.2023-120.
39. Kim M., Hwang S.U., Yoon J.D. et al. Supplementation During in vitro Maturation of Porcine Cumulus-Oocyte Complexes and Subsequent Embryonic Development After Parthenogenetic Activation. Frontiers in Veterinary Science. 2021;8:779298. https://doi.org/10.3389/fvets.2021.779298.
40. Ptak G., Matsukawa K., Palmieri C. et al. Developmental and functional evidence of nuclear immaturity in prepubertal oocytes. Hum Reprod. 2006;21(9):2228–2237. https://doi.org/10.1093/humrep/del178.
41. Yan F., Zhao Q., Li Y., Zheng Z. et al. The role of oxidative stress in ovarian aging: a review. J Ovarian Res. 2022;15(1):118. https://doi.org/10.1186/s13048-022-01010-3.
