Skip to main content

Advertisement

SpringerLink
Log in

Capacitation IVM improves cumulus function and oocyte quality in minimally stimulated mice

  • Gamete Biology
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Oocyte in vitro maturation (IVM) is a patient-friendly reproductive technology but lower success rates than IVF have limited its uptake. Capacitation-IVM (CAPA-IVM) is an innovative new IVM system currently undergoing clinical evaluation. This study aimed to determine temporal effects of the pre-IVM phase of CAPA-IVM on cumulus function and oocyte developmental competence in mildly-stimulated mice.

Methods

Immature cumulus oocyte complexes (COCs) derived from mildly stimulated (23 h PMSG) 28-day-old mice underwent pre-IVM for 0–24 h in medium containing c-type natriuretic peptide (CNP), E2, FSH and insulin, prior to IVM (CAPA-IVM). The effect of pre-IVM duration on cumulus cell function and embryo development post-CAPA-IVM/IVF was assessed.

Results

Day 6 blastocyst rate increased incrementally with increasing pre-IVM duration: 40.6 ± 2.0%, 45.8 ± 1.2%, 52.2 ± 3.5%, 53.3 ± 5.9%, and 59.9 ± 2.5% for 0, 2, 6, 12, and 24 h pre-IVM, respectively (P < 0.01). DNA content/COC, a measure of cumulus cell proliferation, was significantly higher with 24 h pre-IVM group compared to 0, 2, or 6 h pre-IVM (P < 0.001). Pre-IVM for 24 h significantly increased cumulus expansion and mRNA expression of matrix genes Has2 and Tnfaip6 and Areg relative to no pre-IVM control (P < 0.01). Cumulus-oocyte gap-junctional communication (GJC) was maintained throughout 24 h pre-IVM (P < 0.0001), and GJC loss was slowed during the subsequent IVM phase, whilst meiotic resumption was accelerated (P < 0.05). Pre-IVM increased COC ATP and ADP content (P < 0.05), but not AMP, ATP/ADP, and energy charge.

Conclusion

The pre-IVM phase of CAPA-IVM improves the quality of IVM oocytes in a temporally dependent manner and significantly influences cumulus cell function including increased cell proliferation, cumulus expansion, and prolonged cumulus-oocyte GJC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. De Vos M, Smitz J, Thompson JG, Gilchrist RB. The definition of IVM is clear-variations need defining. Hum Reprod. 2016;31:2411–5.

    PubMed  Google Scholar 

  2. Cha KY, Koo JJ, Ko JJ, Choi DH, Han SY, Yoon TK. Pregnancy after in vitro fertilization of human follicular oocytes collected from nonstimulated cycles, their culture in vitro and their transfer in a donor oocyte program. Fertil Steril. 1991;55:109–13.

    CAS  PubMed  Google Scholar 

  3. Ho V, Pham TD, Le AH, Ho TM, Vuong LN. Live birth rate after human chorionic gonadotropin priming in vitro maturation in women with polycystic ovary syndrome. J Ovarian Res. 2018;11:70.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Walls ML, Hunter T, Ryan JP, Keelan JA, Nathan E, Hart RJ. In vitro maturation as an alternative to standard in vitro fertilization for patients diagnosed with polycystic ovaries: a comparative analysis of fresh, frozen and cumulative cycle outcomes. Hum Reprod. 2015;30:88–96.

    CAS  PubMed  Google Scholar 

  5. Gilchrist RB, Luciano AM, Richani D, Zeng HT, Wang X, Vos MD, et al. Oocyte maturation and quality: role of cyclic nucleotides. Reproduction. 2016;152:R143–57.

    CAS  PubMed  Google Scholar 

  6. Funahashi H, Cantley TC, Day BN. Synchronization of meiosis in porcine oocytes by exposure to dibutyryl cyclic adenosine monophosphate improves developmental competence following in vitro fertilization. Biol Reprod. 1997;57:49–53.

    CAS  PubMed  Google Scholar 

  7. Luciano AM, Pocar P, Milanesi E, Modina S, Rieger D, Lauria A, et al. Effect of different levels of intracellular cAMP on the in vitro maturation of cattle oocytes and their subsequent development following in vitro fertilization. Mol Reprod Dev. 1999;54:86–91.

    CAS  PubMed  Google Scholar 

  8. Franciosi F, Coticchio G, Lodde V, Tessaro I, Modina SC, Fadini R, et al. Natriuretic peptide precursor C delays meiotic resumption and sustains gap junction-mediated communication in bovine cumulus-enclosed oocytes. Biol Reprod. 2014;91:61.

    PubMed  Google Scholar 

  9. Romero S, Sánchez F, Lolicato F, Van Ranst H, Smitz J. Immature oocytes from unprimed juvenile mice become a valuable source for embryo production when using c-type natriuretic peptide as essential component of culture medium. Biol Reprod. 2016;95:64.

    PubMed  Google Scholar 

  10. Zhang M, Su YQ, Sugiura K, Xia G, Eppig JJ. Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. Science. 2010;330:366–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang M, Su YQ, Sugiura K, Wigglesworth K, Xia G, Eppig JJ. Estradiol promotes and maintains cumulus cell expression of natriuretic peptide receptor 2 (NPR2) and meiotic arrest in mouse oocytes in vitro. Endocrinology. 2011;152:4377–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Tsuji T, Kiyosu C, Akiyama K, Kunieda T. CNP/NPR2 signaling maintains oocyte meiotic arrest in early antral follicles and is suppressed by EGFR-mediated signaling in preovulatory follicles. Mol Reprod Dev. 2012;79:795–802.

    CAS  PubMed  Google Scholar 

  13. Norris RP, Ratzan WJ, Freudzon M, Mehlmann LM, Krall J, Movsesian MA, et al. Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte. Development. 2009;136:1869–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Vaccari S, Weeks JL, Hsieh M, Menniti FS, Conti M. Cyclic GMP signaling is involved in the luteinizing hormone-dependent meiotic maturation of mouse oocytes. Biol Reprod. 2009;81:595–604.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Nogueira D, Cortvrindt R, De Matos DG, Vanhoutte L, Smitz J. Effect of phosphodiesterase type 3 inhibitor on developmental competence of immature mouse oocytes in vitro. Biol Reprod. 2003;69:2045–52.

    CAS  PubMed  Google Scholar 

  16. Zhang J, Wei Q, Cai J, Zhao X, Ma B. Effect of c-type natriuretic peptide on maturation and developmental competence of goat oocytes matured in vitro. PLoS One. 2015;10:e0132318.

    PubMed  PubMed Central  Google Scholar 

  17. Santiquet NW, Greene AF, Becker J, Barfield JP, Schoolcraft WB, Krisher RL. A pre-in vitro maturation medium containing cumulus oocyte complex ligand-receptor signaling molecules maintains meiotic arrest, supports the cumulus oocyte complex and improves oocyte developmental competence. Mol Hum Reprod. 2017;23:594–606.

    CAS  PubMed  Google Scholar 

  18. Zhang T, Zhang C, Fan X, Li R, Zhang J. Effect of c-type natriuretic peptide pretreatment on in vitro bovine oocyte maturation. In Vitro Cell Dev Biol Anim. 2017;53:199–206.

    CAS  PubMed  Google Scholar 

  19. Sánchez F, Le AH, Ho VNA, Romero S, Van Ranst H, De Vos M, et al. Biphasic in vitro maturation (CAPA-IVM) specifically improves the developmental capacity of oocytes from small antral follicles. J Assist Reprod Genet. 2019. https://doi.org/10.1007/s10815-019-01551-5.

    PubMed  Google Scholar 

  20. Sánchez F, Lolicato F, Romero S, De Vos M, Van Ranst H, Verheyen G, et al. An improved IVM method for cumulus-oocyte complexes from small follicles in polycystic ovary syndrome patients enhances oocyte competence and embryo yield. Hum Reprod. 2017;32:2056–68.

    PubMed  Google Scholar 

  21. Vuong LN, Ho VNA, Ho TM, Dang VQ, Phung TH, Giang NH, et al. The effectiveness and safety of in vitro maturation of oocytes versus in vitro fertilisation in women with high antral follicle count: study protocol for a randomised controlled trial. BMJ Open. 2018;8:e023413.

    PubMed  PubMed Central  Google Scholar 

  22. Gilchrist RB, Thompson JG. Oocyte maturation: emerging concepts and technologies to improve developmental potential in vitro. Theriogenology. 2007;67:6–15.

    PubMed  Google Scholar 

  23. Gilula NB, Epstein ML, Beers WH. Cell-to-cell communication and ovulation. A study of the cumulus-oocyte complex. J Cell Biol. 1978;78:58–75.

    CAS  PubMed  Google Scholar 

  24. Gilchrist RB, Ritter LJ, Armstrong DT. Oocyte-somatic cell interactions during follicle development in mammals. Anim Reprod Sci. 2004;82-83:431–46.

    CAS  PubMed  Google Scholar 

  25. Thouas GA, Korfiatis NA, French AJ, Jones GM, Trounson AO. Simplified technique for differential staining of inner cell mass and trophectoderm cells of mouse and bovine blastocysts. Reprod BioMed Online. 2001;3:25–9.

    PubMed  Google Scholar 

  26. Calafiore R, Falorni A, Ambrosini MV, Basta G, Picchio ML, Brunetti P. A simple method for the DNA content assay of culture maintained pancreatic islets of Langerhans. J Endocrinol Investig. 1991;14:629–33.

    CAS  Google Scholar 

  27. Richani D, Constance K, Lien S, Agapiou D, Stocker WA, Hedger MP, et al. Cumulin and FSH cooperate to regulate Inhibin B and Activin B production by human granulosa-lutein cells in vitro. Endocrinology. 2019;160:853–62.

    PubMed  Google Scholar 

  28. Vanderhyden BC, Caron PJ, Buccione R, Eppig JJ. Developmental pattern of the secretion of cumulus expansion-enabling factor by mouse oocytes and the role of oocytes in promoting granulosa cell differentiation. Dev Biol. 1990;140:307–17.

    CAS  PubMed  Google Scholar 

  29. Luciano AM, Modina S, Vassena R, Milanesi E, Lauria A, Gandolfi F. Role of intracellular cyclic adenosine 3',5'-monophosphate concentration and oocyte-cumulus cells communications on the acquisition of the developmental competence during in vitro maturation of bovine oocyte. Biol Reprod. 2004;70:465–72.

    CAS  PubMed  Google Scholar 

  30. Li HJ, Sutton-McDowall ML, Wang X, Sugimura S, Thompson JG, Gilchrist RB. Extending prematuration with cAMP modulators enhances the cumulus contribution to oocyte antioxidant defence and oocyte quality via gap junctions. Hum Reprod. 2016;31:810–21.

    CAS  PubMed  Google Scholar 

  31. Bustamante S, Gilchrist RB, Richani D. A sensitive method for the separation and quantification of low-level adenine nucleotides using porous graphitic carbon-based liquid chromatography and tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2017;1061-1062:445–51.

    CAS  Google Scholar 

  32. Atkinson DE, Walton GM. Adenosine triphosphate conservation in metabolic regulation. Rat liver citrate cleavage enzyme. J Biol Chem. 1967;242:3239–41.

    CAS  PubMed  Google Scholar 

  33. Thompson JG, Lane M, Gilchrist RB. Metabolism of the bovine cumulus-oocyte complex and influence on subsequent developmental competence. Soc Reprod Fertil Suppl. 2007;64:179–90.

    CAS  PubMed  Google Scholar 

  34. Herrick JR, Brad AM, Krisher RL, Pope WF. Intracellular adenosine triphosphate and glutathione concentrations in oocytes from first estrous, multi-estrous, and testosterone-treated gilts. Anim Reprod Sci. 2003;78:123–31.

    CAS  PubMed  Google Scholar 

  35. Wei Q, Zhou C, Yuan M, Miao Y, Zhao X, Ma B. Effect of C-type natriuretic peptide on maturation and developmental competence of immature mouse oocytes in vitro. Reprod Fertil Dev. 2017;29:319–24.

    CAS  PubMed  Google Scholar 

  36. Richani D, Wang X, Zeng HT, Smitz J, Thompson JG, Gilchrist RB. Pre-maturation with cAMP modulators in conjunction with EGF-like peptides during in vitro maturation enhances mouse oocyte developmental competence. Mol Reprod Dev. 2014;81:422–35.

    CAS  PubMed  Google Scholar 

  37. Gilchrist RB. Recent insights into oocyte-follicle cell interactions provide opportunities for the development of new approaches to in vitro maturation. Reprod Fertil Dev. 2011;23:23–31.

    PubMed  Google Scholar 

  38. Thomas RE, Armstrong DT, Gilchrist RB. Bovine cumulus cell-oocyte gap junctional communication during in vitro maturation in response to manipulation of cell-specific cyclic adenosine 3',5'-monophosophate levels. Biol Reprod. 2004;70:548–56.

    CAS  PubMed  Google Scholar 

  39. Kidder GM, Vanderhyden BC. Bidirectional communication between oocytes and follicle cells: ensuring oocyte developmental competence. Can J Physiol Pharmacol. 2010;88:399–413.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Luciano AM, Sirard MA. Successful in vitro maturation of oocytes: a matter of follicular differentiation. Biol Reprod. 2018;98:162–9.

    PubMed  Google Scholar 

  41. Luciano AM, Franciosi F, Modina SC, Lodde V. Gap junction-mediated communications regulate chromatin remodeling during bovine oocyte growth and differentiation through cAMP-dependent mechanism(s). Biol Reprod. 2011;85:1252–9.

    CAS  PubMed  Google Scholar 

  42. Shuhaibar LC, Egbert JR, Norris RP, Lampe PD, Nikolaev VO, Thunemann M, et al. Intercellular signaling via cyclic GMP diffusion through gap junctions restarts meiosis in mouse ovarian follicles. Proc Natl Acad Sci U S A. 2015;112:5527–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Van Blerkom J, Davis PW, Lee J. ATP content of human oocytes and developmental potential and outcome after in-vitro fertilization and embryo transfer. Hum Reprod. 1995;10:415–24.

    CAS  PubMed  Google Scholar 

  44. Brad AM, Bormann CL, Swain JE, Durkin RE, Johnson AE, Clifford AL, et al. Glutathione and adenosine triphosphate content of in vivo and in vitro matured porcine oocytes. Mol Reprod Dev. 2003;64:492–8.

    CAS  PubMed  Google Scholar 

  45. Zeng HT, Ren Z, Guzman L, Wang X, Sutton-McDowall ML, Ritter LJ, et al. Heparin and cAMP modulators interact during pre-in vitro maturation to affect mouse and human oocyte meiosis and developmental competence. Hum Reprod. 2013;28:1536–45.

    CAS  PubMed  Google Scholar 

  46. Park JY, Su YQ, Ariga M, Law E, Jin SL, Conti M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science. 2004;303:682–4.

    CAS  PubMed  Google Scholar 

  47. Prochazka R, Kalab P, Nagyova E. Epidermal growth factor-receptor tyrosine kinase activity regulates expansion of porcine oocyte-cumulus cell complexes in vitro. Biol Reprod. 2003;68:797–803.

    CAS  PubMed  Google Scholar 

  48. Ritter LJ, Sugimura S, Gilchrist RB. Oocyte induction of EGF responsiveness in somatic cells is associated with the acquisition of porcine oocyte developmental competence. Endocrinology. 2015;156:2299–312.

    CAS  PubMed  Google Scholar 

  49. Richani D, Gilchrist RB. The epidermal growth factor network: role in oocyte growth, maturation and developmental competence. Hum Reprod Update. 2018;24:1–14.

    CAS  PubMed  Google Scholar 

  50. Sugimura S, Ritter LJ, Rose RD, Thompson JG, Smitz J, Mottershead DG, et al. Promotion of EGF receptor signaling improves the quality of low developmental competence oocytes. Dev Biol. 2015;403:139–49.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful for the helpful advice from Dr Sergio Romero (Centro de Fertilidad y Reproduccion Asistida, Lima, Peru), and support from Professor Johan Smitz from the Free University of Brussels, Belgium. The authors thank Sonia Bustamante for technical assistance with LC-MS/MS. Mass spectrometric results were obtained at the Bioanalytical Mass Spectrometry Facility within the Analytical Centre of the University of New South Wales.

Funding

This work was supported by grants (APP1076004, APP1062762, APP1139763) and fellowships (APP1023210, APP1117538) awarded to RBG from the National Health and Medical Research Council of Australia, and from Strategic Funds from the University of New South Wales Sydney. YZ and XL are supported by Overseas Training Funding of Tongji Hospital, China, and Fujian Overseas Study Scholarship China, respectively.

Author information

Authors and Affiliations

  1. Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Y. Zhao

  2. School of Women’s & Children’s Health, University of New South Wales, Sydney, NSW, 2052, Australia

    Y. Zhao, X. Liao, A.E. Krysta, M.J. Bertoldo, D. Richani & R.B. Gilchrist

  3. Reproductive Medicine Center, Fujian Provincial Maternity and Children’s Hospital, Fuzhou, 350000, China

    X. Liao

Authors
  1. Y. Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X. Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A.E. Krysta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M.J. Bertoldo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Richani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R.B. Gilchrist
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

This study was funded by RBG, and designed by RBG, DR, and YZ. YZ performed all experiments under guidance from DR and MJB and with assistance from XL, DR, and MJB. AEK performed COC DNA analyses and DR performed the LC-MS/MS. YZ and RBG wrote the manuscript which was edited and approved by all authors.

Corresponding author

Correspondence to R.B. Gilchrist.

Ethics declarations

All mouse procedures were approved by the UNSW Animal Ethics Committee (ethics number 17/105A) and followed the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, Y., Liao, X., Krysta, A. et al. Capacitation IVM improves cumulus function and oocyte quality in minimally stimulated mice. J Assist Reprod Genet 37, 77–88 (2020). https://doi.org/10.1007/s10815-019-01610-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-019-01610-x

Keywords

Search

Navigation