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Journal of Assisted Reproduction and Genetics

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01-02-2011 | Technical Innovations

Biomarkers of human oocyte developmental competence expressed in cumulus cells before ICSI: a preliminary study

Authors: Mourad Assidi, Markus Montag, Katrin Van Der Ven, Marc-André Sirard

Published in: Journal of Assisted Reproduction and Genetics | Issue 2/2011

Abstract

Purpose

To identify reliable genomic biomarkers expressed in cumulus cells that accurately and non-invasively predict the oocyte developmental competence and reinforce the already used morphological criteria.

Methods

Eight consenting patients were selected for ovarian stimulation and ICSI procedures. Cumulus-oocyte complexes were transvaginally punctured and individually selected based on both good morphological criteria and high zona pellucida birefringence. Following ICSI, two 3-day embryos per patient were transferred. Pregnancy outcome was recorded and proven implantation was thereafter confirmed. Differential gene expression was assessed using two microarray platforms. Further real-time PCR validation, Ingenuity pathways analysis and intra-patient analysis were performed on 17 selected candidates.

Results

Seven genes were differentially (p ≤ 0.05) associated to successful pregnancy and implantation. These biomarkers could be used to predict the oocyte developmental competence.

Conclusions

These genomic markers are a powerful reinforcement of morphological approaches of oocyte selection. Their large-scale validation could increase pregnancy outcome and single embryo transfer efficiency.

Balaban B, Urman B. Effect of oocyte morphology on embryo development and implantation. Reprod Biomed Online. 2006;12:608–15.PubMedCrossRef

Krisher RL. The effect of oocyte quality on development. J Anim Sci. 2004;82(E-Suppl):E14–23.PubMed

Ebner T, Moser M, Sommergruber M, Tews G. Selection based on morphological assessment of oocytes and embryos at different stages of preimplantation development: A review. Hum Reprod Update. 2003;9:251–62.PubMedCrossRef

Yu Y, Mai Q, Chen X, Wang L, Gao L, Zhou C, et al. Assessment of the developmental competence of human somatic cell nuclear transfer embryos by oocyte morphology classification. Hum Reprod. 2009;24:649–57.PubMedCrossRef

Coticchio G, Sereni E, Serrao L, Mazzone S, Iadarola I, Borini A. What criteria for the definition of oocyte quality? Ann N Y Acad Sci. 2004;1034:132–44.PubMedCrossRef

Chan PJ. Developmental potential of human oocytes according to zona pellucida thickness. J In Vitro Fert Embryo Transf. 1987;4:237–41.PubMedCrossRef

Borini A, Lagalla C, Cattoli M, Sereni E, Sciajno R, Flamigni C, et al. Predictive factors for embryo implantation potential. Reprod Biomed Online. 2005;10:653–68.PubMedCrossRef

Tanghe S, Van Soom A, Nauwynck H, Coryn M, de Kruif A. Minireview: Functions of the cumulus oophorus during oocyte maturation, ovulation, and fertilization. Mol Reprod Dev. 2002;61:414–24.PubMedCrossRef

Guerif F, Le Gouge A, Giraudeau B, Poindron J, Bidault R, Gasnier O, et al. Limited value of morphological assessment at days 1 and 2 to predict blastocyst development potential: A prospective study based on 4042 embryos. Hum Reprod. 2007;22:1973–81.PubMedCrossRef

10.

Templeton A. Joseph price oration. The multiple gestation epidemic: The role of the assisted reproductive technologies. Am J Obstet Gynecol. 2004;190:894–8.PubMedCrossRef

11.

Adashi EY, Barri PN, Berkowitz R, Braude P, Bryan E, Carr J, et al. Lunenfeld B, Pope A, Reynolds M, Rosenwaks Z, Shieve LA, Serour GI, Shenfield F, Templeton A, van Steirteghem A, Veeck L, Wennerholm UB: Infertility therapy-associated multiple pregnancies (births): An ongoing epidemic. Reprod Biomed Online. 2003;7:515–42.PubMedCrossRef

12.

Bromer JG, Seli E. Assessment of embryo viability in assisted reproductive technology: Shortcomings of current approaches and the emerging role of metabolomics. Curr Opin Obstet Gynecol. 2008;20:234–41.PubMedCrossRef

13.

Gerris JM. Single embryo transfer and ivf/icsi outcome: A balanced appraisal. Hum Reprod Update. 2005;11:105–21.PubMedCrossRef

14.

Pinborg A. Ivf/icsi twin pregnancies: Risks and prevention. Hum Reprod Update. 2005;11:575–93.PubMedCrossRef

15.

Sunde A. Significant reduction of twins with single embryo transfer in ivf. Reprod Biomed Online. 2007;15 Suppl 3:28–34.PubMedCrossRef

16.

Gerris J. Single-embryo transfer versus multiple-embryo transfer. Reprod Biomed Online. 2009;18 Suppl 2:63–70.PubMedCrossRef

17.

Hamamah S, Déchaud H, Hédon B. Transfert monoembryonnaire: Une alternative pour prévenir et éviter les grossesses multiples. Gynécologie Obstétrique & Fertilité. 2007;35:480–4.CrossRef

18.

Blondin P, Sirard MA. Oocyte and follicular morphology as determining characteristics for developmental competence in bovine oocytes. Mol Reprod Dev. 1995;41:54–62.PubMedCrossRef

19.

Mikkelsen AL, Lindenberg S. Morphology of in-vitro matured oocytes: Impact on fertility potential and embryo quality. Hum Reprod. 2001;16:1714–8.PubMedCrossRef

20.

Hussein TS, Thompson JG, Gilchrist RB. Oocyte-secreted factors enhance oocyte developmental competence. Dev Biol. 2006;296:514–21.PubMedCrossRef

21.

Eppig JJ, Wigglesworth K, Pendola FL. The mammalian oocyte orchestrates the rate of ovarian follicular development. Proc Natl Acad Sci U S A. 2002;99:2890–4.PubMedCrossRef

22.

Hashimoto S, Saeki K, Nagao Y, Minami N, Yamada M, Utsumi K. Effects of cumulus cell density during in vitro maturation of the developmental competence of bovine oocytes. Theriogenology. 1998;49:1451–63.PubMedCrossRef

23.

Sirard M-A, Trounson A. Follicular factors affecting oocyte maturation and developmental competence. In: TAOG RG, editor. Biology and pathology of the oocyte: Its role in fertility and reproductive medecine. Cambridge: Cambridge University Press; 2003. p. 305–15.

24.

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.PubMed

25.

Wang Q, Sun QY. Evaluation of oocyte quality: Morphological, cellular and molecular predictors. Reprod Fertil Dev. 2007;19:1–12.PubMedCrossRef

26.

Gardner DK, Sakkas D. Assessment of embryo viability: The ability to select a single embryo for transfer--a review. Placenta. 2003;24(Suppl B):S5–12.PubMedCrossRef

27.

Assou S, Haouzi D, Mahmoud K, Aouacheria A, Guillemin Y, Pantesco V, et al. A non-invasive test for assessing embryo potential by gene expression profiles of human cumulus cells: A proof of concept study. Mol Hum Reprod. 2008;14:711–9.PubMedCrossRef

28.

Anderson RA, Sciorio R, Kinnell H, Bayne RA, Thong KJ, de Sousa PA, et al. Cumulus gene expression as a predictor of human oocyte fertilisation, embryo development and competence to establish a pregnancy. Reproduction. 2009;138:629–37.PubMedCrossRef

29.

Montag M, Schimming T, Koster M, Zhou C, Dorn C, Rosing B, et al. Ven der Ven K: Oocyte zona birefringence intensity is associated with embryonic implantation potential in icsi cycles. Reprod Biomed Online. 2008;16:239–44.PubMedCrossRef

30.

Madaschi C, Aoki T. de Almeida Ferreira Braga DP, de Cassia Savio Figueira R, Semiao Francisco L, Iaconelli A, Jr., Borges E, Jr.: Zona pellucida birefringence score and meiotic spindle visualization in relation to embryo development and icsi outcomes. Reprod Biomed Online. 2009;18:681–6.PubMedCrossRef

31.

Montag M, van der Ven H. Symposium: Innovative techniques in human embryo viability assessment. Oocyte assessment and embryo viability prediction: Birefringence imaging. Reprod Biomed Online. 2008;17:454–60.PubMedCrossRef

32.

Ebner T, Balaban B, Moser M, Shebl O, Urman B. Ata B. Tews G: Automatic user-independent zona pellucida imaging at the oocyte stage allows for the prediction of preimplantation development. Fertil Steril; 2009.

33.

Mangoli V, Dandekar S, Desai S, Mangoli R. The outcome of art in males with impaired spermatogenesis. J Hum Reprod Sci. 2008;1:73–6.PubMedCrossRef

34.

Hamel M, Dufort I, Robert C, Gravel C, Leveille MC, Leader A, et al. Identification of differentially expressed markers in human follicular cells associated with competent oocytes. Hum Reprod. 2008;23:1118–27.PubMedCrossRef

35.

Robert C, Gagne D, Bousquet D, Barnes FL, Sirard MA. Differential display and suppressive subtractive hybridization used to identify granulosa cell messenger rna associated with bovine oocyte developmental competence. Biol Reprod. 2001;64:1812–20.PubMedCrossRef

36.

Assidi M, Dufort I, Ali A, Hamel M, Algriany O, Dielemann S, et al. Identification of potential markers of oocyte competence expressed in bovine cumulus cells matured with follicle-stimulating hormone and/or phorbol myristate acetate in vitro. Biol Reprod. 2008;79:209–22.PubMedCrossRef

37.

NIA: National institute on aging (nia/nih), laboratory of genetics, baltimore md , USA. http://lgsungrcnianihgov/ANOVA/ 2010

38.

IPA: Ingenuity pathways analysis, ipa, v8.0;. Ingenuity® Systems, www.ingenuitycom 2010

39.

Hamel M, Dufort I, Robert C, Leveille MC, Leader A, Sirard MA. Genomic assessment of follicular marker genes as pregnancy predictors for human ivf. Mol Hum Reprod. 2010;16:87–96.PubMedCrossRef

40.

McKenzie LJ, Pangas SA, Carson SA, Kovanci E, Cisneros P, Buster JE, et al. Human cumulus granulosa cell gene expression: A predictor of fertilization and embryo selection in women undergoing ivf. Hum Reprod. 2004;19:2869–74.PubMedCrossRef

41.

van Montfoort AP, Geraedts JP, Dumoulin JC, Stassen AP, Evers JL, Ayoubi TA. Differential gene expression in cumulus cells as a prognostic indicator of embryo viability: A microarray analysis. Mol Hum Reprod. 2008;14:157–68.PubMedCrossRef

42.

Hunter RHF. Physiology of the graafian follicle and ovulation, ed Cambridge University Press. Cambridge University Press: Cambridge; 2003.

43.

Hernandez-Gonzalez I, Gonzalez-Robayna I, Shimada M, Wayne CM, Ochsner SA, White L, et al. Gene expression profiles of cumulus cell oocyte complexes during ovulation reveal cumulus cells express neuronal and immune-related genes: Does this expand their role in the ovulation process? Mol Endocrinol. 2006;20:1300–21.PubMedCrossRef

44.

Motta PM, Nottola SA, Pereda J, Croxatto HB, Familiari G. Ultrastructure of human cumulus oophorus: A transmission electron microscopic study on oviductal oocytes and fertilized eggs. Hum Reprod. 1995;10:2361–7.PubMed

45.

Lucidi P, Bernabo N, Turriani M, Barboni B, Mattioli M. Cumulus cells steroidogenesis is influenced by the degree of oocyte maturation. Reprod Biol Endocrinol. 2003;1:45.PubMedCrossRef

46.

Gilchrist RB, Lane M, Thompson JG. Oocyte-secreted factors: Regulators of cumulus cell function and oocyte quality. Hum Reprod Update. 2008;14:159–77.PubMedCrossRef

47.

Sugiura K, Su YQ, Diaz FJ, Pangas SA, Sharma S, Wigglesworth K, et al. Oocyte-derived bmp15 and fgfs cooperate to promote glycolysis in cumulus cells. Development. 2007;134:2593–603.PubMedCrossRef

48.

Host E, Gabrielsen A, Lindenberg S, Smidt-Jensen S. Apoptosis in human cumulus cells in relation to zona pellucida thickness variation, maturation stage, and cleavage of the corresponding oocyte after intracytoplasmic sperm injection. Fertil Steril. 2002;77:511–5.PubMedCrossRef

49.

Feuerstein P, Cadoret V, Dalbies-Tran R, Guerif F, Bidault R, Royere D. Gene expression in human cumulus cells: One approach to oocyte competence. Hum Reprod. 2007;22:3069–77.PubMedCrossRef

50.

Familiari G, Heyn R, Relucenti M, Nottola SA, Sathananthan AH. Ultrastructural dynamics of human reproduction, from ovulation to fertilization and early embryo development. Int Rev Cytol. 2006;249:53–141.PubMedCrossRef

51.

Lee KS, Joo BS, Na YJ, Yoon MS, Choi OH, Kim WW. Cumulus cells apoptosis as an indicator to predict the quality of oocytes and the outcome of ivf-et. J Assist Reprod Genet. 2001;18:490–8.PubMedCrossRef

52.

Haouzi D, Hamamah S. Pertinence of apoptosis markers for the improvement of in vitro fertilization (ivf). Curr Med Chem. 2009;16:1905–16.PubMedCrossRef

53.

Hussein TS, Froiland DA, Amato F, Thompson JG, Gilchrist RB. Oocytes prevent cumulus cell apoptosis by maintaining a morphogenic paracrine gradient of bone morphogenetic proteins. J Cell Sci. 2005;118:5257–68.PubMedCrossRef

54.

Su YQ, Sugiura K, Wigglesworth K, O’Brien MJ, Affourtit JP, Pangas SA, et al. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: Bmp15 and gdf9 control cholesterol biosynthesis in cumulus cells. Development. 2008;135:111–21.PubMedCrossRef

55.

Paradis F, Moore HS, Pasternak JA, Novak S, Dyck MK, Dixon WT, Foxcroft GR: Pig preovulatory oocytes modulate cumulus cell protein and gene expression in vitro. Mol Cell Endocrinol 2010

56.

Assou S, Haouzi D. De Vos J. Hamamah S: Human cumulus cells as biomarkers for embryo and pregnancy outcomes. Mol Hum Reprod; 2010.

57.

Hasegawa J, Yanaihara A, Iwasaki S, Mitsukawa K, Negishi M, Okai T. Reduction of connexin 43 in human cumulus cells yields good embryo competence during icsi. J Assist Reprod Genet. 2007;24:463–6.PubMedCrossRef

58.

Hunault CC, Eijkemans MJ, Pieters MH. te Velde ER, Habbema JD, Fauser BC, Macklon NS: A prediction model for selecting patients undergoing in vitro fertilization for elective single embryo transfer. Fertil Steril. 2002;77:725–32.PubMedCrossRef

59.

Verberg MF, Eijkemans MJ, Macklon NS, Heijnen EM, Fauser BC, Broekmans FJ. Predictors of ongoing pregnancy after single-embryo transfer following mild ovarian stimulation for ivf. Fertil Steril. 2008;89:1159–65.PubMedCrossRef

60.

Teves ME, Guidobaldi HA, Unates DR, Sanchez R, Miska W, Publicover SJ, et al. Molecular mechanism for human sperm chemotaxis mediated by progesterone. PLoS One. 2009;4:e8211.PubMedCrossRef

61.

Haouzi D, Assou S, Mahmoud K, Hedon B, De Vos J, Dewailly D, et al. Lh/hcgr gene expression in human cumulus cells is linked to the expression of the extracellular matrix modifying gene tnfaip6 and to serum estradiol levels on day of hcg administration. Hum Reprod. 2009;24:2868–78.PubMedCrossRef

62.

Russell DL, Doyle KM, Ochsner SA, Sandy JD, Richards JS. Processing and localization of adamts-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation. J Biol Chem. 2003;278:42330–9.PubMedCrossRef

63.

Tsafriri A. Ovulation as a tissue remodelling process. Proteolysis and cumulus expansion. Adv Exp Med Biol. 1995;377:121–40.PubMed

64.

Huo LJ, Fan HY, Liang CG, Yu LZ, Zhong ZS, Chen DY, et al. Regulation of ubiquitin-proteasome pathway on pig oocyte meiotic maturation and fertilization. Biol Reprod. 2004;71:853–62.PubMedCrossRef

65.

Lee HK, Yang Y, Su Z, Hyeon C, Lee TS, Lee HW, et al. Dynamic ca2 + -dependent stimulation of vesicle fusion by membrane-anchored synaptotagmin 1. Science. 2010;328:760–3.PubMedCrossRef

66.

Colvin RA, Means TK, Diefenbach TJ, Moita LF, Friday RP, Sever S, et al. Hacohen N. Luster AD: Synaptotagmin-mediated vesicle fusion regulates cell migration. Nat Immunol; 2010.

67.

Gustavsson N, Han W. Calcium-sensing beyond neurotransmitters: Functions of synaptotagmins in neuroendocrine and endocrine secretion. Biosci Rep. 2009;29:245–59.PubMedCrossRef

68.

Fantin A, Maden CH, Ruhrberg C. Neuropilin ligands in vascular and neuronal patterning. Biochem Soc Trans. 2009;37:1228–32.PubMedCrossRef

69.

Shimizu T, Jayawardana BC, Nishimoto H, Kaneko E, Tetsuka M, Miyamoto A. Hormonal regulation and differential expression of neuropilin (nrp)-1 and nrp-2 genes in bovine granulosa cells. Reproduction. 2006;131:555–9.PubMedCrossRef

70.

Miyabayashi K, Shimizu T, Kawauchi C, Sasada H, Sato E. Changes of mrna expression of vascular endothelial growth factor, angiopoietins and their receptors during the periovulatory period in ecg/hcg-treated immature female rats. J Exp Zool A Comp Exp Biol. 2005;303:590–7.PubMed

71.

Bhaskar L, Krishnan VS, Thampan RV. Cytoskeletal elements and intracellular transport. J Cell Biochem. 2007;101:1097–108.PubMedCrossRef

72.

Allworth AE, Albertini DF. Meiotic maturation in cultured bovine oocytes is accompanied by remodeling of the cumulus cell cytoskeleton. Dev Biol. 1993;158:101–12.PubMedCrossRef

73.

Barrett SL, Albertini DF. Cumulus cell contact during oocyte maturation in mice regulates meiotic spindle positioning and enhances developmental competence. J Assist Reprod Genet. 2010;27:29–39.PubMedCrossRef

74.

Albertini DF. Cytoplasmic microtubular dynamics and chromatin organization during mammalian oogenesis and oocyte maturation. Mutat Res. 1992;296:57–68.PubMed

75.

Sutovsky P, Flechon JE, Pavlok A. Microfilaments, microtubules and intermediate filaments fulfil differential roles during gonadotropin-induced expansion of bovine cumulus oophorus. Reprod Nutr Dev. 1994;34:415–25.PubMedCrossRef

76.

Zhang X, Jafari N, Barnes RB, Confino E, Milad M, Kazer RR. Studies of gene expression in human cumulus cells indicate pentraxin 3 as a possible marker for oocyte quality. Fertil Steril. 2005;83 Suppl 1:1169–79.PubMedCrossRef

77.

Cillo F, Brevini TA, Antonini S, Paffoni A, Ragni G, Gandolfi F. Association between human oocyte developmental competence and expression levels of some cumulus genes. Reproduction. 2007;134:645–50.PubMedCrossRef

78.

Cieniewicz AM, Woodruff RI. Passage through vertebrate gap junctions of 17/18kda molecules is primarily dependent upon molecular configuration. Tissue Cell. 2010;42:47–52.PubMedCrossRef

79.

Shimada M, Maeda T, Terada T. Dynamic changes of connexin-43, gap junctional protein, in outer layers of cumulus cells are regulated by pkc and pi 3-kinase during meiotic resumption in porcine oocytes. Biol Reprod. 2001;64:1255–63.PubMedCrossRef

80.

Sutovsky P, Flechon JE, Flechon B, Motlik J, Peynot N, Chesne P, et al. Dynamic changes of gap junctions and cytoskeleton during in vitro culture of cattle oocyte cumulus complexes. Biol Reprod. 1993;49:1277–87.PubMedCrossRef

81.

Atlas D: Signaling role of the voltage-gated calcium channel as the molecular ‘on/off’ switch of secretion. Cell Signal 2010

82.

Davis JS, Weakland LL, Farese RV, West LA. Luteinizing hormone increases inositol trisphosphate and cytosolic free ca2+ in isolated bovine luteal cells. J Biol Chem. 1987;262:8515–21.PubMed

83.

Mattioli M, Gioia L, Barboni B. Calcium elevation in sheep cumulus-oocyte complexes after luteinising hormone stimulation. Mol Reprod Dev. 1998;50:361–9.PubMedCrossRef

84.

Jose O, Hernandez-Hernandez O, Chirinos M, Gonzalez-Gonzalez ME, Larrea F, Almanza A, et al. Recombinant human zp3-induced sperm acrosome reaction: Evidence for the involvement of t- and l-type voltage-gated calcium channels. Biochem Biophys Res Commun. 2010;395:530–4.PubMedCrossRef

85.

Fukami K, Nakao K, Inoue T, Kataoka Y, Kurokawa M, Fissore RA, et al. Requirement of phospholipase cdelta4 for the zona pellucida-induced acrosome reaction. Science. 2001;292:920–3.PubMedCrossRef

86.

Katoh Y, Shiba Y, Mitsuhashi H, Yanagida Y, Takatsu H, Nakayama K. Tollip and tom1 form a complex and recruit ubiquitin-conjugated proteins onto early endosomes. J Biol Chem. 2004;279:24435–43.PubMedCrossRef

87.

Seet LF, Hong W. Endofin recruits clathrin to early endosomes via tom1. J Cell Sci. 2005;118:575–87.PubMedCrossRef

88.

Yamakami M, Yokosawa H. Tom1 (target of myb 1) is a novel negative regulator of interleukin-1- and tumor necrosis factor-induced signaling pathways. Biol Pharm Bull. 2004;27:564–6.PubMedCrossRef

89.

Sayasith K, Bouchard N, Dore M, Sirois J. Regulation of bovine tumor necrosis factor-alpha-induced protein 6 in ovarian follicles during the ovulatory process and promoter activation in granulosa cells. Endocrinology. 2008;149:6213–25.PubMedCrossRef

90.

Yamashita Y, Hishinuma M, Shimada M. Activation of pka, p38 mapk and erk1/2 by gonadotropins in cumulus cells is critical for induction of egf-like factor and tace/adam17 gene expression during in vitro maturation of porcine cocs. J Ovarian Res. 2009;2:20.PubMedCrossRef

91.

Russell DL, Robker RL. Molecular mechanisms of ovulation: Co-ordination through the cumulus complex. Hum Reprod Update. 2007;13:289–312.PubMedCrossRef

92.

Hillier SG. Paracrine support of ovarian stimulation. Mol Hum Reprod. 2009;15:843–50.PubMedCrossRef

Title: Biomarkers of human oocyte developmental competence expressed in cumulus cells before ICSI: a preliminary study
Authors: Mourad Assidi
Markus Montag
Katrin Van Der Ven
Marc-André Sirard
Publication date: 01-02-2011
Publisher: Springer US
Published in: Journal of Assisted Reproduction and Genetics / Issue 2/2011
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-010-9491-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Biomarkers of human oocyte developmental competence expressed in cumulus cells before ICSI: a preliminary study

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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