Abstract
Purpose
The study aims to determine differences in micro-RNA (miRNA) expression in granulosa (GC) and cumulus cells (CC) between young women with diminished ovarian reserve (DOR) or normal ovarian reserve (NOR). Secondary objective was to identify downstream signaling pathways that could ultimately indicate causes of lower developmental competence of oocytes from young women with DOR.
Methods
The method of the study is prospective cohort study.
Results
Of the miRNA, 125 are differentially expressed in GC between DOR and NOR. Only nine miRNA were different in CC; therefore, we focused analysis on GC. In DOR GC, miR-100-5p, miR-16-5p, miR-30a-3p, and miR-193a-3p were significantly downregulated, while miR-155-5p, miR-192-5p, miR-128-3p, miR-486-5p, miR130a-3p, miR-92a-3p, miR-17-3p, miR-221-3p, and miR-175p were increased. This pattern predicted higher cell proliferation in the DOR GC. The primary pathways include MAPK, Wnt, and TGFbeta.
Conclusions
The miRNA pattern identified critical functions in cell proliferation and survival associated with DOR. GC in women with DOR seems to respond differently to the LH surge.
Similar content being viewed by others
References
Eppig JJ. Oocyte control of ovarian follicular development and function in mammals. Reproduction. 2001;122:829–38.
Kidder GM, Vanderhyden BC. Bidirectional communication between oocytes and follicle cells: ensuring oocyte developmental competence. Can J Physiol Pharmacol. 2010;88:399–413.
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.
Gilabert-Estelles J, Braza-Boils A, Ramon LA, Zorio E, Medina P, Espana F, et al. Role of microRNAs in gynecological pathology. Curr Med Chem. 2012;19:2406–13.
Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2014;42:D68–73.
Mack GS. MicroRNA gets down to business. Nat Biotechnol. 2007;25:631–8.
Oliveto S, Mancino M, Manfrini N, Biffo S. Role of microRNAs in translation regulation and cancer. World J Biol Chem. 2017;8:45–56.
Passetti F, Ferreira CG, Costa FF. The impact of microRNAs and alternative splicing in pharmacogenomics. Pharmacogenomics J. 2009;9:1–13.
Paul P, Chakraborty A, Sarkar D, Langthasa M, Rahman M, Bari M, Singha RS, Malakar AK, Chakraborty S. Interplay between miRNAs and human diseases. J Cell Physiol 2017.
Ha TY. MicroRNAs in human diseases: from Cancer to cardiovascular disease. Immune Netw. 2011;11:135–54.
Fiedler SD, Carletti MZ, Hong X, Christenson LK. Hormonal regulation of MicroRNA expression in periovulatory mouse mural granulosa cells. Biol Reprod. 2008;79:1030–7.
McGinnis LK, Luense LJ, Christenson LK. MicroRNA in ovarian biology and disease. Cold Spring Harb Perspect Med. 2015;5:a022962.
Ro S, Song R, Park C, Zheng H, Sanders KM, Yan W. Cloning and expression profiling of small RNAs expressed in the mouse ovary. RNA. 2007;13:2366–80.
Otsuka M, Zheng M, Hayashi M, Lee JD, Yoshino O, Lin S, et al. Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice. J Clin Invest. 2008;118:1944–54.
Hossain MM, Ghanem N, Hoelker M, Rings F, Phatsara C, Tholen E, et al. Identification and characterization of miRNAs expressed in the bovine ovary. BMC Genomics. 2009;10:443.
da Silveira JC, Winger QA, Bouma GJ, Carnevale EM. Effects of age on follicular fluid exosomal microRNAs and granulosa cell transforming growth factor-? signalling during follicle development in the mare. Reprod Fertil Dev 2015.
McBride D, Carre W, Sontakke SD, Hogg CO, Law A, Donadeu FX, et al. Identification of miRNAs associated with the follicular-luteal transition in the ruminant ovary. Reproduction. 2012;144:221–33.
Yin M, Lu M, Yao G, Tian H, Lian J, Liu L, et al. Transactivation of microRNA-383 by steroidogenic factor-1 promotes estradiol release from mouse ovarian granulosa cells by targeting RBMS1. Mol Endocrinol. 2012;26:1129–43.
Navakanitworakul R, Hung WT, Gunewardena S, Davis JS, Chotigeat W, Christenson LK. Characterization and Small RNA content of extracellular vesicles in follicular fluid of developing bovine antral follicles. Sci Rep. 2016;6:25486.
Santonocito M, Vento M, Guglielmino MR, 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;102:1751–61. e1751
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 (Camb). 2014;17:90–8.
Roth LW, McCallie B, Alvero R, Schoolcraft WB, Minjarez D, Katz-Jaffe MG. Altered microRNA and gene expression in the follicular fluid of women with polycystic ovary syndrome. J Assist Reprod Genet. 2014;31:355–62.
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;98:3068–79.
Wood JR, Dumesic DA, Abbott DH, Strauss JF 3rd. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab. 2007;92:705–13.
La Marca A, Minasi MG, Sighinolfi G, Greco P, Argento C, Grisendi V, et al. Female age, serum antimullerian hormone level, and number of oocytes affect the rate and number of euploid blastocysts in in vitro fertilization/intracytoplasmic sperm injection cycles. Fertil Steril. 2017;108:777–83. e772
Iwase A, Nakamura T, Osuka S, Takikawa S, Goto M, Kikkawa F. Anti-Mullerian hormone as a marker of ovarian reserve: what have we learned, and what should we know? Reprod Med Biol. 2016;15:127–36.
Jevnaker AM, Khuu C, Kjole E, Bryne M, Osmundsen H. Expression of members of the miRNA17-92 cluster during development and in carcinogenesis. J Cell Physiol. 2011;226:2257–66.
Cohen J, Mounsambote L, Prier P, Mathieu D’Argent E, Selleret L, Chabbert-Buffet N, et al. Outcomes of first IVF/ICSI in young women with diminished ovarian reserve. Minerva Ginecol. 2016;
Pacella L, Zander-Fox DL, Armstrong DT, Lane M. Women with reduced ovarian reserve or advanced maternal age have an altered follicular environment. Fertil Steril. 2012;98:986–94. e981-982
Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. Definition EwgoPOR. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the bologna criteria. Hum Reprod. 2011;26:1616–24.
Andrews S. FastQC: a quality control tool for high throughput sequence data. 2010. Available online at: http://www.bioinformatics.babraham.ac.uk/projects/fastqc.
Li H, Durbin R. Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 2009;25:1754–60.
Jiang P, Wu H, Wang W, Ma W, Sun X, MiPred LZ. Classification of real and pseudo microRNA precursors using random forest prediction model with combined features. Nucleic Acids Res. 2007;35:W339–44.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995:289–300.
Chaffin CL, Schwinof KM, Stouffer RL. Gonadotropin and steroid control of granulosa cell proliferation during the periovulatory interval in rhesus monkeys. Biol Reprod. 2001;65:755–62.
Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008;132:875–86.
Liu XS, Chopp M, Wang XL, Zhang L, Hozeska-Solgot A, Tang T, et al. MicroRNA-17-92 cluster mediates the proliferation and survival of neural progenitor cells after stroke. J Biol Chem. 2013;288:12478–88.
Liu J, Yao W, Yao Y, Du X, Zhou J, Ma B, et al. MiR-92a inhibits porcine ovarian granulosa cell apoptosis by targeting Smad7 gene. FEBS Lett. 2014;588:4497–503.
Fan HY, Liu Z, Cahill N, Richards JS. Targeted disruption of Pten in ovarian granulosa cells enhances ovulation and extends the life span of luteal cells. Mol Endocrinol. 2008;22:2128–40.
Shi L, Liu S, Zhao W, Shi J. miR-483-5p and miR-486-5p are down-regulated in cumulus cells of metaphase II oocytes from women with polycystic ovary syndrome. Reprod BioMed Online. 2015;31:565–72.
Nilsson EE, Skinner MK. Kit ligand and basic fibroblast growth factor interactions in the induction of ovarian primordial to primary follicle transition. Mol Cell Endocrinol. 2004;214:19–25.
Nilsson EE, Detzel C, Skinner MK. Platelet-derived growth factor modulates the primordial to primary follicle transition. Reproduction. 2006;131:1007–15.
Ben-Haroush A, Abir R, Ao A, Jin S, Kessler-Icekson G, Feldberg D, et al. Expression of basic fibroblast growth factor and its receptors in human ovarian follicles from adults and fetuses. Fertil Steril. 2005;84(Suppl 2):1257–68.
Baumgarten SC, Armouti M, Ko C, Stocco C. IGF1R Expression in Ovarian Granulosa Cells is Essential for Steroidogenesis, Follicle Survival, and Fertility in Female Mice. Endocrinology 2017.
Baumgarten SC, Convissar SM, Fierro MA, Winston NJ, Scoccia B, Stocco C. IGF1R signaling is necessary for FSH-induced activation of AKT and differentiation of human cumulus granulosa cells. J Clin Endocrinol Metab. 2014;99:2995–3004.
Stapp AD, Gomez BI, Gifford CA, Hallford DM, Hernandez Gifford JA. Canonical WNT signaling inhibits follicle stimulating hormone mediated steroidogenesis in primary cultures of rat granulosa cells. PLoS One. 2014;9:e86432.
Zielak-Steciwko AE, Browne JA, McGettigan PA, Gajewska M, Dzieciol M, Szulc T, et al. Expression of microRNAs and their target genes and pathways associated with ovarian follicle development in cattle. Physiol Genomics. 2014;46:735–45.
Cannon JD, Cherian-Shaw M, Chaffin CL. Proliferation of rat granulosa cells during the periovulatory interval. Endocrinology. 2005;146:414–22.
Ribeiro A, Freitas C, Matos L, Gouveia A, Gomes F, Silva Carvalho JL, et al. Age-related expression of TGF beta family receptors in human cumulus oophorus cells. J Assist Reprod Genet. 2017;34:1121–9.
Al-Edani T, Assou S, Ferrieres A, Bringer Deutsch S, Gala A, Lecellier CH, et al. Female aging alters expression of human cumulus cells genes that are essential for oocyte quality. Biomed Res Int. 2014;2014:964614.
Acknowledgements
The research was supported by NIH grant HD082484 awarded to LKM and LKC.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
ESM 1
(DOCX 25 kb)
Rights and permissions
About this article
Cite this article
Woo, I., Christenson, L.K., Gunewardena, S. et al. Micro-RNAs involved in cellular proliferation have altered expression profiles in granulosa of young women with diminished ovarian reserve. J Assist Reprod Genet 35, 1777–1786 (2018). https://doi.org/10.1007/s10815-018-1239-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-018-1239-9