Gene Expression Profiling of Cumulus-oocyte Complex in Infertile Women: A Systematic Review and Integrated Bioinformatic Analysis
DOI:
https://doi.org/10.33102/mjosht.560Keywords:
Cumulus cells, Gene expression, Infertility, In vitro fertilization, OocytesAbstract
The cumulus-oocyte complex (COC) is an important complex for oocyte maturation. Gene expression in the cumulus cells surrounding the oocyte is crucial for regulating maturation. Abnormal gene expression in the cumulus-oocyte complex may inhibit oocyte maturation and subsequently lead to infertility. A thorough understanding of impacted gene expression profiles and molecular pathways in infertile women is necessary. However, the gene expression profiles vary between studies. Thus, a comprehensive literature search across EBSCOhost, PubMed, ScienceDirect, and Scopus databases was conducted to robustly identify gene expression profiles of cumulus-oocyte complexes and the molecular pathways involved in infertility development. Terms including (“Infertile women” OR Sterility OR Subfertility OR Infertility OR “Sub-fertility”) AND (“Gene expression” OR Profiling OR Transcriptome) AND (“In-vitro fertilization” OR “In-vitro fertilisation” OR IVF) were used as keywords in all fields. 2090 studies were retrieved, and all were screened against the inclusion and exclusion criteria. After the screening, five studies were selected, and 897 differentially expressed genes (DEGs) were identified across them. The integrated bioinformatic analysis using DAVID, STRING, and Cytoscape revealed a protein-protein interaction (PPI) network comprising 30 high-intermolecular-interaction clusters. Based on Gene Ontology (GO) annotations, most DEGs are expressed in the extracellular space, cytosol, and mitochondria. Correspondingly, the DEGs were identified as modulating communication with the extracellular environment via signalling pathways and regulating proliferation via DNA transcription and the cell cycle. This systematic review further elucidates the genes and molecular mechanisms within the cumulus-oocyte complex involved in the development of infertility.
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[1] N. Thaker, R. Dhande, and P. Parihar, "Role of Transvaginal Sonography in the Diagnosis of Female Infertility: A Comprehensive Review," Cureus, vol. 15, no. 12, p. e50048, Dec 2023, doi: 10.7759/cureus.50048.
[2] P. S. Deshpande and A. S. Gupta, "Causes and Prevalence of Factors Causing Infertility in a Public Health Facility," J Hum Reprod Sci, vol. 12, no. 4, pp. 287-293, Oct-Dec 2019, doi: 10.4103/jhrs.JHRS_140_18.
[3] Z. Wang et al., "The oocyte cumulus complex regulates mouse sperm migration in the oviduct," Commun Biol, vol. 5, no. 1, p. 1327, Dec 3 2022, doi: 10.1038/s42003-022-04287-8.
[4] B. Turathum, E. M. Gao, and R. C. Chian, "The Function of Cumulus Cells in Oocyte Growth and Maturation and in Subsequent Ovulation and Fertilization," Cells, vol. 10, no. 9, Sep 2 2021, doi: 10.3390/cells10092292.
[5] D. Szklarczyk et al., "The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets," (in eng), Nucleic Acids Res, vol. 49, no. D1, pp. D605-d612, Jan 8 2021, doi: 10.1093/nar/gkaa1074.
[6] P. Shannon et al., "Cytoscape: a software environment for integrated models of biomolecular interaction networks," (in eng), Genome Res, vol. 13, no. 11, pp. 2498-504, Nov 2003, doi: 10.1101/gr.1239303.
[7] S. Gasca et al., "Identifying new human oocyte marker genes: a microarray approach," Reprod. BioMed. Online, vol. 14, no. 2, pp. 175-183, 2007/01/01/ 2007, doi: https://doi.org/10.1016/S1472-6483(10)60785-7.
[8] X. Zhang, N. Jafari, R. B. Barnes, E. Confino, M. Milad, and R. R. Kazer, "Studies of gene expression in human cumulus cells indicate pentraxin 3 as a possible marker for oocyte quality," (in eng), Fertil Steril, vol. 83 Suppl 1, pp. 1169-79, Apr 2005, doi: 10.1016/j.fertnstert.2004.11.030.
[9] G. Tanriverdi et al., "Notch signaling pathway in cumulus cells can be a novel marker to identify poor and normal responder IVF patients," Journal of Assisted Reproduction & Genetics, Article vol. 30, no. 10, pp. 1319-1326, 2013, doi: 10.1007/s10815-013-0072-4.
[10] S. Wathlet et al., "New candidate genes to predict pregnancy outcome in single embryo transfer cycles when using cumulus cell gene expression," Fertility & Sterility, Article vol. 98, no. 2, pp. 432-439.e4, 2012, doi: 10.1016/j.fertnstert.2012.05.007.
[11] T. Burnik Papler, E. Vrtačnik Bokal, A. Maver, and L. Lovrečić, "Specific gene expression differences in cumulus cells as potential biomarkers of pregnancy," Reprod. BioMed. Online, vol. 30, no. 4, pp. 426-433, 2015/04/01/ 2015, doi: https://doi.org/10.1016/j.rbmo.2014.12.011.
[12] X. Xu, D. Chen, Z. Zhang, Z. Wei, and Y. Cao, "Molecular signature in human cumulus cells related to embryonic developmental potential," (in English), Reprod. Sci., Article vol. 22, no. 2, pp. 173-180, 2015, doi: 10.1177/1933719114536471.
[13] M. Dai, Y. Xu, G. Gong, and Y. Zhang, "Roles of immune microenvironment in the female reproductive maintenance and regulation: novel insights into the crosstalk of immune cells," (in eng), Front Immunol, vol. 14, p. 1109122, 2023, doi: 10.3389/fimmu.2023.1109122.
[14] M. Tang, M. Zhao, and Y. Shi, "New insight into the role of macrophages in ovarian function and ovarian aging," (in eng), Front Endocrinol (Lausanne), vol. 14, p. 1282658, 2023, doi: 10.3389/fendo.2023.1282658.
[15] D. Zhang, Y. Yu, T. Duan, and Q. Zhou, "The role of macrophages in reproductive-related diseases," (in eng), Heliyon, vol. 8, no. 11, p. e11686, Nov 2022, doi: 10.1016/j.heliyon.2022.e11686.
[16] J. Ding, Y. Zhang, X. Cai, L. Diao, C. Yang, and J. Yang, "Crosstalk between trophoblast and macrophage at the maternal-fetal interface: current status and future perspectives," Frontiers in Immunology, vol. 12, p. 758281, 2021.
[17] C. Xu, X. L. Xie, N. Kang, and H. Q. Jiang, "Evaluation of ITGB1 expression as a predictor of the therapeutic effects of immune checkpoint inhibitors in gastric cancer," (in eng), BMC Gastroenterol, vol. 23, no. 1, p. 298, Sep 4 2023, doi: 10.1186/s12876-023-02930-0.
[18] N. Naim, F. R. G. Amrit, T. B. McClendon, J. L. Yanowitz, and A. Ghazi, "The molecular tug of war between immunity and fertility: Emergence of conserved signaling pathways and regulatory mechanisms," (in eng), Bioessays, vol. 42, no. 12, p. e2000103, Dec 2020, doi: 10.1002/bies.202000103.
[19] C. A. Martinez, M. Alvarez-Rodriguez, M. Casado-Bedmar, and H. Rodriguez-Martinez, "In Vitro Maturation of Cumulus-Oocyte Complexes and In Vitro Sperm Capacitation Significantly Increase the Expression and Enhance the Location of the CXCL12 and CXCR4 Anchoring Attractant Complex in Pigs," (in eng), Animals (Basel), vol. 11, no. 1, Jan 11 2021, doi: 10.3390/ani11010153.
[20] M. Zhang et al., "C-X-C motif chemokine ligand 12 improves the developmental potential of bovine oocytes by activating SH2 domain-containing tyrosine phosphatase 2 during maturation†," (in eng), Biol Reprod, vol. 109, no. 3, pp. 282-298, Sep 12 2023, doi: 10.1093/biolre/ioad079.
[21] R.-N. Zhang et al., "The CXCL12-CXCR4 signaling promotes oocyte maturation by regulating cumulus expansion in sheep," Theriogenology, vol. 107, pp. 85-94, 2018/02/01/ 2018, doi: https://doi.org/10.1016/j.theriogenology.2017.10.039.
[22] A. Nikolov and N. Popovski, "Role of Gelatinases MMP-2 and MMP-9 in Healthy and Complicated Pregnancy and Their Future Potential as Preeclampsia Biomarkers," (in eng), Diagnostics (Basel), vol. 11, no. 3, Mar 9 2021, doi: 10.3390/diagnostics11030480.
[23] T. N. Wight, I. Kang, and M. J. Merrilees, "Versican and the control of inflammation," (in eng), Matrix Biol, vol. 35, pp. 152-61, Apr 2014, doi: 10.1016/j.matbio.2014.01.015.
[24] K. R. Dunning et al., "Activation of Mouse Cumulus-Oocyte Complex Maturation In Vitro Through EGF-Like Activity of Versican1," Biology of Reproduction, vol. 92, no. 5, 2015, doi: 10.1095/biolreprod.114.127274.
[25] B. Martazanova et al., "Versican (VCAN) mRNA expression in cumulus cells predicts embryo quality, but does not predict pregnancy outcome in patients with reduced ovarian reserve," Fertility and Sterility, vol. 110, no. 4, p. e310, 2018, doi: 10.1016/j.fertnstert.2018.07.874.
[26] I. Guijarro-Muñoz, M. Compte, A. Álvarez-Cienfuegos, L. Álvarez-Vallina, and L. Sanz, "Lipopolysaccharide Activates Toll-like Receptor 4 (TLR4)-mediated NF-κB Signaling Pathway and Proinflammatory Response in Human Pericytes* *This work was supported by Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III Grants PI08/90856 and PS09/00227 and Fundación Investigación Biomédica Hospital Puerta de Hierro (to L. S.) and by Ministerio de Economía y Competitividad Grant BIO2011-22738 and Comunidad de Madrid Grant S2010/BMD-2312 (to L. A.-V.)," Journal of Biological Chemistry, vol. 289, no. 4, pp. 2457-2468, 2014/01/24/ 2014, doi: https://doi.org/10.1074/jbc.M113.521161.
[27] K. Kitaya and T. Yasuo, "Aberrant expression of selectin E, CXCL1, and CXCL13 in chronic endometritis," (in eng), Mod Pathol, vol. 23, no. 8, pp. 1136-46, Aug 2010, doi: 10.1038/modpathol.2010.98.
[28] D. J. Brat, A. C. Bellail, and E. G. Van Meir, "The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis," (in eng), Neuro Oncol, vol. 7, no. 2, pp. 122-33, Apr 2005, doi: 10.1215/s1152851704001061.
[29] Y. Y. Song, D. Liang, D. K. Liu, L. Lin, L. Zhang, and W. Q. Yang, "The role of the ERK signaling pathway in promoting angiogenesis for treating ischemic diseases," (in eng), Front Cell Dev Biol, vol. 11, p. 1164166, 2023, doi: 10.3389/fcell.2023.1164166.
[30] S. Cambier, M. Gouwy, and P. Proost, "The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention," Cellular & Molecular Immunology, vol. 20, no. 3, pp. 217-251, 2023/03/01 2023, doi: 10.1038/s41423-023-00974-6.
[31] E. H. Ruder, T. J. Hartman, and M. B. Goldman, "Impact of oxidative stress on female fertility," (in eng), Curr Opin Obstet Gynecol, vol. 21, no. 3, pp. 219-22, Jun 2009, doi: 10.1097/gco.0b013e32832924ba.
[32] Z. Su et al., "Association between oxidative balance score and female infertility from the national health and nutrition examination survey 2013-2018," (in eng), Front Endocrinol (Lausanne), vol. 15, p. 1386021, 2024, doi: 10.3389/fendo.2024.1386021.
[33] A. I. Cappa, M. de Paola, P. Wetten, G. A. De Blas, and M. A. Michaut, "Live imaging of cortical granule exocytosis reveals that in vitro matured mouse oocytes are not fully competent to secrete their content," (in eng), Biol Open, vol. 7, no. 12, Dec 3 2018, doi: 10.1242/bio.031872.
[34] L. P. Cheeseman, J. Boulanger, L. M. Bond, and M. Schuh, "Two pathways regulate cortical granule translocation to prevent polyspermy in mouse oocytes," Nature Communications, vol. 7, no. 1, p. 13726, 2016/12/19 2016, doi: 10.1038/ncomms13726.
[35] S. Bertho, M. Clapp, T. U. Banisch, J. Bandemer, E. Raz, and F. L. Marlow, "Zebrafish dazl regulates cystogenesis and germline stem cell specification during the primordial germ cell to germline stem cell transition," (in eng), Development, vol. 148, no. 7, Apr 1 2021, doi: 10.1242/dev.187773.
[36] K. Ikami et al., "Branched germline cysts and female-specific cyst fragmentation facilitate oocyte determination in mice," Proceedings of the National Academy of Sciences, vol. 120, no. 20, p. e2219683120, 2023, doi: doi:10.1073/pnas.2219683120.
[37] T. Umehara et al., "Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary," (in eng), Sci Adv, vol. 8, no. 24, p. eabn4564, Jun 17 2022, doi: 10.1126/sciadv.abn4564.
[38] A. C. Spradling, W. Niu, Q. Yin, M. Pathak, and B. Maurya, "Conservation of oocyte development in germline cysts from Drosophila to mouse," (in eng), Elife, vol. 11, Nov 29 2022, doi: 10.7554/eLife.83230.
[39] Y. Kuchitsu and M. Fukuda, "Revisiting Rab7 Functions in Mammalian Autophagy: Rab7 Knockout Studies," (in eng), Cells, vol. 7, no. 11, Nov 19 2018, doi: 10.3390/cells7110215.
[40] Y. Feng, D. He, Z. Yao, and D. J. Klionsky, "The machinery of macroautophagy," Cell Research, vol. 24, no. 1, pp. 24-41, 2014/01/01 2014, doi: 10.1038/cr.2013.168.
[41] R. Singh et al., "Autophagy regulates lipid metabolism," (in eng), Nature, vol. 458, no. 7242, pp. 1131-5, Apr 30 2009, doi: 10.1038/nature07976.
[42] X. Guo et al., Farnesyl Diphosphate Synthase (FDPS) Regulates Granulosa Cells Proliferation of Polycystic Ovary Syndrome (PCOS) by Modulating the Rac1/MAPK/ERK signaling. 2023.
[43] C.-J. Zhou, X.-Y. Wang, Z. Han, D.-H. Wang, Y.-Z. Ma, and C.-G. Liang, "Loss of CENPF leads to developmental failure in mouse embryos," Cell Cycle, vol. 18, no. 20, pp. 2784-2799, 2019/10/18 2019, doi: 10.1080/15384101.2019.1661173.
[44] A. Arias, A. Quiroz, N. Santander, E. Morselli, and D. Busso, "Implications of High-Density Cholesterol Metabolism for Oocyte Biology and Female Fertility," (in eng), Front Cell Dev Biol, vol. 10, p. 941539, 2022, doi: 10.3389/fcell.2022.941539.
[45] N. L. Carpintero, O. A. Suárez, C. C. Mangas, C. G. Varea, and R. G. Rioja, "Follicular steroid hormones as markers of oocyte quality and oocyte development potential," (in eng), J Hum Reprod Sci, vol. 7, no. 3, pp. 187-93, Jul 2014, doi: 10.4103/0974-1208.142479.
[46] T. Liu et al., "Lipid Metabolic Process Involved in Oocyte Maturation During Folliculogenesis," (in English), Frontiers in Cell and Developmental Biology, Review vol. 10, 2022-March-31 2022, doi: 10.3389/fcell.2022.806890.
[47] R. Modre-Osprian, I. Osprian, B. Tilg, G. Schreier, K. M. Weinberger, and A. Graber, "Dynamic simulations on the mitochondrial fatty acid Beta-oxidation network," BMC Systems Biology, vol. 3, no. 1, p. 2, 2009/01/06 2009, doi: 10.1186/1752-0509-3-2.
[48] K. R. Dunning, K. Cashman, D. L. Russell, J. G. Thompson, R. J. Norman, and R. L. Robker, "Beta-Oxidation Is Essential for Mouse Oocyte Developmental Competence and Early Embryo Development1," Biology of Reproduction, vol. 83, no. 6, pp. 909-918, 2010, doi: 10.1095/biolreprod.110.084145.
[49] B. Pan et al., "Integrated ultrasensitive metabolomics and single-cell transcriptomics identify crucial regulators of sheep oocyte maturation and early embryo development in vitro," Journal of Advanced Research, 2024/09/02/ 2024, doi: https://doi.org/10.1016/j.jare.2024.08.040.
[50] E. Warzych and P. Lipinska, "Energy metabolism of follicular environment during oocyte growth and maturation," (in eng), J Reprod Dev, vol. 66, no. 1, pp. 1-7, Feb 14 2020, doi: 10.1262/jrd.2019-102.
[51] X. Zhang, X. Gao, R. A. Coots, C. S. Conn, B. Liu, and S. B. Qian, "Translational control of the cytosolic stress response by mitochondrial ribosomal protein L18," (in eng), Nat Struct Mol Biol, vol. 22, no. 5, pp. 404-10, May 2015, doi: 10.1038/nsmb.3010.
[52] A. Kirillova, J. E. J. Smitz, G. T. Sukhikh, and I. Mazunin, "The Role of Mitochondria in Oocyte Maturation," (in eng), Cells, vol. 10, no. 9, Sep 19 2021, doi: 10.3390/cells10092484.
[53] A. Cheong, D. Archambault, R. Degani, E. Iverson, K. D. Tremblay, and J. Mager, "Nuclear-encoded mitochondrial ribosomal proteins are required to initiate gastrulation," (in eng), Development, vol. 147, no. 10, May 26 2020, doi: 10.1242/dev.188714.
[54] J. L. Chiang et al., "Mitochondria in Ovarian Aging and Reproductive Longevity," (in eng), Ageing Res Rev, vol. 63, p. 101168, Nov 2020, doi: 10.1016/j.arr.2020.101168.
[55] Z. Abidin and E. P. Treacy, "Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia," (in eng), Int J Mol Sci, vol. 20, no. 20, Oct 22 2019, doi: 10.3390/ijms20205236.
[56] A. I. Coelho, M. E. Rubio-Gozalbo, J. B. Vicente, and I. Rivera, "Sweet and sour: an update on classic galactosemia," (in eng), J Inherit Metab Dis, vol. 40, no. 3, pp. 325-342, May 2017, doi: 10.1007/s10545-017-0029-3.
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