Skip to main content

Advertisement

SpringerLink
Log in

Plasticity of granulosa cells: on the crossroad of stemness and transdifferentiation potential

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

Abstract

The ovarian follicle represents the basic functional unit of the ovary and consists of an oocyte, which is surrounded by granulosa cells (GCs). GCs play an important role in the growth and development of the follicle. They are subject to increased attention since it has recently been shown that the subpopulation of GCs within the growing follicle possesses exceptionally plasticity showing stem cell characteristics. In assisted reproduction programs, oocytes are retrieved from patients together with GCs, which are currently discarded daily, but could be an interesting subject to be researched and potentially used in regenerative medicine in the future. Isolated GCs expressed stem cell markers such as OCT-4, NANOG and SOX-2, showed high telomerase activity, and were in vitro differentiated into other cell types, otherwise not present within ovarian follicles. Recently another phenomenon demonstrated in GCs is transdifferentiation, which could explain many ovarian pathological conditions. Possible applications in regenerative medicine are also given.

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

Similar content being viewed by others

References

  1. Albrecht KH, Eicher EM. Evidence that Sry is expressed in pre-Sertoli cells and Sertoli and granulosa cells have a common precursor. Dev Biol. 2001;240:92–107.

    Article  PubMed  CAS  Google Scholar 

  2. Atlasi Y, Mowla SJ, Ziaee SA, et al. OCT4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells. 2008;26:3068–74.

    Article  PubMed  CAS  Google Scholar 

  3. Barrero MJ, Belmonte JCI. Regenerating the epigenome. EMBO Rep. 2011;12:208–15.

    Article  PubMed  CAS  Google Scholar 

  4. Bayne S, Li H, Jones ME, et al. Estrogen deficiency reversibly induces telomere shortening in mouse granulosa cells and ovarian aging in vivo. Protein Cell. 2011;2:333–46.

    Article  PubMed  CAS  Google Scholar 

  5. Boerboom D, Paguet M, Hsieh M, et al. Misregulated Wnt/beta-catenin signaling leads to ovarian granulosa cell tumor development. Cancer Res. 2005;65:9206–15.

    Article  PubMed  CAS  Google Scholar 

  6. Boyer A, Goff AK, Boerboom D. WNT signaling in ovarian follicle biology and tumorigenesis. Trends Endocrinol Metab. 2010;21:25–32.

    Article  PubMed  CAS  Google Scholar 

  7. Bukovsky A, Caudle MR. Immunoregulation of follicular renewal, selection, POF, and menopause in vivo, vs. neo-oogenesis in vitro, POF and ovarian infertility treatment, and a clinical trial. Reprod Biol Endocrinol. 2012. doi:10.1186/1477-7827-10-97.

    PubMed  Google Scholar 

  8. Bukovsky A. Ovarian stem cell niche and follicular renewal in mammals. Anat Rec (Hoboken). 2011;294:1284–306.

    Article  CAS  Google Scholar 

  9. Bukovsky A, Caudle MR, Svetlikova M. Steroid-mediated differentiation of neural/neuronal cells from epithelial ovarian precursors in vitro. Cell Cycle. 2008;7:3577–83.

    Article  PubMed  CAS  Google Scholar 

  10. Butts S, Riethman H, Ratcliffe S, et al. Correlation of telomere length and telomerase activity with occult ovarian insufficiency. J Clin Endocrinol Metab. 2009;94:4835–43.

    Article  PubMed  CAS  Google Scholar 

  11. Chen H, Wang W, Mo Y, et al. Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during in vitro fertilization treatment. J Assist Reprod Genet. 2011;28:797–807.

    Article  PubMed  CAS  Google Scholar 

  12. Cheng EH, Chen SU, Lee TH, et al. Evaluation of telomere length in cumulus cells as a potential biomarker of oocyte and embryo quality. Hum Reprod. 2013. doi:10.1093/humrep/det004.

    Google Scholar 

  13. Chronowska E. Regulation of telomerase activity in ovarian granulosa cells. Indian J Exp Biol. 2012;50:595–601.

    PubMed  CAS  Google Scholar 

  14. Clevers H, Nusse R. Wnt/β-Catenin signaling and disease. Cell. 2012;149:1192–205.

    Article  PubMed  CAS  Google Scholar 

  15. Daniels R, Hall V, Trounson AO. Analysis of gene transcription in bovine nuclear transfer embryos reconstructed with granulosa cell nuclei. Biol Reprod. 2000;63:1034–40.

    Article  PubMed  CAS  Google Scholar 

  16. Edwards RG. Follicular fluid. J Reprod Fertil. 1974;37:189–219.

    Article  PubMed  CAS  Google Scholar 

  17. Erickson G. The graafian follicle: a functional definition. In: Adashi EY, editor. Ovulation: evolving scientific and clinical concepts. New York: Springer; 2000. p. 31–48.

    Chapter  Google Scholar 

  18. Fan HY, O’Connor A, Shitanaka M, et al. β-Catenin (CTNNB1) promotes preovulatory follicular development but represses LH-mediated ovulation and luteinization. Mol Endocrinol. 2010;24:1529–42.

    Article  PubMed  CAS  Google Scholar 

  19. Flores I, Canela A, Vera E, et al. The longest telomeres: a general signature of adult stem cell compartments. Genes Dev. 2008;22:654–67.

    Article  PubMed  CAS  Google Scholar 

  20. Glister C, Kemp CF, Knight PG. Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4, -6 and -7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin. Reproduction. 2002;127:239–54.

    Article  Google Scholar 

  21. Gong SP, Lee ST, Lee EJ, et al. Embryonic stem cell-like cells established by culture of adult ovarian cells in mice. Fertil Steril. 2010;93:2594–601.

    Article  PubMed  Google Scholar 

  22. Grunwald K, Feldmann K, Melsheimer P, et al. Aneuploidy in human granulosa lutein cells obtained from gonadotrophin-stimulated follicles and its relation to intrafollicular hormone concentrations. Hum Reprod. 1998;10:2679–87.

    Article  Google Scholar 

  23. Håkelien AM, Landsverk HB, Robl JM, et al. Reprogramming fibroblasts to express T-cell functions using cell extracts. Nature. 2002;20:460–6.

    Article  Google Scholar 

  24. Hanson JA, Ambaye AB. Adult testicular granulosa cell tumor: a review of the literature for clinopathologic predictors of malignancy. Arch Pathol Lab Med. 2011;135:143–6.

    PubMed  Google Scholar 

  25. Heng BC, Cao T, Bested SM, et al. “Waste” follicular aspirate from fertility treatment – a potential source of human germline stem cells? Stem Cells Dev. 2005;14:11–4.

    Article  PubMed  Google Scholar 

  26. Hirshfield AN. Patterns of [3H] thymidine incorporation differ in immature rats and mature, cycling rats. Biol Reprod. 1986;34:229–35.

    Article  PubMed  CAS  Google Scholar 

  27. Hiyama E, Hiyama K. Telomere and telomerase in stem cells. Brit J Cancer. 2007;96:1020–4.

    Article  PubMed  CAS  Google Scholar 

  28. Hoffmeyer K, Raggioli A, Rudloff S, et al. Wnt/β-Catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336:1549–54.

    Article  PubMed  CAS  Google Scholar 

  29. Honda A, Hirose M, Hara K, et al. Isolation, characterization, and in vitro and in vivo differentiation of putative thecal stem cells. Proc Natl Acad Sci USA. 2007;104:12389–94.

    Article  PubMed  CAS  Google Scholar 

  30. Iijima Y, Nagai T, Mizukami M, et al. Beating is necessary for transdifferentiation of skeletal muscle-derived cells into cardiomyocytes. FASEB J. 2003;17:1361–3.

    PubMed  CAS  Google Scholar 

  31. Jamieson S, Fuller PJ. Molecular pathogenesis of granulosa cell tumors of the ovary. Endocr Rev. 2012;33:109–44.

    Article  PubMed  CAS  Google Scholar 

  32. Jopling C, Boue S, Izpisua Belmonte JC. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat Rev Mol Cell Biol. 2011;12:79–89.

    Article  PubMed  CAS  Google Scholar 

  33. Kaleli S, Yanikkaya-Demirel G, Erel CT, et al. High rate of aneuploidy in luteinized granulosa cells obtained from follicular fluid in women who underwent controlled ovarian hyperstimulation. Fertil Steril. 2005;84:802–4.

    Article  PubMed  Google Scholar 

  34. Karuputhula NB, Chattopadhyay R, Chakravarty B, et al. Oxidative status in granulosa cells of infertile women undergoing IVF. Syst Biol Reprod Med. 2013;59:91–8.

    Article  PubMed  CAS  Google Scholar 

  35. Kinugawa C, Murakami T, Okamura K, et al. Telomerase activity in normal ovaries and premature ovarian failure. Tohoku J Exp Med. 2000;190:231–8.

    Article  PubMed  CAS  Google Scholar 

  36. Kléber M, Sommer L. Wnt signaling and the regulation of stem cell function. Curr Opin Cell Biol. 2004;16:681–7.

    Article  PubMed  Google Scholar 

  37. Knight PG, Muttukrishna S, Groome NP. Development and application of a two-site enzyme immunoassay for the determination of “total” activin-A concentrations in serum and follicular fluid. J Endocrinol. 1996;148:267–79.

    Article  PubMed  CAS  Google Scholar 

  38. Komori T. Regulation of osteoblast differentiation by Runx2. Adv Exp Med Biol. 2010;658:43–9.

    Article  PubMed  CAS  Google Scholar 

  39. Kossowska-Tomaszczuk K, De Geyter C. Cells with stem cell characteristics in somatic compartments of the ovary. Biomed Res Int. 2013. doi:10.1155/2013/310859.

    PubMed  Google Scholar 

  40. Kossowska-Tomaszczuk K, Pelezar P, Güven S, et al. A novel three-dimensional culture system allows prolonged culture of functional human granulosa cells and mimics the ovarian environment. Tissue Eng A. 2010;16:2063–73.

    Article  CAS  Google Scholar 

  41. Kossowska-Tomaszczuk K, De Geyter C, De Geyter M, et al. The multipotency of luteinizing granulosa cells collected from mature ovarian follicles. Stem Cells. 2009;27:210–9.

    Article  PubMed  CAS  Google Scholar 

  42. Lavranos TC, Mathis JM, Latham SE, et al. Evidence for ovarian granulosa stem cells: telomerase activity and localization of the telomerase ribonucleic acid component in bovine ovarian follicles. Biol Reprod. 1999;61:358–66.

    Article  PubMed  CAS  Google Scholar 

  43. Lee HW, Blasco MA, Gottlieb GJ, et al. Essential role of mouse telomerase in highly proliferative organs. Nature. 1998;392:569–74.

    Article  PubMed  CAS  Google Scholar 

  44. Lima JF, Jin L, de Araujo AR, et al. FOXL2 mutations in granulosa cell tumors occurring in males. Arch Pathol Lab Med. 2012;136:825–8.

    Article  PubMed  CAS  Google Scholar 

  45. Liu S, Wang Y, Wang L, et al. Transdifferentiation of fibroblasts into adipocyte-like cells by chicken adipogenic transcription factors. Comp Biochem Physiol A Mol Integr Physiol. 2010;156:502–8.

    Article  PubMed  Google Scholar 

  46. Luu HH, Song W, Luo X, et al. Distinct role of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells. J Orthop Res. 2007;25:665–77.

    Article  PubMed  CAS  Google Scholar 

  47. Mattioli M, Gloria A, Turriani M, et al. Osteo-regenerative potential of ovarian granulosa cells: an in vitro and in vivo study. Theriogenology. 2012;77:1425–37.

    Article  PubMed  CAS  Google Scholar 

  48. Misselevich I, Boss JH. Metaplastic bone in a mucinous cystadenoma of the ovary. Pathol Res Pract. 2000;196:847–8.

    Article  PubMed  CAS  Google Scholar 

  49. Monti M, Redi C. Oogenesis specific genes (Nobox, Oct4, Bmp15, Gdf9, Oogenesin1 and Oogenesin2) are differentially expressed during natural and gonadotropin-induced mouse follicular development. Mol Reprod Dev. 2009;76:994–1003.

    Article  PubMed  CAS  Google Scholar 

  50. Mooney EE, Vaidya KP, Tavassoli FA. Ossifying well-differentiated Sertoli-Leydig cell tumor of the ovary. Ann Diagn Pathol. 2000;4:34–8.

    Article  PubMed  CAS  Google Scholar 

  51. Mora JM, Fenwick MA, Castle L, et al. Characterization and significance of adhesion and junction-related proteins in mouse ovarian follicles. Biol Reprod. 2012;86:1–14.

    Article  Google Scholar 

  52. Morizane M, Ohara N, Mori T, et al. Ossifying luteinized thecoma of the ovary. Arch Gynecol Obstet. 2003;267:167–9.

    Article  PubMed  CAS  Google Scholar 

  53. Morrison SJ, Prowse KR, Ho P, et al. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity. 1996;5:207–16.

    Article  PubMed  CAS  Google Scholar 

  54. Mukonoweshuro P, Oriowolo A. Stromal osseous metaplasia in a low-grade ovarian adenocarcinoma. Gynecol Oncol. 2005;99:222–4.

    Article  PubMed  CAS  Google Scholar 

  55. Nguyen T, Lee S, Hatzirodos N, et al. Spatial differences within the membrana granulosa in the expression of focimatrix and steroidogenic capacity. Mol Cell Endocrinol. 2012;363:62–73.

    Article  PubMed  CAS  Google Scholar 

  56. Okada TS. Transdifferentiation: flexibility in cell differentiation. Oxford: Oxford University Press; 1991.

    Google Scholar 

  57. Oki Y, Ono H, Motohashi T, et al. Dedifferentiated follicular granulosa cells derived from pig ovary can transdifferentiate into osteoblasts. Biochem J. 2012;447:239–48.

    Article  PubMed  CAS  Google Scholar 

  58. Otsuka F, Shimasaki S. A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: Its role in regulating granulosa cell mitosis. Proc Natl Acad Sci USA. 2002;99:8060–5.

    Article  PubMed  CAS  Google Scholar 

  59. Pandey A, Gupta SC, Gupta N, et al. Comparative potential of cultured skin fibroblast, cumulus, and granulosa cell to produce somatic cell nuclear transfer (SCNT) preimplantation embryos in buffaloes (Bubalus bubalis) in relation to gene expressions. Cell Reprogram. 2010;12:357–68.

    Article  PubMed  CAS  Google Scholar 

  60. Park ES, Park J, Franceschi RT, Jo M. The role for runt related transcription factor 2 (RUNX2) as a transcriptional repressor in luteinizing granulosa cells. Mol Cell Endocrinol. 2012;362:165–75.

    Article  PubMed  CAS  Google Scholar 

  61. Parte S, Bhartiya D, Telang J, et al. Detection, characterization, and spontaneous differentiation in vitro of very small embryonic-like putative stem cells in adult mammalian ovary. Stem Cells Dev. 2011;20:1451–64.

    Article  PubMed  CAS  Google Scholar 

  62. Perán M, Marchal JA, Rodríguez-Serrano F, et al. Transdifferentiation: why and how? Cell Biol Int. 2011;35:373–9.

    Article  PubMed  Google Scholar 

  63. Red-Horse K, Ueno H, Weissman I, et al. Coronary arteries form by developmental reprogramming of venous cells. Nature. 2010;464:549–53.

    Article  PubMed  CAS  Google Scholar 

  64. Rodgers RJ, Irving-Rodgers HF, van Wezel IL, et al. Dynamics of the membrana granulosa during expansion of the ovarian follicular antrum. Mol Cell Endocrinol. 2001;171:41–8.

    Article  PubMed  CAS  Google Scholar 

  65. Silva JC R e, Andrade D, Becker AP, et al. Isolated osseous ovarian metaplasia: case report. Eur J Gynaecol Oncol. 2010;31:469–70.

    Google Scholar 

  66. Russo V, Berardinelli P, Martelli A, et al. Expression of telomerase reverse transcriptase subunit (TERT) and telomere sizing in pig ovarian follicles. J Histochem Cytochem. 2006;54:443–55.

    Article  PubMed  CAS  Google Scholar 

  67. Schmidt D, Ovitt CE, Anlag K, et al. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development. 2004;131:933–42.

    Article  PubMed  CAS  Google Scholar 

  68. Shukla AR, Huff DS, Canning DA, et al. Juvenile granulosa cell tumor of the testis: contemporary clinical management and pathological diagnosis. J Urol. 2004;171:1900–2.

    Article  PubMed  Google Scholar 

  69. Sittadjody S, Saul JM, Joo S, et al. Engineered multilayer ovarian tissue that secretes sex steroids and peptide hormones in response to gonadotropins. Biomaterials. 2012;34:2412–20.

    Article  PubMed  Google Scholar 

  70. Stand M, Micchelli CA. Quiescent gastric stem cells maintain the adult Drosophila stomach. Proc Natl Acad Sci USA. 2011;108:17696–701.

    Article  Google Scholar 

  71. Su YQ, Sugiura K, Eppig JJ. Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Semin Reprod Med. 2009;27:32–42.

    Article  PubMed  CAS  Google Scholar 

  72. Sugimoto K, Gordon SP, Meyerowitz EM. Regeneration in plants and animals: dedifferentiation, transdifferentiation, or just differentiation? Trends Cell Biol. 2011;21:212–8.

    Article  PubMed  CAS  Google Scholar 

  73. Tian XC, Kubota C, Enright B, et al. Cloning animals by somatic cell nuclear transfer – biological factors. Reprod Biol Endocrinol. 2003. doi:10.1186/1477-7827-1-98.

    PubMed  Google Scholar 

  74. Tománek M, Chronowska E, Kott T, et al. Telomerase activity in pig granulosa cells proliferating and differentiating in vitro. Anim Reprod Sci. 2008;104:284–98.

    Article  PubMed  Google Scholar 

  75. Tsonis PA, Madhavan M, Tancous EE, et al. A newt’s eye view of lens regeneration. Int J Dev Biol. 2004;48:975–80.

    Article  PubMed  Google Scholar 

  76. Uhlenhaut NH, Jakob S, Anlag K, et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell. 2009;139:1130–42.

    Article  PubMed  CAS  Google Scholar 

  77. Varras M, Griva T, Kalles V, et al. Markers of stem cells in human ovarian granulosa cells: is there a clinical significance in ART? J Ovarian Res. 2012. doi:10.1186/1757-2215-5-36.

    PubMed  Google Scholar 

  78. Virant-Klun I, Zech N, Rozman P, et al. Putative stem cells with an embryonic character isolated from the ovarian surface epithelium of women with no naturally present follicles and oocytes. Differentiation. 2008;76:843–56.

    Article  PubMed  CAS  Google Scholar 

  79. Virant-Klun I, Rozman P, Cvjeticanin B, et al. Parthenogenetic embryo-like structures in the human ovarian surface epithelium cell culture in postmenopausal women with no naturally present follicles and oocytes. Stem Cells Dev. 2009;18:137–49.

    Article  PubMed  CAS  Google Scholar 

  80. Virant-Klun I, Skutella T, Stimpfel M, et al. Ovarian surface epithelium in patients with severe ovarian infertility: a potential source of cells expressing markers of pluripotent/multipotent stem cells. J Biomed Biotechnol. 2011. doi:10.1155/2011/381928.

    PubMed  Google Scholar 

  81. Wang HX, Li TY, Kidder GM. WNT2 regulates DNA synthesis in mouse granulosa cells through beta-catenin. Biol Reprod. 2010;82:865–75.

    Article  PubMed  CAS  Google Scholar 

  82. Wells DN, Misica PM, Tervit HR. Production of cloned calves following nuclear transfer with cultured adult mural granulosa cells. Biol Reprod. 1999;60:996–1005.

    Article  PubMed  CAS  Google Scholar 

  83. Yamagata Y, Nakamura Y, Umayahara K, et al. Changes in telomerase activity in experimentally induced atretic follicles of immature rats. Endocr J. 2002;49:589–95.

    Article  PubMed  CAS  Google Scholar 

  84. Yang L, Li S, Hatch H, et al. In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci USA. 2002;99:8078–83.

    Article  PubMed  CAS  Google Scholar 

  85. Yong EL, Baird DT, Yates R, et al. Hormonal regulation of the growth and steroidogenic function of human granulosa cells. J Clin Endocrinol Metab. 1992;74:842–9.

    Article  PubMed  CAS  Google Scholar 

  86. Zhang X, Yang M, Lin L, et al. Runx2 overexpression enhances osteoblastic differentiation and mineralization in adipose-derived stem cells in vitro and in vivo. Calcif Tissue Int. 2006;79:169–78.

    Article  PubMed  CAS  Google Scholar 

  87. Zuccotti M, Merico V, Belli M, et al. OCT4 and the acquisition of oocyte developmental competence during folliculogenesis. Int J Dev Biol. 2012;56:853–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors indicate no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, University Medical Centre Ljubljana, Šlajmerjeva 3, 1000, Ljubljana, Slovenia

    Edo Dzafic, Martin Stimpfel & Irma Virant-Klun

Authors
  1. Edo Dzafic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Stimpfel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irma Virant-Klun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Irma Virant-Klun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dzafic, E., Stimpfel, M. & Virant-Klun, I. Plasticity of granulosa cells: on the crossroad of stemness and transdifferentiation potential. J Assist Reprod Genet 30, 1255–1261 (2013). https://doi.org/10.1007/s10815-013-0068-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-013-0068-0

Keywords

Search

Navigation