Skip to main content


Log in

Ovarian stem cells—resolving controversies

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


A recent review on ovarian stem cells by Horan and Williams entitled “Oocyte Stem Cells: Fact or Fantasy?” suggests that the debate on ovarian stem cells (OSCs) is still not over. They did not even discuss the presence of two distinct populations of stem cells in the ovary in their review. OSCs are located in the ovary surface epithelium and Tilly’s group reported them in the size range of 5–8 μm whereas Virant-Klun’s group has reported pluripotent, 2–4 μm OSCs. Our group reported OSCs of two distinct sizes including pluripotent very small embryonic-like stem cells (VSELs) which are smaller in size than RBCs (similar to those reported by Virant-Klun’s group) and slightly bigger (similar to those reported by Tilly’s group) tissue committed progenitors (OSCs) that presumably differentiate from VSELs. These stem/progenitor cells express receptors for follicle stimulating hormone (FSH) and are activated by FSH. Our opinion article provides explanation to several open-ended questions raised in the review on OSCs by Horan and Williams. VSELs survive chemotherapy; maintain life-long homeostasis; loss of their function due to a compromised niche results in age-related senescence and presence of overlapping pluripotent markers suggest that they may also be implicated in epithelial ovarian cancers.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others


  1. Horan CJ, Williams SA. Oocyte stem cells: fact or fantasy? Reproduction. 2017;154(1):R23–35.

    Article  CAS  PubMed  Google Scholar 

  2. Woods DC, Tilly JL. Isolation, characterization and propagation of mitotically active germ cells from adult mouse and human ovaries. Nat Protoc. 2013;8(5):966–88.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Virant-Klun I, Zech N, Rozman P, Vogler A, Cvjeticanin B, Klemenc 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  CAS  PubMed  Google Scholar 

  4. Parte S, Bhartiya D, Telang J, Daithankar V, Salvi V, Zaveri K, 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;

  5. Parte S, Patel H, Sriraman K, Bhartiya D. Isolation and characterization of stem cells in the adult mammalian ovary. Methods Mol Biol. 2015;1235:203–29.

    Article  CAS  PubMed  Google Scholar 

  6. Sriraman K, Bhartiya D, Anand S, Bhutda S. Mouse ovarian very small embryonic-like stem cells resist chemotherapy and retain ability to initiate oocyte-specific differentiation. Reprod Sci. 2015;22(7):884–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bhartiya D. Ovarian stem cells are always accompanied by very small embryonic-like stem cells in adult mammalian ovary. J Ovarian Res. 2015;

  8. Esmaeilian Y, Atalay A, Erdemli E. Putative germline and pluripotent stem cells in adult mouse ovary and their in vitro differentiation potential into oocyte-like and somatic cells. Zygote. 2017;25(3):358–75.

    Article  CAS  PubMed  Google Scholar 

  9. Bhartiya D, Shaikh A, Anand S, Patel H, et al. Endogenous, very small embryonic-like stem cells: critical review, therapeutic potential and a look ahead. Hum Reprod Update. 2016;23(1):41–76.

    Article  PubMed  Google Scholar 

  10. Patel H, Bhartiya D. Testicular stem cells express follicle stimulating hormone receptors and are directly modulated by FSH. Reprod Sci. 2016;23(11):1493–508.

    Article  CAS  PubMed  Google Scholar 

  11. Anand S, Bhartiya D, Sriraman K, Mallick A. Underlying mechanisms that restore spermatogenesis on transplanting healthy niche cells in busulphan treated mouse testis. Stem Cell Rev. 2016;12(6):682–97.

    Article  CAS  PubMed  Google Scholar 

  12. Li L, Clevers H. Coexistence of quiescent and active adult stem cells in mammals. Science. 2010;327(5965):542–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. De Rosa L, De Luca M. Cell biology: dormant and restless skin stem cells. Nature. 2012;489(7415):215–7.

    Article  PubMed  Google Scholar 

  14. Zarate-Garcia L, Lane SI, Merriman JA, Jones KT. FACS-sorted putative oogonial stem cells from the ovary are neither DDX4-positive nor germ cells. Sci Rep. 2016;15(6):279–91.

    Google Scholar 

  15. Navaroli DM, Tilly JL, Woods DC. Isolation of mammalian oogonial stem cells by antibody-based fluorescence-activated cell sorting. Methods Mol Biol. 2016;1457:253–68.

    Article  CAS  PubMed  Google Scholar 

  16. Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428(6979):145–50.

    Article  CAS  PubMed  Google Scholar 

  17. Liu Y, Wu C, Lyu Q, Yang D, Albertini DF, Keefe DL, et al. Germline stem cells and neo-oogenesis in the adult human ovary. Dev Biol. 2007;306(1):112–20.

    Article  CAS  PubMed  Google Scholar 

  18. Parte S, Bhartiya D, Patel H, Daithankar V, Chauhan A, Zaveri K, et al. Dynamics associated with spontaneous differentiation of ovarian stem cells in vitro. J Ovarian Res. 2014;

  19. Johnson J, Bagley J, Skaznik-Wikiel M, Lee HJ, Adams GB, Niikura Y, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell. 2005;122(2):303–15.

    Article  CAS  PubMed  Google Scholar 

  20. Eggan K, Jurga S, Gosden R, Min IM, Wagers AJ. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature. 2006;441(7097):1109–14.

    Article  CAS  PubMed  Google Scholar 

  21. Lei L, Spradling AC. Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles. Proc Natl Acad Sci U S A. 2013;110(21):8585–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bhartiya D, Sriraman K, Parte S, Patel H. Ovarian stem cells: absence of evidence is not evidence of absence. J Ovarian Res. 2013;

  23. Lei L, Spradling AC. Mouse oocytes differentiate through organelle enrichment from sister cyst germ cells. Science. 2016;352(6281):95–9.

    Article  CAS  PubMed  Google Scholar 

  24. Bhartiya D, Sriraman K, Gunjal P, Modak H. Gonadotropin treatment augments postnatal oogenesis and primordial follicle assembly in adult mouse ovaries? J Ovarian Res. 2012;

  25. Patel H, Bhartiya D, Parte S, Gunjal P, Yedurkar S, Bhatt M. Follicle stimulating hormone modulates ovarian stem cells through alternately spliced receptor variant FSH-R3. J Ovarian Res. 2013;

  26. Bhartiya D, Parte S, Patel H, Sriraman K, Zaveri K, Hinduja I. Novel action of FSH on stem cells in adult mammalian ovary induces postnatal oogenesis and primordial follicle assembly. Stem Cells Int. 2016;

  27. Fazeli Z, Abedindo A, Omrani MD, Ghaderian SMH. Mesenchymal stem cells (MSCs) therapy for recovery of fertility: a systematic review. Stem Cell Rev. 2017;

  28. McLaughlin M, Kelsey TW, Wallace WH, Anderson RA, Telfer EE. Non-growing follicle density is increased following adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy in the adult human ovary. HumReprod. 2017;32(1):165–74.

    CAS  Google Scholar 

  29. Parte S, Bhartiya D, Manjramkar DD, Chauhan A, Joshi A. Stimulation of ovarian stem cells by follicle stimulating hormone and basic fibroblast growth factor during cortical tissue culture. J Ovarian Res. 2013;

  30. May-Panloup P, Boucret L, Chao de la Barca JM, Desquiret-Dumas V, Ferré-L’Hotellier V, et al. Ovarian ageing: the role of mitochondria in oocytes and follicles. Hum Reprod Update. 2016;22(6):725–43.

    Article  CAS  PubMed  Google Scholar 

  31. Niikura Y, Niikura T, Tilly JL. Aged mouse ovaries possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment. Aging (Albany NY). 2009;1:971–8.

    Article  CAS  Google Scholar 

  32. Bhartiya D. Use of very small embryonic-like stem cells to avoid legal, ethical, and safety issues associated with oncofertility. JAMA Oncol. 2016;2(5):689.

    Article  PubMed  Google Scholar 

  33. Bhartiya D, Anand S, Parte S. VSELs may obviate cryobanking of gonadal tissue in cancer patients for fertility preservation. J Ovarian Res. 2015;

  34. Bhartiya D, Anand S, Patel H, Parte S. Making gametes from alternate sources of stem cells: past, present and future. Reprod Biol Endocrinol. 2014;

  35. Bhartiya D. Letter to the editor: rejuvenate eggs or regenerate ovary? Mol Cell Endocrinol. 2017;

  36. Bhartiya D, Anand S. Letter to the editor: effects of oncotherapy on testicular stem cells and niche. Mol Hum Reprod. 2017;23(9):654–5.

    Article  PubMed  Google Scholar 

  37. Bhartiya D. Pluripotent stem cells in adult tissues: struggling to be acknowledged over two decades. Stem Cell Rev. 2017;

  38. Yoshihara M, Hayashizaki Y, Murakawa Y. Genomic instability of iPSCs: challenges towards their clinical applications. Stem Cell Rev. 2017;13(1):7–16.

    Article  CAS  PubMed  Google Scholar 

  39. Reardon S. Mutated mitochondria could hold back stem-cell therapies. Nature. 2016;

  40. Kitada M, Wakao S, Dezawa M. Muse cells and induced pluripotent stem cell: implication of the elite model. Cell Mol Life Sci. 2012;69:3739–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu X, Li W, Fu X, Xu Y. The immunogenicity and immune tolerance of pluripotent stem cell derivatives. Front Immunol. 2017;8:645.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Edessy M, Hosni HN, Shady Y, Waf Y, Bakr S, Kamel M. Autologous stem cells therapy, the first baby of idiopathic premature ovarian failure. Acta Med Int. 2016;3:19–23.

    Article  Google Scholar 

  43. Virant-Klun I, Kenda-Suster N, Smrkolj S. Small putative NANOG, SOX2, and SSEA-4-positive stem cells resembling very small embryonic-like stem cells in sections of ovarian tissue in patients with ovarian cancer. J Ovarian Res. 2016;

Download references


Authors acknowledge the earlier students and project staff in the lab who also contributed to the field. Also help from various funding agencies is also acknowledged. NIRRH accession number for the manuscript is OTH/501/07-2017.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Deepa Bhartiya.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhartiya, D., Patel, H. Ovarian stem cells—resolving controversies. J Assist Reprod Genet 35, 393–398 (2018).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: