Abstract
The existence of ovarian germline stem cells (GSCs) has been challenged by various research groups. The hypothesis that mammalian ovaries contain germ cells with regenerative potential continues to be tested. Recent advancements in stem cell science have led to new information in the area, leaving the question open. Anatomically, cells purported to be undifferentiated ovarian GSCs are located near the surface epithelium and express the markers for undifferentiated stem cells. Various studies have proposed the presence of specific immunological markers for ovarian GSCs but this topic is highly contentious. The mainstay of the studies performed on ovarian GSCs has demonstrated that their transplantation into otherwise sterile postnatal mice facilitated the mice to produce embryos and offspring. In another study, ovarian GCSs were identified in reproductive-age women, which put to test the established dogma of a fixed reserve pool of oocytes before birth in humans as well. If proliferative ovarian GSCs are indeed present, their impact upon the timing of menopause needs to be better understood. Last, ovarian GSCs have also been implicated in ovarian cancers. Several studies have explored a relationship between cancer stem cells (CSCs) and putative ovarian GSCs. All of these intriguing accomplishments and open questions about the prospects of using ovarian GSCs in this field are discussed in detail in this chapter.
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Abbreviations
- ALDH:
-
Aldehyde dehydrogenase
- BMP4:
-
Bone morphogenetic protein 4
- CSC:
-
Cancer stem cell
- Ddx-4:
-
DEAD box polypeptide 4
- FACS:
-
Fluorescence activated cell sorting
- FBS:
-
Fetal bovine serum
- FGSC:
-
Female germline stem cell
- FISH:
-
Fluorescence in situ hybridization
- FSH:
-
Follicle stimulating hormone
- GCN:
-
Germ cell nest
- GF:
-
Growth factor
- GFP:
-
Green fluorescent protein
- GSC:
-
Germline stem cell
- GV:
-
Germinal vesicle
- HGC:
-
Human granulosa cell
- IVD:
-
In vitro-derived
- IVM:
-
In vitro maturation
- LHX8:
-
LIM homeobox protein 8
- MACS:
-
Magnetic-activated cell sorting
- MEF:
-
Mouse embryonic fibroblast
- MSC:
-
Mesenchymal stem cell
- OLC:
-
Oocyte-like structure
- OSC:
-
Ovarian stem cell
- OSE:
-
Ovarian surface epithelium
- PB:
-
Peripheral blood
- PCNA:
-
Proliferative cell nuclear antigen
- PCOS:
-
Polycystic ovary syndrome
- POF:
-
Premature ovarian failure
- SSEA:
-
Stage-specific embryonic antigen
- SSEA-4:
-
Stage-specific embryonic antigen-4
- StPB-C:
-
Short-type pituitary gland and brain-cadherin
- VSEL:
-
Very small embryonic-like cells
- α-MEM:
-
α-Modified Eagle’s Medium
References
Adams PD, Jasper H, Rudolph KL (2015) Aging-induced stem cell mutations as drivers for disease and cancer. Cell Stem Cell 16(6):601–612. https://doi.org/10.1016/j.stem.2015.05.002
Allbee AW, Rincon-Limas DE, Biteau B (2018) Lmx1a is required for the development of the ovarian stem cell niche in Drosophila. Development 145(8):dev163394. https://doi.org/10.1242/dev.163394
Allen E (1923) Ovogenesis during sexual maturity. Am J Anatomy 31(5):439–481. https://doi.org/10.1002/aja.1000310502
Baharvand H, Saber M, Nezhad FE (2019) Isolation of oogonial stem cells. Google patents
Bao R, Xu P, Wang Y et al (2018) Bone marrow derived mesenchymal stem cells transplantation rescues premature ovarian insufficiency induced by chemotherapy. Gynecol Endocrinol 34(4):320–326. https://doi.org/10.1080/09513590.2017.1393661
Bates GW (2019) Polycystic ovary syndrome: a reproductive and metabolic web of risk, comorbidities, and disease. Fertil Steril 111(3):471–472. https://doi.org/10.1016/j.fertnstert.2019.01.028
Bellio C, DiGloria C, Foster R et al (2019) PARP inhibition induces enrichment of DNA repair–proficient CD133 and CD117 positive ovarian cancer stem cells. Mol Cancer Res 17(2):431–445. https://doi.org/10.1158/1541-7786.MCR-18-0594
Bharti D, Jang S-J, Lee S-Y et al (2020) In vitro generation of oocyte like cells and their in vivo efficacy: how far we have been succeeded. Cell 9(3):557. https://doi.org/10.3390/cells9030557
Bhartiya D (2015) Ovarian stem cells are always accompanied by very small embryonic-like stem cells in adult mammalian ovary. J Ovarian Res 8(1):70. https://doi.org/10.1186/s13048-015-0200-0
Bhartiya D, Patel H (2018) Ovarian stem cells—resolving controversies. J Assisted Reprod Genet 35(3):393–398. https://doi.org/10.1007/s10815-017-1080-6
Bhartiya D, Sharma D (2020) Ovary does harbor stem cells-size of the cells matter! J Ovarian Res 13(1):1–3. https://doi.org/10.1186/s13048-020-00647-2
Bhartiya D, Unni S, Parte S et al (2013) Very small embryonic-like stem cells: implications in reproductive biology. Biomed Res Int 2013:682326
Bhartiya D, Patel H, Sharma D (2019) Heterogeneity of stem cells in the ovary. Adv Exp Med Biol 1169:213–223. https://doi.org/10.1007/978-3-030-24108-7_11
Bui H-T, Van Thuan N, Kwon D-N et al (2014) Identification and characterization of putative stem cells in the adult pig ovary. Development 141(11):2235–2244. https://doi.org/10.1242/dev.104554
Bukovsky A, Caudle MR, Svetlikova M et al (2004) Origin of germ cells and formation of new primary follicles in adult human ovaries. Reprod Biol Endocrinol 2(1):20. https://doi.org/10.1007/978-1-60327-214-8_16
Bukovsky A, Svetlikova M, Caudle MR (2005) Oogenesis in cultures derived from adult human ovaries. Reprod Biol Endocrinol 3(1):17
Castrillon DH, Quade BJ, Wang T (2000) The human VASA gene is specifically expressed in the germ cell lineage. Proc Natl Acad Sci 97(17):9585–9590
Chaicharoenaudomrung N, Kunhorm P, Noisa P (2019) Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling. World J Stem Cells 11(12):1065. https://doi.org/10.4252/wjsc.v11.i12.1065
Chen S, Lewallen M, Xie T (2013) Adhesion in the stem cell niche: biological roles and regulation. Development 140(2):255–265. https://doi.org/10.1242/dev.083139
Choi Y-J, Gurunathan S, Kim J-H (2018) Graphene oxide–silver nanocomposite enhances cytotoxic and apoptotic potential of salinomycin in human ovarian cancer stem cells (OvCSCs): a novel approach for cancer therapy. Int J Mol Sci 19(3):710
Clarkson YL, McLaughlin M, Waterfall M et al (2018) Initial characterisation of adult human ovarian cell populations isolated by DDX4 expression and aldehyde dehydrogenase activity. Sci Rep 8(1):1–11
da Silva ML, Caplan AI, Nardi NB (2008) In search of the in vivo identity of mesenchymal stem cells. Stem Cells 26(9):2287–2299
De Rosa L, De Luca M (2012) Dormant and restless skin stem cells. Nature 489(7415):215–217
DeCarolis NA, Kirby ED, Wyss-Coray T, Palmer TD (2015) The role of the microenvironmental niche in declining stem-cell functions associated with biological aging. Cold Spring Harb Perspect Med 5(12):a025874
Dunlop CE (2017) Isolation, characterisation and in vitro potential of oogonial stem cells. http://hdl.handle.net/1842/25408
Dunlop CE, Telfer EE, Anderson RA (2013) Ovarian stem cells—potential roles in infertility treatment and fertility preservation. Maturitas 76(3):279–283
Esmaeilian Y, Atalay A, Erdemli E (2015) Post-natal oogenesis: a concept for controversy that intensified during the last decade. Zygote 23(3):315–326
Faddy M (2000) Follicle dynamics during ovarian ageing. Mol Cell Endocrinol 163(1–2):43–48
Fu X-f, He Y-l, Xie C-H et al (2008) Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage. Cytotherapy 10(4):353–363
Fujimaki S, Wakabayashi T, Takemasa T (2015) The regulation of stem cell aging by Wnt signaling. Histol Histopathol 30(12):1411–1430
Galasso A, Iakovleva D, Baena-Lopez LA (2019) Caspase-dependent activation of Hedgehog-signalling sustains proliferation and differentiation of ovarian somatic stem cells. BioRxiv 722330
Hanna CB, Hennebold JD (2014) Ovarian germline stem cells: an unlimited source of oocytes? Fertil Steril 101(1):20–30
He Y, Chen D, Yang L (2018) The therapeutic potential of bone marrow mesenchymal stem cells in premature ovarian failure. Stem Cell Res Ther 9(1):263
Herraiz S, Buigues A, Díaz-García C (2018) Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertil Steril 109(5):908–918. e902
Herraiz S, Pellicer N, Romeu M, Pellicer A (2019) Treatment potential of bone marrow-derived stem cells in women with diminished ovarian reserves and premature ovarian failure. Curr Opin Obstet Gynecol 31(3):156–162
Hummitzsch K, Anderson R A, Wilhelm D et al (2015) Stem cells, progenitor cells, and lineage decisions in the ovary. Endocr Rev 36(1):65–91
Hummitzsch K, Irving-Rodgers HF, Schwartz J (2019) Development of the mammalian ovary and follicles. In: The ovary. Elsevier, Amsterdam, pp 71–82
Ishiguro T, Sato A, Ohata H et al (2016) Establishment and characterization of an in vitro model of ovarian cancer stem-like cells with an enhanced proliferative capacity. Cancer Res 76(1):150–160
Islam SS, Aboussekhra A (2019) Sequential combination of cisplatin with eugenol targets ovarian cancer stem cells through the Notch-Hes1 signalling pathway. J Exp Clin Cancer Res 38(1):382
Jasper H, Kennedy BK (2012) Niche science: the aging stem cell. Cell Cycle 11(16):2959–2960
Johnson J, Canning J, Kaneko T (2004) Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428(6979):145–150
Johnson J, Jessamyn B, Malgorzata S-W et al (2005) Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 122(2):303–315. https://doi.org/10.1016/j.cell.2005.06.031
Kerr J, Brogan L, Myers M (2012) The primordial follicle reserve is not renewed after chemical or-irradiation mediated depletion. Reproduction 143(4):469–476
Kitamura H, Torigoe T, Hirohashi Y (2013) Prognostic impact of the expression of ALDH1 and SOX2 in urothelial cancer of the upper urinary tract. Mod Pathol 26(1):117–124
Kryczek I, Liu S, Roh M (2012) Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells. J Cancer 130(1):29–39
Kucia M, Machalinski BA, Ratajczak MZ (2006) The developmental deposition of epiblast/germ cell-line derived cells in various organs as a hypothetical explanation of stem cell plasticity. Acta Neurobiol Exp (Wars) 66(4):331–341
Lee SJ, Schover LR, Partridge AH (2006) American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 24(18):2917–2931
Lei L, Spradling AC (2013) Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles. Proc Natl Acad Sci 110(21):8585–8590
Li L, Clevers H (2010) Coexistence of quiescent and active adult stem cells in mammals. Science 327(5965):542–545
Liang R, Ghaffari S (2014) Stem cells, redox signaling, and stem cell aging. Antioxid Redox Signal 20(12):1902–1916
Martin JJ, Woods DC, Tilly JL (2019) Implications and current limitations of oogenesis from female germline or oogonial stem cells in adult mammalian ovaries. Cell 8(2):93
Massasa E, Costa XS, Taylor HS (2010) Failure of the stem cell niche rather than loss of oocyte stem cells in the aging ovary. Aging (Albany NY) 2(1):1
Mazzoldi EL, Pastò A, Pilotto G (2020) Comparison of the genomic profile of cancer stem cells and their non-stem counterpart: the case of ovarian cancer. J Clin Med 9(2):368
McClellan KA, Gosden R, Taketo T (2003) Continuous loss of oocytes throughout meiotic prophase in the normal mouse ovary. Dev Biol 258(2):334–348
Mendelson A, Frenette PS (2014) Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 20(8):833
Navaroli DM, Tilly JL, Woods DC (2016) Isolation of mammalian oogonial stem cells by antibody-based fluorescence-activated cell sorting. Methods Mol Biol 1457:253–268
Niikura Y, Niikura T, Tilly JL (2009) Aged mouse ovaries possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment. Aging (Albany NY) 1(12):971
Oktay K, Oktem O (2007) Regeneration of oocytes after chemotherapy: connecting the evidence from mouse to human. J Clin Oncol 25(22):3185–3187
Parte S, Bhartiya D, Telang J et al (2011) Detection, characterization, and spontaneous differentiation in vitro of very small embryonic-like putative stem cells in adult mammalian ovary. Stem Cells Dev 20(8):1451–1464
Parte S, Bhartiya D, Manjramkar DD et al (2013) Stimulation of ovarian stem cells by follicle stimulating hormone and basic fibroblast growth factor during cortical tissue culture. J Ovarian Res 6(1):20
Parte S, Bhartiya D, Patel H, Daithankar V et al (2014) Dynamics associated with spontaneous differentiation of ovarian stem cells in vitro. J Ovarian Res 7(1):25
Parte SC, Smolenkov A, Batra SK et al (2017) Ovarian cancer stem cells: unraveling a germline connection. Stem Cells Dev 26(24):1781–1803
Parvari S, Yazdekhasti H, Rajabi Z et al (2016) Differentiation of mouse ovarian stem cells toward oocyte-like structure by coculture with granulosa cells. Cell Reprogram 18(6):419–428
Patel H, Bhartiya D, Parte S (2018) Further characterization of adult sheep ovarian stem cells and their involvement in neo-oogenesis and follicle assembly. J Ovarian Res 11(1):3
Raghavan S, Mehta P, Ward MR et al (2017) Personalized medicine–based approach to model patterns of chemoresistance and tumor recurrence using ovarian cancer stem cell spheroids. Clin Cancer Res 23(22):6934–6945
Rodgers R, Lavranos T, Van Wezel I et al (1999) Development of the ovarian follicular epithelium. Mol Cell Endocrinol 151(1–2):171–179
Seghinsara AM, Banimohammad M (2018) New facts about ovarian stem cells: the origin and the fate. Int J Womens Health Reprod Sci 6(2):127–133
Sharrow AC, Perkins B, Collector MI et al (2016) Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: towards targeted stem cell therapy. Gynecol Oncol 142(2):341–348
Shim HJ, Lee EM, Nguyen LD (2014) High-dose irradiation induces cell cycle arrest, apoptosis, and developmental defects during Drosophila oogenesis. PLoS One 9(2):e89009
Silvestris E, D’Oronzo S, Cafforio P et al (2015) Perspective in infertility: the ovarian stem cells. J Ovarian Res 8(1):55
Silvestris E, Cafforio P, D’Oronzo S et al (2018) In vitro differentiation of human oocyte-like cells from oogonial stem cells: single-cell isolation and molecular characterization. Hum Reprod 33(3):464–473
Silvestris E, D’Oronzo S, Cafforio P et al (2019) In vitro generation of oocytes from ovarian stem cells (OSCs): in search of major evidence. Int J Mol Sci 20(24):6225
Singh B, Mal G, Gautam SK, Mukesh M (2019) Oogonia stem cells in farm animals. In: Advances in animal biotechnology. Springer, Berlin, pp 227–229
Sriraman K, Bhartiya D, Anand S et al (2015) Mouse ovarian very small embryonic-like stem cells resist chemotherapy and retain ability to initiate oocyte-specific differentiation. Reprod Sci 22(7):884–903
Stimpfel M, Skutella T, Cvjeticanin B et al (2013) Isolation, characterization and differentiation of cells expressing pluripotent/multipotent markers from adult human ovaries. Cell Tissue Res 354(2):593–607
Sui B, Hu C, Jin Y (2016) Mitochondrial metabolic failure in telomere attrition-provoked aging of bone marrow mesenchymal stem cells. Biogerontology 17(2):267–279
Telfer EE, Albertini DF (2012) The quest for human ovarian stem cells. Nat Med 18(3):353
Telfer E, Anderson R (2019) The existence and potential of germline stem cells in the adult mammalian ovary. Climacteric 22(1):22–26
Tilly JL, Telfer EE (2009) Purification of germline stem cells from adult mammalian ovaries: a step closer towards control of the female biological clock? Human Mol Reprod 15(7):393–398
Vickers NJ (2017) Animal communication: when I’m calling you, will you answer too? Curr Biol 27(14):R713–R715
Vied C, Reilein A, Field NS et al (2012) Regulation of stem cells by intersecting gradients of long-range niche signals. Dev Cell 23(4):836–848
Virant-Klun I (2015) Postnatal oogenesis in humans: a review of recent findings. Stem Cells Cloning 8:49
Virant-Klun I, Stimpfel M (2016) Novel population of small tumour-initiating stem cells in the ovaries of women with borderline ovarian cancer. Sci Rep 6:34730. https://doi.org/10.1038/srep34730
Virant-Klun I, Ech N, Rožman P (2008) Putative stem cells with an embryonic character isolated from the ovarian surface epithelium of women with no naturally present follicles and oocytes. Differentiation 76(8):843–856. https://doi.org/10.1111/j.1432-0436.2008.00268.x
Virant-Klun I, Stimpfel M, Cvjeticanin B (2013) Small SSEA-4-positive cells from human ovarian cell cultures: related to embryonic stem cells and germinal lineage? J Ovarian Res 6(1):24
Virant-Klun I, Kenda-Suster N, Smrkolj S (2016) 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 9(1):12
Virant-Klun I, Skerl P, Novakovic S (2019) Similar population of CD133+ and DDX4+ VSEL-like stem cells sorted from human embryonic stem cell, ovarian, and ovarian cancer ascites cell cultures: the real embryonic stem cells? Cell 8(7):706
Wagner M, Yoshihara M, Douagi I et al (2020) Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells. Nat Commun 11(1):1–15. https://doi.org/10.1038/s41467-020-14936-3
Waldeye W (1870) Eierstock und Ei. Engelmann, Leipzig
Wang N, Satirapod C, Ohguchi Y et al (2017) Genetic studies in mice directly link oocytes produced during adulthood to ovarian function and natural fertility. Sci Rep 7(1):1–16. https://doi.org/10.1038/s41598-017-10033-6
Wenzel L, Dogan-Ates A, Habbal R (2005) Defining and measuring reproductive concerns of female cancer survivors. JNCI Monogr 2005(34):94–98. https://doi.org/10.1093/jncimonographs/lgi017
White YA, Woods DC, Takai Y (2012) Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nat Med 18(3):413. https://doi.org/10.1038/nm.2669
Woods DC, Tilly JL (2013) An evolutionary perspective on adult female germline stem cell function from flies to humans. Paper presented at the seminars in reproductive medicine
Xu H, Zhu X, Li W (2018a) Isolation and in vitro culture of ovarian stem cells in Chinese soft-shell turtle (Pelodiscus sinensis). J Cell Biochem 119(9):7667–7677. https://doi.org/10.1002/jcb.27114
Xu J, Zheng T, Hong W (2018b) Mechanism for the decision of ovarian surface epithelial stem cells to undergo neo-oogenesis or ovarian tumorigenesis. Cell Physiol Biochem 50(1):214–232
Yajima M, Wessel GM (2015) Essential elements for translation: the germline factor Vasa functions broadly in somatic cells. Development 142(11):1960–1970
Yazdekhasti H, Rajabi Z, Parvari S (2016) Used protocols for isolation and propagation of ovarian stem cells, different cells with different traits. J ovarian Res 9(1):68
Ye H, Zheng T, Li W (2017) Ovarian stem cell nests in reproduction and ovarian aging. Cell Physiol Biochem 43(5):1917–1925
Zarate-Garcia L, Lane SI, Merriman JA (2016) FACS-sorted putative oogonial stem cells from the ovary are neither DDX4-positive nor germ cells. Sci Rep 6:27991. https://doi.org/10.1038/srep27991
Zhang D, Fouad H, Zoma WD (2008) Expression of stem and germ cell markers within nonfollicle structures in adult mouse ovary. Reprod Sci 15(2):139–146. https://doi.org/10.1177/1933719107310708
Zhang H, Zheng W, Shen Y (2012) Experimental evidence showing that no mitotically active female germline progenitors exist in postnatal mouse ovaries. Proc Natl Acad Sci 109(31):12580–12585. https://doi.org/10.1073/pnas.1206600109
Zolbin MM, Mokhtari T, Amidi F et al (2018) Isolation and localization of cells expressing Sca-1 in the adult mouse ovary: an evidence for presence of mesenchymal stem cells. J Contemp Med Sci 4(2):70–73
Zolbin MM, Ersoy GS, Aliakbari F (2020) Basal characterization and in vitro differentiation of putative stem cells derived from the adult mouse ovary. In Vitro Cell Dev Biol Anim 56(1):59–66
Zou K, Yuan Z, Yang Z et al (2009) Production of offspring from a germline stem cell line derived from neonatal ovaries. Nat Cell Biol 11(5):631–636. https://doi.org/10.1038/ncb1869
Zou K, Hou L, Sun K (2011) Improved efficiency of female germline stem cell purification using fragilis-based magnetic bead sorting. Stem Cells Dev 20(12):2197–2204. https://doi.org/10.1089/scd.2011.0091
Zuba-Surma EK, Kucia M, Wu W (2008) Very small embryonic-like stem cells are present in adult murine organs: ImageStream-based morphological analysis and distribution studies. Cytometry Part A J Int Sco Anal Cytol 73(12):1116–1127. https://doi.org/10.1002/cyto.a.20667
Zuba-Surma E, Wu W, Ratajczak J (2009) Very small embryonic-like stem cells in adult tissues—potential implications for aging. Mech Age Dev 130(1–2):58–66. https://doi.org/10.1016/j.mad.2008.02.003
Zuckerman S, Zuckerman S, Zuckerman S et al (1951) The number of oocytes in the mature ovary. Recent Prog Horm Res 6:63–108
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Zolbin, M.M. et al. (2021). Ovarian Stem Cells and Progenitors and Their Regenerative Capabilities. In: Haider, K.H. (eds) Stem cells: From Potential to Promise. Springer, Singapore. https://doi.org/10.1007/978-981-16-0301-3_4
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