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Putative germline and pluripotent stem cells in adult mouse ovary and their in vitro differentiation potential into oocyte-like and somatic cells

Published online by Cambridge University Press:  03 July 2017

Yashar Esmaeilian ,
Arzu Atalay  and
Esra Erdemli
Yashar Esmaeilian*
Affiliation:
Biotechnology Institute, University of Ankara, Ankara 06500, Turkey
Arzu Atalay
Affiliation:
Biotechnology Institute, University of Ankara, Ankara, Turkey
Esra Erdemli
Affiliation:
Department of Histology and Embryology, School of Medicine, University of Ankara, Ankara, Turkey
*
All correspondence to: Yashar Esmaeilian. Biotechnology Institute, University of Ankara, Ankara 06500, Turkey. Tel: +90 312 2225816. Fax: +90 312 2225872. E-mail: [email protected]
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Summary

According to classical knowledge of reproductive biology, in the ovary of female mammals there is a limited number of oocytes and there is no possibility of renewal if the oocytes are lost due to disease or injury. However, in recent years, the results of some studies on renewal and formation of oocytes and follicles in the adult mammalian ovary have led to the questioning of this opinion. The aim of our study is to demonstrate the presence of putative germline and pluripotent stem cells in the adult mouse ovary and their differentiation potential into germ and somatic cells. In ovary tissues and cells harvested from pre-differentiation step, the expression of pluripotent and germline stem cell markers was analysed by reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence staining and western blotting. Embryoid bodies that formed in this step were analysed using immunofluorescence staining and transmission electron microscopy. Ovarian stem cells were induced to differentiate into oocyte, osteoblast, chondrocyte and neural cells. Besides morphological observation, differentiated cells were analysed by RT-PCR, histochemical and immunofluorescence staining. Expression of germline and pluripotent stem cell markers both in mRNA and at the protein level were detected in the pre-differentiated cells and ovary tissues. As a result of the differentiation process, the formation of oocyte-like cells, osteoblasts, chondrocytes and neural cells was observed and characteristics of differentiated cells were confirmed using the methods mentioned above. Our study results revealed that the adult mouse ovary contains germline and pluripotent stem cells with the capacity to differentiate into oocyte-like cells, osteoblasts, chondrocytes and neural cells.

Keywords

ChondrogenesisGermline stem cellNeurogenesisOogenesisOsteogenesisOvaryPluripotent stem cell
Type
Research Article
Information
Zygote , Volume 25 , Issue 3 , June 2017 , pp. 358 - 375
Copyright
Copyright © Cambridge University Press 2017 

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References

Allen, E. & Creadick, R.N. (1937). Ovogenesis during sexual maturity. the first stage, mitoses in the germinal epithelium, as shown by the colchicine technique. Am. J. Anat. 69, 191–5.Google Scholar
Anderson, L.D. & Hirshfield, A.N. (1992). An overview of follicular development in the ovary: from embryo to the fertilized ovum in vitro . Md. Med. J. 41, 614–20.Google Scholar
Artem'eva, N. (1961). Regenerative capacity of rat ovary after compensatory hypertrophy. Bull. Exp. Biol. Med. 51, 76–81.Google Scholar
Au, P.C., Whitley, J., Vaux, D., Selwood, L. & Familari, M. (2008). Identification of novel and known ovary-specific genes including ZP2, in a marsupial, the stripe-faced dunnart. Mol. Reprod. Dev. 75, 318–25.Google Scholar
Bhartiya, D., Sriraman, K., Gunjal, P. & Modak, H. (2012). Gonadotropin treatment augments postnatal oogenesis and primordial follicle assembly in adult mouse ovaries. J. Ovarian Res. 5, 32.Google Scholar
Borum, K. (1961). Oogenesis in the mouse. A study of the meiotic prophase. Exp. Cell Res. 24, 495–507.CrossRefGoogle Scholar
Bukovsky, A., Caudle, M.R., Virant-Klun, I., Gupta, S.K., Dominguez, R., Svetlikova, M. & Xu, F. (2009). Immune physiology and oogenesis in fetal and adult humans, ovarian infertility, and totipotency of adult ovarian stem cells. Birth Defects Res. C Embryo Today, 87, 64–89.Google Scholar
Bukovsky, A., Svetlikova, M. & Caudle, M.R. (2005). Oogenesis in cultures derived from adult human ovaries. Reprod. Biol. Endocrinol. 3, 1–13.Google Scholar
Byskov, A.G., Hoyer, P.E., Andersen, C.Y., Kristensen, S.G., Jespersen, A. & Mollgard, K. (2011). No evidence for the presence of oogonia in the human ovary after their final clearance during the first two years of life. Hum. Reprod. 26, 2129–39.Google Scholar
Danova-Alt, R., Heider, A., Egger, D., Cross, M. & Alt, R. (2012). Very small embryonic-like stem cells purified from umbilical cord blood lack stem cell characteristics. PLoS One 7, e34899.CrossRefGoogle ScholarPubMed
Ding, X., Liu, G., Xu, B., Wu, C., Hui, N., Ni, X., Wang, J., Du, M., Teng, X. & Wu, J. (2016). Human GV oocytes generated by mitotically active germ cells obtained from follicular aspirates. Sci. Rep. 6, 28218.CrossRefGoogle ScholarPubMed
Drukala, J., Paczkowska, E., Kucia, M., Mlynska, E., Krajewski, A., Machalinski, B., Madeja, Z. & Ratajczak, M.Z. (2012). Stem cells, including a population of very small embryonic-like stem cells, are mobilized into peripheral blood in patients after skin burn injury. Stem Cell Rev. 8, 184–94.CrossRefGoogle ScholarPubMed
Eiselleova, L., Peterkova, I., Neradil, J., Slaninova, I., Hampl, A. & Dvorak, P. (2008). Comparative study of mouse and human feeder cells for human embryonic stem cells. Int. J. Dev. Biol. 52, 353–63.Google Scholar
Esmaeilian, Y., Atalay, A. & Erdemli, E. (2015). Post-natal oogenesis: a concept for controversy that intensified during the last decade. Zygote 23, 315–26.Google Scholar
Esmaeilian, Y., Gur Dedeoglu, B., Atalay, A. & Erdemli, E. (2012). Investigation of stem cells in adult and prepubertal mouse ovaries. Adv. Biosci. Biotechnol. 3, 936–44.Google Scholar
Faddy, M.J. (2000). Follicle dynamics during ovarian ageing. Mol. Cell. Endocrinol. 163, 43–8.Google Scholar
Faddy, M.J., Jones, E.C. & Edwards, R.G. (1976). An analytical model for ovarian follicle dynamics. J. Exp. Zool. 197, 173–85.CrossRefGoogle ScholarPubMed
Franchi, L.L., Mandl, A.M. & Zuckerman, S. (1962). The development of the ovary and the process of oogenesis. In The Ovary (ed. Zuckerman, S.) Academic Press, London, pp. 1–88.Google Scholar
Gheorghisan-Galateanu, A.A., Hinescu, M.E. & Enciu, A.M. (2014). Ovarian adult stem cells: hope or pitfall? J. Ovarian Res. 7, 1.Google Scholar
Gong, S.P., Lee, S.T., Lee, E.J., Kim, D.Y., Lee, G., Chi, S.G., Ryu, B.-K., Lee, C.H., Yum, K.E. & Lee, H.-J. (2010). Embryonic stem cell-like cells established by culture of adult ovarian cells in mice. Fertil. Steril. 93, 2594–601.Google Scholar
Gook, D.A., Edgar, D.H., Borg, J. & Martic, M. (2008). Detection of zona pellucida proteins during human folliculogenesis. Hum. Reprod. 23, 394–402.Google Scholar
Grondahl, M.L., Borup, R., Vikesa, J., Ernst, E., Andersen, C.Y. & Lykke-Hartmann, K. (2013). The dormant and the fully competent oocyte: comparing the transcriptome of human oocytes from primordial follicles and in metaphase II. Mol. Hum. Reprod. 19, 600–17.Google Scholar
Grootenhuis, A., Philipsen, H., de Breet-Grijsbach, J. & Van Duin, M. (1995). Immunocytochemical localization of ZP3 in primordial follicles of rabbit, marmoset, rhesus monkey and human ovaries using antibodies against human ZP3. J. Reprod. Fert. Suppl. 50, 43–54.Google Scholar
Guo, K., Li, C.H., Wang, X.Y., He, D.J. & Zheng, P. (2016). Germ stem cells are active in postnatal mouse ovary under physiological conditions. Mol. Hum. Reprod. 22, 316–28.Google Scholar
Johnson, J., Canning, J., Kaneko, T., Pru, J.K. & Tilly, J.L. (2004). Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428, 145–50.Google Scholar
Kassmer, S.H., Jin, H., Zhang, P.X., Bruscia, E.M., Heydari, K., Lee, J.H., Kim, C.F., Kassmer, S.H. & Krause, D.S. (2013). Very small embryonic-like stem cells from the murine bone marrow differentiate into epithelial cells of the lung. Stem Cells 31, 2759–66.CrossRefGoogle ScholarPubMed
Kassmer, S.H. & Krause, D.S. (2013). Very small embryonic‐like cells: biology and function of these potential endogenous pluripotent stem cells in adult tissues. Mol. Reprod. Dev. 80, 677–90.Google Scholar
Kim, J.M., Liu, H., Tazaki, M., Nagata, M. & Aoki, F. (2003). Changes in histone acetylation during mouse oocyte meiosis. J. Cell. Biol. 162, 37–46.Google Scholar
Kingery, H.M. (1917). Oogenesis in the white mouse. J. Morphol. 30, 261–315.Google Scholar
Kucia, M., Wysoczynski, M., Ratajczak, J. & Ratajczak, M.Z. (2008). Identification of very small embryonic like (VSEL). stem cells in bone marrow. Cell Tissue Res. 331, 125–34.Google Scholar
Lee, H.J., Sakamoto, H., Luo, H., Skaznik-Wikiel, M.E., Friel, A.M., Niikura, T., Tilly, J.C., Niikura, Y., Klein, R., Styer, A.K., Zukerberg, L.R., Tilly, J.L. & Rueda, B.R. (2007). Loss of CABLES1, a cyclin-dependent kinase-interacting protein that inhibits cell cycle progression, results in germline expansion at the expense of oocyte quality in adult female mice. Cell Cycle 6, 2678–84.CrossRefGoogle ScholarPubMed
Lee, Y.M., Kim, T.H., Lee, J.H., Lee, W.J., Jeon, R.H., Jang, S.J., Ock, S.A., Lee, S.L., Park, B.W. & Rho, G.J. (2016). Overexpression of Oct4 in porcine ovarian stem/stromal cells enhances differentiation of oocyte-like cells in vitro and ovarian follicular formation in vivo . J. Ovarian Res. 9, 24.Google Scholar
Lei, L. & Spradling, A.C. (2013). Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles. Proc. Natl. Acad. Sci. USA 110, 8585–90.Google Scholar
Liu, Y.F., Wu, C., Lyu, Q.F., Yang, D.Z., Albertini, D.F., Keefe, D.L. & Liu, L. (2007). Germline stem cells and neo-oogenesis in the adult human ovary. Dev. Biol. 306, 112–20.CrossRefGoogle ScholarPubMed
Mandelbaum, J. (2000). Oocytes. Hum. Reprod. 15 Suppl 4, 11–8.Google Scholar
McLaren, A. (1984). Meiosis and differentiation of mouse germ cells. Symp. Soc. Exp. Biol. 38, 7–23.Google Scholar
Meng, G., Zur Nieden, N., Liu, S., Cormier, J., Kallos, M. & Rancourt, D. (2008). Properties of murine embryonic stem cells maintained on human foreskin fibroblasts without LIF. Mol. Reprod. Dev. 75, 614–22.Google Scholar
Miyanishi, M., Mori, Y., Seita, J., Chen, J.Y., Karten, S., Chan, C.K., Nakauchi, H. & Weissman, I.L. (2013). Do pluripotent stem cells exist in adult mice as very small embryonic stem cells? Stem Cell Rep. 1, 198–208.Google Scholar
Pan, Z., Sun, M., Liang, X., Li, J., Zhou, F., Zhong, Z. & Zheng, Y. (2016). The controversy, challenges, and potential benefits of putative female germline stem cells research in mammals. Stem Cells Int. 2016, 1728278.Google Scholar
Pansky, B. & Mossman, H.W. (1953). The regenerative capacity of the rabbit ovary. Anat. Rec. 116, 19–51.Google Scholar
Parfenov, V., Potchukalina, G., Dudina, L., Kostyuchek, D. & Gruzova, M. (1989). Human antral follicles: oocyte nucleus and the karyosphere formation (electron microscopic and autoradiographic data). Gamete Res. 22, 219–31.Google Scholar
Parte, S., Bhartiya, D., Manjramkar, D.D., Chauhan, A. & Joshi, A. (2013). Stimulation of ovarian stem cells by follicle stimulating hormone and basic fibroblast growth factor during cortical tissue culture. J. Ovarian Res. 6, 1–10.Google Scholar
Parte, S., Bhartiya, D., Patel, H., Daithankar, V., Chauhan, A., Zaveri, K. & Hinduja, I. (2014). Dynamics associated with spontaneous differentiation of ovarian stem cells in vitro . J. Ovarian Res. 7, 25.Google Scholar
Parte, S., Bhartiya, D., Telang, J., Daithankar, V., Salvi, V., Zaveri, K. & Hinduja, I. (2011). Detection, characterization, and spontaneous differentiation in vitro of very small embryonic-like putative stem cells in adult mammalian ovary. Stem Cell Dev. 20, 1451–64.Google Scholar
Patel, H., Bhartiya, D., Parte, S., Gunjal, P., Yedurkar, S. & Bhatt, M. (2013). Follicle stimulating hormone modulates ovarian stem cells through alternately spliced receptor variant FSH-R3. J. Ovarian Res. 6, 52.Google Scholar
Pelosi, E., Omari, S., Michel, M., Ding, J., Amano, T., Forabosco, A., Schlessinger, D. & Ottolenghi, C. (2013). Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice. Nat. Commun. 4, 1843.CrossRefGoogle ScholarPubMed
Peters, H. (1970). Migration of gonocytes into the mammalian gonad and their differentiation. Philos. Trans. R Soc. Lond. B Biol. Sci. 259, 91–101.Google Scholar
Peters, H., Levy, E. & Crone, M. (1962). Deoxyribonucleic acid synthesis in oocytes of mouse embryos. Nature 195, 915–6.Google Scholar
Ratajczak, M.Z., Marycz, K., Poniewierska-Baran, A., Fiedorowicz, K., Zbucka-Kretowska, M. & Moniuszko, M. (2014). Very small embryonic-like stem cells as a novel developmental concept and the hierarchy of the stem cell compartment. Adv. Med. Sci. 59, 273–80.Google Scholar
Ratajczak, M.Z., Shin, D.-M., Liu, R., Mierzejewska, K., Ratajczak, J., Kucia, M. & Zuba-Surma, E.K. (2012). Very small embryonic/epiblast-like stem cells (VSELs). and their potential role in ageing and organ rejuvenation-an update and comparison to other primitive small stem cells isolated from adult tissues. Aging (Albany NY), 4, 235–46.Google Scholar
Richardson, S.J., Senikas, V. & Nelson, J.F. (1987). Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J. Clin. Endocrinol. Metab. 65, 1231–7.Google Scholar
Shinoda, G., De Soysa, T.Y., Seligson, M.T., Yabuuchi, A., Fujiwara, Y., Huang, P.Y., Hagan, J.P., Gregory, R.I., Moss, E.G. & Daley, G.Q. (2013). Lin28a regulates germ cell pool size and fertility. Stem Cell 31, 1001–9.Google Scholar
Sriraman, K., Bhartiya, D., Anand, S. & Bhutda, S. (2015). Mouse ovarian very small embryonic-like stem cells resist chemotherapy and retain ability to initiate oocyte-specific differentiation. Reprod. Sci. 22, 884–903.Google Scholar
Stimpfel, M., Skutella, T., Cvjeticanin, B., Meznaric, M., Dovc, P., Novakovic, S., Cerkovnik, P., Vrtacnik-Bokal, E. & Virant-Klun, I. (2013). Isolation, characterization and differentiation of cells expressing pluripotent/multipotent markers from adult human ovaries. Cell Tissue Res. 354, 593–607.Google Scholar
Szade, K., Bukowska-Strakova, K., Nowak, W.N., Szade, A., Kachamakova-Trojanowska, N., Zukowska, M., Jozkowicz, A. & Dulak, J. (2013). Murine bone marrow Lin−Sca-1+CD45 − very small embryonic-like (VSEL) cells are heterogeneous population lacking Oct-4A expression. PLoS One 8, e63329.CrossRefGoogle ScholarPubMed
Tamm, C., Pijuan Galito, S. & Anneren, C. (2013). A comparative study of protocols for mouse embryonic stem cell culturing. PLoS One 8, e81156.Google Scholar
Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S. & Jones, J.M. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–7.Google Scholar
Tingen, C.M., Kiesewetter, S.E., Jozefik, J., Thomas, C., Tagler, D., Shea, L. & Woodruff, T.K. (2011). A macrophage and theca cell-enriched stromal cell population influences growth and survival of immature murine follicles in vitro . Reproduction 141, 809–20.Google Scholar
Vacanti, M.P., Roy, A., Cortiella, J., Bonassar, L. & Vacanti, C.A. (2001). Identification and initial characterization of spore‐like cells in adult mammals. J. Cell. Biochem. 80, 455–60.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
Vermandevaneck, G.J. (1956). Neo-ovogenesis in the adult monkey – consequences of atresia of ovocytes. Anatom. Record 125, 207–24.Google Scholar
Virant-Klun, I., Rozman, P., Cvjeticanin, B., Vrtacnik-Bokal, E., Novakovic, S., Rulicke, T., Dovc, P. & Meden-Vrtovec, H. (2009). Parthenogenetic embryo-like structures in the human ovarian surface epithelium cell culture in postmenopausal women with no naturally present follicles and oocytes. Stem Cell Dev. 18, 137–49.Google Scholar
Virant-Klun, I., Zech, N., Rozman, P., Vogler, A., Cvjeticanin, B., Klemenc, P., Malicev, E. & Meden-Vrtovec, H. (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, 843–56.CrossRefGoogle ScholarPubMed
Waldeyer-Hartz, W.V. (1870). Eierstock und Ei, Engelmann, Leipzig.Google Scholar
Wang, N. & Tilly, J.L. (2010). Epigenetic status determines germ cell meiotic commitment in embryonic and postnatal mammalian gonads. Cell Cycle 9, 339–49.CrossRefGoogle ScholarPubMed
White, Y.A., Woods, D.C., Takai, Y., Ishihara, O., Seki, H. & Tilly, J.L. (2012). Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nat. Med. 18, 413–21.Google Scholar
Wojakowski, W., Tendera, M., Kucia, M., Zuba-Surma, E., Paczkowska, E., Ciosek, J., Halasa, M., Krol, M., Kazmierski, M., Buszman, P., Ochala, A., Ratajczak, J., Machalinski, B. & Ratajczak, M.Z. (2009). Mobilization of bone marrow-derived Oct-4+SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction. J. Am. Coll. Cardiol. 53, 1–9.Google Scholar
Woods, D.C. & Tilly, J.L. (2012). The next (re)generation of ovarian biology and fertility in women: is current science tomorrow's practice? Fertil. Steril. 98, 3–10.Google Scholar
Ye, H., Li, X., Zheng, T., Liang, X., Li, J., Huang, J., Pan, Z. & Zheng, Y. (2016). The effect of the immune system on ovarian function and features of ovarian germline stem cells. Springerplus 5, 990.Google Scholar
Yuan, J., Zhang, D., Wang, L., Liu, M., Mao, J., Yin, Y., Ye, X., Liu, N., Han, J. & Gao, Y. (2013). No evidence for neo‐oogenesis may link to ovarian senescence in adult monkey. Stem Cells 31, 2538–50.Google Scholar
Zhang, H., Liu, L., Li, X., Busayavalasa, K., Shen, Y., Hovatta, O., Gustafsson, J.A. & Liu, K. (2014). Life-long in vivo cell-lineage tracing shows that no oogenesis originates from putative germline stem cells in adult mice. Proc. Natl. Acad. Sci. USA 111, 17983–8.Google Scholar
Zhang, H., Panula, S., Petropoulos, S., Edsgard, D., Busayavalasa, K., Liu, L., Li, X., Risal, S., Shen, Y., Shao, J., Liu, M., Li, S., Zhang, D., Zhang, X., Gerner, R.R., Sheikhi, M., Damdimopoulou, P., Sandberg, R., Douagi, I., Gustafsson, J.A., Liu, L., Lanner, F., Hovatta, O. & Liu, K. (2015). Adult human and mouse ovaries lack DDX4-expressing functional oogonial stem cells. Nat. Med. 21, 1116–8.Google Scholar
Zhang, H., Zheng, W.J., Shen, Y., Adhikari, D., Ueno, H. & Liu, K. (2012). Experimental evidence showing that no mitotically active female germline progenitors exist in postnatal mouse ovaries. Proc. Natl. Acad. Sci. USA 109, 12580–5.Google Scholar
Zhang, P., Lv, L.X. & Xing, W.J. (2010). Early meiotic-specific protein expression in post-natal rat ovaries. Reprod. Domest. Anim. 45, e447–e53.Google Scholar
Zhang, X.L., Wu, J., Wang, J., Shen, T., Li, H., Lu, J., Gu, Y., Kang, Y., Wong, C.H., Ngan, C.Y., Shao, Z., Wu, J. & Zhao, X. (2016). Integrative epigenomic analysis reveals unique epigenetic signatures involved in unipotency of mouse female germline stem cells. Genome Biol. 17, 162.Google Scholar
Zou, K., Yuan, Z., Yang, Z., Luo, H., Sun, K., Zhou, L., Xiang, J., Shi, L., Yu, Q. & Zhang, Y. (2009). Production of offspring from a germline stem cell line derived from neonatal ovaries. Nat. Cell Biol. 11, 631–6.Google Scholar
Zuba-Surma, E.K., Guo, Y., Taher, H., Sanganalmath, S.K., Hunt, G., Vincent, R.J., Kucia, M., Abdel-Latif, A., Tang, X.L., Ratajczak, M.Z., Dawn, B. & Bolli, R. (2011). Transplantation of expanded bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) improves left ventricular function and remodelling after myocardial infarction. J. Cell Mol. Med. 15, 1319–28.CrossRefGoogle ScholarPubMed
Zuckerman, S. (1951). The number of oocytes in the mature ovary. Recent Prog. Horm. Res. 6, 63–109.Google Scholar
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