Novel Action of FSH on Stem Cells in Adult Mammalian Ovary Induces Postnatal Oogenesis and Primordial Follicle Assembly

Deepa Bhartiya, Seema Parte, Hiren Patel, Kalpana Sriraman, Kusum Zaveri, Indira Hinduja, Deepa Bhartiya, Seema Parte, Hiren Patel, Kalpana Sriraman, Kusum Zaveri, Indira Hinduja

Abstract

Adult mammalian ovary has been under the scanner for more than a decade now since it was proposed to harbor stem cells that undergo postnatal oogenesis during reproductive period like spermatogenesis in testis. Stem cells are located in the ovary surface epithelium and exist in adult and menopausal ovary as well as in ovary with premature failure. Stem cells comprise two distinct populations including spherical, very small embryonic-like stem cells (VSELs which express nuclear OCT-4 and other pluripotent and primordial germ cells specific markers) and slightly bigger ovarian germ stem cells (OGSCs with cytoplasmic OCT-4 which are equivalent to spermatogonial stem cells in the testes). These stem cells have the ability to spontaneously differentiate into oocyte-like structures in vitro and on exposure to a younger healthy niche. Bone marrow may be an alternative source of these stem cells. The stem cells express FSHR and respond to FSH by undergoing self-renewal, clonal expansion, and initiating neo-oogenesis and primordial follicle assembly. VSELs are relatively quiescent and were recently reported to survive chemotherapy and initiate oogenesis in mice when exposed to FSH. This emerging understanding and further research in the field will help evolving novel strategies to manage ovarian pathologies and also towards oncofertility.

Figures

Figure 1
Figure 1
FSH-FSHR3-stem cell interaction in ovary surface epithelium. (a) H&E stained sheep OSE smear. Two distinct populations of stem cells (encircled) including VSELs (arrow) which are smaller than the red blood cells and slightly bigger OGSCs (asterix) are clearly visualized even after gently scraping sheep ovary fixed overnight in neutral buffered formalin. Red blood cells and epithelial cells are also clearly visualized [12]. (b) (i)–(vi) Characterization of ovarian stem cells using pluripotent OCT-4 and SSEA4 markers. Smaller VSELs express nuclear OCT-4 and cell surface SSEA4 whereas slightly bigger OGSCs express cytoplasmic OCT-4 and minimal SSEA4. Note the VSELs do not stain with DAPI [13]. (c) (i) Sheep OSE smear immunostained with FSHR antibody. Note epithelial cells are negative whereas the stem cells exhibit distinct positive stain. (ii) Confocal microcopy localization of FSHR on VSELs and OGSCs and on a germ cell nest. (iii)-(iv) In situ hybridization of FSHR on ovarian stem cells after FSH treatment using oligo probes specific for FSHR1 and FSHR3, respectively. Note active transcription of FSHR3 mRNA in the cytoplasm of stem cells after FSH treatment whereas FSHR1 is expressed in the stem cells and the expression is not affected by FSH treatment. (d) qRT-PCR analysis of FSHR1 and FSHR3 after 3 and 15 h of FSH treatment. Note that only FSHR3 levels are increased transiently after 3 and return to basal levels by 15 h. (c) and (d) Panels show earlier published from 3 different experiments represented individually by Patel et al. [14]. Please refer to the cited references for further details.
Figure 2
Figure 2
Novel action of FSH on adult mammalian ovary. (a) Effect of pregnant mare serum gonadotropin (PMSG) on intact and chemoablated mice ovaries. (A)-(B) PMSG treatment to intact ovaries results in increased cohorts of primordial follicles below the OSE compared to untreated control [15]. (C)-(D) Chemoablated mouse OSE also responds to PMSG treatment. Note overall thickening of OSE after PMSG treatment compared to untreated control. Chemoablated ovaries are otherwise devoid of follicles [16]. (b) Effect of FSH on human ovary surface epithelium cortical tissue in vitro [17]. H&E stained paraffin section on D0 at the start of culture exhibits a prominent OSE and the cortical tissue is almost degenerated by D3 in culture whereas FSH exerts a survival effect on the cortical tissue and note the hypertrophied nature of the OSE. Please refer to the cited references for further details.

References

    1. Messinis I. E., Messini C. I., Dafopoulos K. The role of gonadotropins in the follicular phase. Annals of the New York Academy of Sciences. 2010;1205:5–11. doi: 10.1111/j.1749-6632.2010.05660.x.
    1. Johnson J., Canning J., Kaneko T., Pru J. K., Tilly J. L. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428(6979):145–150. doi: 10.1038/nature02316.
    1. Kingery H. M. Oogenesis in the white mouse. Journal of Morphology. 1917;30(1):261–315. doi: 10.1002/jmor.1050300108.
    1. Simkins C. S. Development of the human ovary from birth to sexual maturity. The American Journal of Anatomy. 1932;51(2):465–505. doi: 10.1002/aja.1000510208.
    1. Motta P. M., Makabe S. Germ cells in the ovarian surface during fetal development in humans. A three dimensional microanatomical study by scanning and transmission electron microscopy. Journal of Submicroscopic Cytology. 1986;18(2):271–290.
    1. Auersperg N., Wong A. S. T., Choi K.-C., Kang S. K., Leung P. C. K. Ovarian surface epithelium: biology, endocrinology, and pathology. Endocrine Reviews. 2001;22(2):255–288. doi: 10.1210/er.22.2.255.
    1. Goodell M. A., Brose K., Paradis G., Conner A. S., Mulligan R. C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. The Journal of Experimental Medicine. 1996;183(4):1797–1806. doi: 10.1084/jem.183.4.1797.
    1. Jonker J. W., Freeman J., Bolscher E., et al. Contribution of the ABC transporters Bcrp1 and Mdr1a/1b to the side population phenotype in mammary gland and bone marrow of mice. Stem Cells. 2005;23(8):1059–1065. doi: 10.1634/stemcells.2005-0150.
    1. Szotek P. P., Pieretti-Vanmarcke R., Masiakos P. T., et al. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(30):11154–11159. doi: 10.1073/pnas.0603672103.
    1. Peng S., Maihle N. J., Huang Y. Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene. 2010;29(14):2153–2159. doi: 10.1038/onc.2009.500.
    1. Flesken-Nikitin A., Hwang C.-I., Cheng C.-Y., Michurina T. V., Enikolopov G., Nikitin A. Y. Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature. 2013;495(7440):241–245. doi: 10.1038/nature11979.
    1. Parte S., Patel H., Sriraman K., Bhartiya D. Isolation and characterization of stem cells in the adult mammalian ovary. Methods in Molecular Biology. 2015;1235:203–229.
    1. 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 and Development. 2011;20(8):1451–1464. doi: 10.1089/scd.2010.0461.
    1. 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. Journal of Ovarian Research. 2013;6(1, article 52) doi: 10.1186/1757-2215-6-52.
    1. Bhartiya D., Sriraman K., Gunjal P., Modak H. Gonadotropin treatment augments postnatal oogenesis and primordial follicle assembly in adult mouse ovaries? Journal of Ovarian Research. 2012;5, article 32 doi: 10.1186/1757-2215-5-32.
    1. 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. Reproductive Sciences. 2015 doi: 10.1177/1933719115576727.
    1. Parte S., Bhartiya D., Manjramkar D. D., Chauhan A., Joshi A. Stimulation of ovarian stem cells by follicle stimulating hormone and basic fibroblast growth factor during cortical tissue culture. Journal of Ovarian Research. 2013;6, article 20 doi: 10.1186/1757-2215-6-20.
    1. Johnson J., Bagley J., Skaznik-Wikiel M., et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell. 2005;122(2):303–315. doi: 10.1016/j.cell.2005.06.031.
    1. Lee H.-J., Selesniemi K., Niikura Y., et al. Bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. Journal of Clinical Oncology. 2007;25(22):3198–3204. doi: 10.1200/JCO.2006.10.3028.
    1. Niikura Y., Niikura T., Tilly J. L. Aged mouse ovaries possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment. Aging. 2009;1(12):971–978.
    1. White Y. A. R., Woods D. C., Takai Y., Ishihara O., Seki H., Tilly J. L. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nature Medicine. 2012;18(3):413–421. doi: 10.1038/nm.2669.
    1. Imudia A. N., Wang N., Tanaka Y., White Y. A. R., Woods D. C., Tilly J. L. Comparative gene expression profiling of adult mouse ovary-derived oogonial stem cells supports a distinct cellular identity. Fertility and Sterility. 2013;100(5):1451.e2–1458.e2. doi: 10.1016/j.fertnstert.2013.06.036.
    1. Park E.-S., Woods D. C., Tilly J. L. Bone morphogenetic protein 4 promotes mammalian oogonial stem cell differentiation via Smad1/5/8 signaling. Fertility and Sterility. 2013;100(5):1468–1475. doi: 10.1016/j.fertnstert.2013.07.1978.
    1. Bukovsky A., Caudle M. R., Svetlikova M., Upadhyaya N. B. Origin of germ cells and formation of new primary follicles in adult human ovaries. Reproductive Biology and Endocrinology. 2004;2, article 20 doi: 10.1186/1477-7827-2-20.
    1. Bukovsky A., Svetlikova M., Caudle M. R. Oogenesis in cultures derived from adult human ovaries. Reproductive Biology and Endocrinology. 2005;3, article 17 doi: 10.1186/1477-7827-3-17.
    1. Bukovsky A., Caudle M. R., Gupta S. K., et al. Mammalian neo-oogenesis and expression of meiosis-specific protein SCP3 in adult human and monkey ovaries. Cell Cycle. 2008;7(5):683–686. doi: 10.4161/cc.7.5.5453.
    1. Bukovsky A., Caudle M. R. Immunoregulation of follicular renewal, selection, POF, and menopause in vivo, vs. neo-oogenesis in vitro, POF and ovarian infertility treatment, and a clinical trial. Reproductive Biology and Endocrinology. 2012;10, article 97 doi: 10.1186/1477-7827-10-97.
    1. Virant-Klun I., Zech N., Rožman 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(8):843–856. doi: 10.1111/j.1432-0436.2008.00268.x.
    1. Virant-Klun I., Rožman 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 and Development. 2009;18(1):137–150. doi: 10.1089/scd.2007.0238.
    1. Virant-Klun I., Skutella T., Stimpfel M., Sinkovec J. Ovarian surface epithelium in patients with severe ovarian infertility: a potential source of cells expressing markers of pluripotent/multipotent stem cells. Journal of Biomedicine and Biotechnology. 2011;2011:12. doi: 10.1155/2011/381928.381928
    1. Virant-Klun I., Skutella T., Hren M., et al. Isolation of small ssea-4-positive putative stem cells from the ovarian surface epithelium of adult human ovaries by two different methods. BioMed Research International. 2013;2013:15. doi: 10.1155/2013/690415.690415
    1. Virant-Klun I., Skutella T., Kubista M., Vogler A., Sinkovec J., Meden-Vrtovec H. Expression of pluripotency and oocyte-related genes in single putative stem cells from human adult ovarian surface epithelium cultured in vitro in the presence of follicular fluid. BioMed Research International. 2013;2013:18. doi: 10.1155/2013/861460.861460
    1. Stimpfel M., Skutella T., Cvjeticanin B., et al. Isolation, characterization and differentiation of cells expressing pluripotent/multipotent markers from adult human ovaries. Cell and Tissue Research. 2013;354(2):593–607. doi: 10.1007/s00441-013-1677-8.
    1. Bhartiya D., Sriraman K., Parte S., Patel H. Ovarian stem cells: absence of evidence is not evidence of absence. Journal of Ovarian Research. 2013;6(1, article 65) doi: 10.1186/1757-2215-6-65.
    1. Parte S., Bhartiya D., Patel H., et al. Dynamics associated with spontaneous differentiation of ovarian stem cells in vitro. Journal of Ovarian Research. 2014;7(1, article 25) doi: 10.1186/1757-2215-7-25.
    1. Virant-Klun I. Postnatal oogenesis in humans: a review of recent findings. Stem Cells and Cloning. 2015;8:49–60. doi: 10.2147/SCCAA.S32650.
    1. Zuba-Surma E. K., Kucia M., Abdel-Latif A., et al. Morphological characterization of very small embryonic-like stem cells (VSELs) by ImageStream system analysis. Journal of Cellular and Molecular Medicine. 2008;12(1):292–303. doi: 10.1111/j.1582-4934.2007.00154.x.
    1. Bhartiya D., Kasiviswanathan S., Unni S. K., et al. Newer insights into premeiotic development of germ cells in adult human testis using Oct-4 as a stem cell marker. Journal of Histochemistry & Cytochemistry. 2010;58(12):1093–1106. doi: 10.1369/jhc.2010.956870.
    1. Woods D. C., Tilly J. L. An evolutionary perspective on adult female germline stem cell function from flies to humans. Seminars in Reproductive Medicine. 2013;31(1):24–32. doi: 10.1055/s-0032-1331794.
    1. Virant-Klun I., Stimpfel M., Cvjeticanin B., Vrtacnik-Bokal E., Skutella T. Small SSEA-4-positive cells from human ovarian cell cultures: related to embryonic stem cells and germinal lineage? Journal of Ovarian Research. 2013;6(1, article 24) doi: 10.1186/1757-2215-6-24.
    1. Ratajczak M. Z., Zuba-Surma E., Wojakowski W., et al. Very small embryonic-like stem cells (VSELs) represent a real challenge in stem cell biology: recent pros and cons in the midst of a lively debate. Leukemia. 2014;28(3):473–484. doi: 10.1038/leu.2013.255.
    1. Lei L., Spradling A. C. Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(21):8585–8590. doi: 10.1073/pnas.1306189110.
    1. Byskov A. G., Høyer P. E., Andersen C. Y. D., Kristensen S. G., Jespersen A., Møllgård K. No evidence for the presence of oogonia in the human ovary after their final clearance during the first two years of life. Human Reproduction. 2011;26(8):2129–2139. doi: 10.1093/humrep/der145.
    1. Bhartiya D. The continued presence of stem cells and oogonia in the adult mammalian ovary. Human Reproduction. 2012;27(3, article 938) doi: 10.1093/humrep/der423.
    1. Zhang H., Zheng W., Shen Y., Adhikari D., Ueno H., Liu K. Experimental evidence showing that no mitotically active female germline progenitors exist in postnatal mouse ovaries. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(31):12580–12585. doi: 10.1073/pnas.1206600109.
    1. Zhang H., Liu L., Li X., et al. Life-long in vivo cell-lineage tracing shows that no oogenesis originates from putative germline stem cells in adult mice. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(50):17983–17988. doi: 10.1073/pnas.1421047111.
    1. Yuan J., Zhang D., Wang L., et al. No evidence for neo-oogenesis may link to ovarian senescence in adult monkey. Stem Cells. 2013;31(11):2538–2550. doi: 10.1002/stem.1480.
    1. Bhartiya D., Parte S., Patel H., Anand S., Sriraman K., Gunjal P. Pluripotent very small embryonic-like stem cells in adult mammalian gonads. In: Ratajczak M., editor. Adult Stem Cell Therapies: Alternatives to Plasticity. New York, NY, USA: Springer; 2014. pp. 191–209. (Stem Cell Biology and Regenerative Medicine).
    1. Bhartiya D., Unni S., Parte S., Anand S. Very small embryonic-like stem cells: implications in reproductive biology. BioMed Research International. 2013;2013:10. doi: 10.1155/2013/682326.682326
    1. de Felici M. Germ stem cells in the mammalian adult ovary: considerations by a fan of the primordial germ cells. Molecular Human Reproduction. 2010;16(9):632–636. doi: 10.1093/molehr/gaq006.
    1. Scaldaferri M. L., Klinger F. G., Farini D., et al. Hematopoietic activity in putative mouse primordial germ cell populations. Mechanisms of Development. 2015;136:53–63. doi: 10.1016/j.mod.2015.02.002.
    1. Bui H.-T., Van Thuan N., Kwon D.-N., et al. Identification and characterization of putative stem cells in the adult pig ovary. Development. 2014;141(11):2235–2244. doi: 10.1242/dev.104554.
    1. Jasencakova Z., Meister A., Walter J., Turner B. M., Schubert I. Histone H4 acetylation of euchromatin and heterochromatin is cell cycle dependent and correlated with replication rather than with transcription. The Plant Cell. 2000;12(11):2087–2100. doi: 10.1105/tpc.12.11.2087.
    1. Crowley T. E., Kaine E. M., Yoshida M., Nandi A., Wolgemuth D. J. Reproductive cycle regulation of nuclear import, euchromatic localization, and association with components of pol II mediator of a mammalian double-bromodomain protein. Molecular Endocrinology. 2002;16(8):1727–1737. doi: 10.1210/me.2001-0353.
    1. Sairam M. R., Babu P. S. The tale of follitropin receptor diversity: a recipe for fine tuning gonadal responses? Molecular and Cellular Endocrinology. 2007;260–262:163–171. doi: 10.1016/j.mce.2005.11.052.
    1. Babu P. S., Danilovich N., Sairam M. R. Hormone-induced receptor gene splicing: enhanced expression of the growth factor type I follicle-stimulating hormone receptor motif in the developing mouse ovary as a new paradigm in growth regulation. Endocrinology. 2001;142(1):381–389. doi: 10.1210/en.142.1.381.
    1. Sullivan R. R., Faris B. R., Eborn D., Grieger D. M., Cino-Ozuna A. G., Rozell T. G. Follicular expression of follicle stimulating hormone receptor variants in the ewe. Reproductive Biology and Endocrinology. 2013;11(1, article 113) doi: 10.1186/1477-7827-11-113.
    1. Bhartiya D., Singh J. FSH-FSHR3-stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer. Reproduction. 2015;149(1):R35–R48. doi: 10.1530/rep-14-0220.
    1. Mierzejewska K., Borkowska S., Suszynska E., et al. Hematopoietic stem/progenitor cells express several functional sex hormone receptors—novel evidence for a potential developmental link between hematopoiesis and primordial germ cells. Stem Cells and Development. 2015;24(8):927–937. doi: 10.1089/scd.2014.0546.
    1. Rani C. S. S., Moudgal N. R. Examination of the role of FSH in periovulatory events in the hamster. Journal of Reproduction and Fertility. 1977;50(1):37–45. doi: 10.1530/jrf.0.0500037.
    1. Anand S., Bhartiya D., Sriraman K., Patel H., Manjramkar D. D. Very small embryonic-like stem cells survive and restore spermatogenesis after busulphan treatment in mouse testis. Journal of Stem Cell Research and Therapy. 2015;4, article 216 doi: 10.4172/2157-7633.1000216.
    1. Legro R. S., Adashi E. Y. Introduction: Germline stem cell therapy in humans: two are not enough. Fertility and Sterility. 2014;101(1):1–2. doi: 10.1016/j.fertnstert.2013.11.031.
    1. Bhartiya D., Hinduja I., Patel H., Bhilawadikar R. Making gametes from pluripotent stem cells—a promising role for very small embryonic-like stem cells. Reproductive Biology and Endocrinology. 2014;12(1):p. 114. doi: 10.1186/1477-7827-12-114.
    1. Anand S., Patel H., Bhartiya D. Chemoablated mouse seminiferous tubular cells enriched for very small embryonic-like stem cells undergo spontaneous spermatogenesis in vitro. Reproductive Biology and Endocrinology. 2015;13(1):p. 33. doi: 10.1186/s12958-015-0031-2.
    1. Patel H., Bhartiya D. Novel action of follicle stimulating hormone (FSH) on mouse testicular stem cells. Andrology, Supplement. 2015;(abstract no. 63):p. 93.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir