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. 2008 Jun 12;149(9):4307–4311. doi: 10.1210/en.2008-0458

Stem Cell Contribution to Ovarian Development, Function, and Disease

Jonathan L Tilly 1, Bo R Rueda 1
PMCID: PMC2553384  PMID: 18556344

Abstract

By virtue of the fact that oocytes not only serve to produce embryos after fertilization but also can effectively reprogram adult somatic cell nuclei to a pluripotent state, much of the interest in the role of stem cells in ovarian biology has been focused on the germline. However, very recent studies have revealed that somatic stem cells may also be of considerable relevance to the study of normal ovarian function. Furthermore, stem cell dysfunction may underlie or contribute to disease states such as ovarian cancer and polycystic ovary syndrome. Our objective is to explore these concepts in greater detail, with the hope of stimulating further research efforts into understanding what role stem cells may play in the physiology and pathology of the mammalian female gonads.

OVARIAN GERMLINE AND somatic stem cells have been studied in Drosophila for many years. This work has elucidated genetic pathways important for germline stem cell (GSC) self-renewal vs. differentiation, the role of germline-somatic stem cell interaction in oogenesis during adult life, and the architecture of the ovarian stem cell niche (1). However, the longstanding dogma that female mammals do not possess a comparable ability to produce new oocytes after birth (2) has until recently (3,4,5,6,7,8) precluded a parallel analysis of the role of stem cells in vertebrate ovarian function. Although reports that adult mammalian females do in fact produce new oocytes and follicles are controversial (9), this minireview will not delve into this debate because these viewpoints have already been addressed in detail elsewhere (10,11,12). Instead, we will evaluate an increasing number of contemporary studies supporting the existence of stem cells in adult mammalian females that can influence ovarian function and fertility, and perhaps also contribute to disease states such as polycystic ovary syndrome (PCOS) and cancer.

Stem Cells and Oogenesis

The first demonstration that cells other than primordial germ cells (PGC) spontaneously form what appear to be oocytes was reported in 2003 (13) from an in vitro study of transgenic mouse embryonic stem cells (ESC) carrying a green fluorescent protein (GFP) reporter gene under the control of a modified Oct-3/4 promoter that conveys germline-specific expression. Using these transgenic ESC, Hübner et al. (13) showed the spontaneous generation of oocytes enclosed within structures that resembled developing ovarian follicles, as determined by morphological characteristics, gene expression profiles, and estradiol synthesis. Subsequent work confirmed these findings but further revealed that ESC-derived oocytes fail to progress through meiosis and thus are incompetent for fertilization (14). Nevertheless, these experiments set the stage for subsequent efforts to determine not only whether this meiotic defect can be overcome (15), as has recently been reported for ESC-derived sperm (16), but also whether stem cells other than those derived from preimplantation embryos (viz., ESC) possess a similar germline potential.

With regard to the latter, non-PGC germline potential has now been linked to at least four different cell populations, representing either stem cells or pools of cells known to possess stem cell activity. The first two of these, mouse bone marrow (BM) and peripheral blood (PB), were reported in a study that used transplantation-based technology to demonstrate that BM or PB from adult females of the same germline-specific GFP-transgenic line used by Hübner et al. (13) in their study of ESC-derived oocytes could form germ cells in ovaries of chemotherapy-conditioned wild-type female recipients (4). Like that reported for ESC-derived oocytes, BM- and PB-derived oocytes generated in recipient females exhibit a maturational arrest at early stages of follicle development and do not yield mature eggs after natural (17) or induced (18) ovulation. Nevertheless, the conclusion that stem cells with germline potential reside in BM of adult mammals aligns with both historical data from others (19,20), as well as with parallel observations of male germ cell formation from BM-derived cells of mice (21,22) and men (23). Interestingly, even though BM-derived germ cells exhibit a maturational block (17,18,21,23), a recent study has shown that premature ovarian failure and infertility observed in chemotherapy-conditioned adult female mice can be rescued by transplantation of BM from nontreated adult female donors (17). Although the mechanisms underlying these outcomes remain to be elaborated, these observations may tie into additional studies of the impact of BM-derived cells on ovarian function discussed below (see Granulosa Cell Derivation from Stem Cells).

Shortly after the germline potential of mouse BM- and PB-derived cells was reported (4), a study followed in which fetal pig skin stem cells cultured in vitro were shown to generate oocytes contained in small follicle-like structures (24). Again like ESC-derived oocytes (13,14), the germ cells formed from skin stem cells exhibit a meiotic block but still coordinate the formation of follicular structures capable of secreting significant levels of estradiol under basal conditions and in response to treatment with FSH (24).

Of interest was the finding that some of these follicle-like structures extrude the oocytes contained within, and these large extruded cells exhibit several characteristic features of ovulated eggs including the presence of an outer zona pellucida matrix as well as interaction with and penetration by sperm (25). Although no embryos were detected after sperm penetration, some of the large oocytes derived from skin stem cells spontaneously activate and develop into blastocyst-like structures in vitro (24). The following year adult rat pancreatic stem cells were reported to form large cell aggregates containing what appear to be oocytes (26). Collectively, these findings suggest that stem cells of diverse tissue origins and developmental stages possess germline potential.

Before concluding this section, we would like to point out that putative stem cells capable of forming oocyte-like cells in vitro have just recently been isolated from adult human ovary tissue (27,28). What makes this study all the more intriguing is that the ovarian tissue used to purify these cells was obtained from postmenopausal women or women with premature ovarian failure. Thus, it is unlikely that these putative stem cells are simply derived from parthenogenetic activation of oocytes. The challenge for the future will be to fully assess the characteristics of oocytes formed from these and other non-PGC sources, with the objective of producing fertilization-competent eggs and live offspring. Whereas this goal may be viewed by some critics of this work as nothing more than wishful thinking, the topic has already received legislative attention in anticipation of what may lie ahead with respect to use of such artificial gametes in assisted human reproduction (see http://www.guardian.co.uk/politics/2008/mar/09/houseofcommons.medicalresearch).

Even if the aforementioned objective were achieved, this would not address whether stem cells support postnatal oogenesis in mammalian females under normal physiological conditions. To this end, an increasing number of studies are providing at least circumstantial evidence for the existence and function of GSC in females (3,4,5,6,7,8). Because much of this work has been overviewed in detail elsewhere, herein we will restrict our discussions to the possibility of developing new therapies that target putative GSC in females as a means to increase oocyte output. The concept of therapeutic stimulation of postnatal oogenesis emerged coincident with studies contradicting the dogma that mammalian females are born with a nonrenewable pool of oocytes at birth (3,4). Although this work is still at fairly early stages of investigation, proof-of-concept that enhanced oocyte production during adulthood can be achieved is available. It was shown in mice that a single injection of the histone deacetylase inhibitor, trichostatin-A, rapidly and significantly increases the number of primordial follicles in juvenile, young adult, and aging females (4). These data identify epigenetic modification of chromatin structure as a key regulatory event in the control of postnatal oogenesis in mammals. Preliminary follow-up work further indicates that retinoic acid receptor signaling and histone acetylation cooperatively interact to influence expression of the meiosis commitment gene, Stra8 (stimulated by retinoic acid 8), and to promote oocyte formation in adult mice (29). Thus, as more pieces are added to the puzzle of how GSC activity is controlled in adult mammalian females, therapeutic control of this pathway may one day become a reality.

Granulosa Cell Derivation from Stem Cells

Like that discussed above for the putative GSC that support postnatal oogenesis, stem cells that give rise to granulosa cells have yet to be conclusively identified. However, indirect evidence for the ability of stem cells to generate granulosa cells is available from two different lines of study. The first relates to findings discussed earlier that ESC and skin stem cells spontaneously form small ovarian follicle-like structures in vitro. These follicles possess the capacity for estradiol biosynthesis and, in the case of skin stem cell-derived follicles, express FSH receptor (FSHR) and respond to FSH with increased estradiol production (13,24). The ability to synthesize and secrete estrogens is not in itself evidence that the somatic cells contained within these follicle-like structures are granulosa cells. However, these data, coupled with evidence of FSHR expression and FSH responsiveness, strongly support the idea that stem cells can give rise to functional granulosa cells, at least in vitro.

The second line of study, which is preliminary but compelling enough to warrant some discussion here, revolves around the use of FSHR-null mice (30) to test whether premature ovarian failure arising from a granulosa cell-intrinsic defect could be rescued by transplanting stem cells. It was reported that iv infusion of FSHR-null females with BM from wild-type female donors increases the total number and collective diameter of the follicles present in the mutants (31). Furthermore, estrogen levels were raised 2.5- to 7.5-fold, whereas FSH levels declined by 50%, in the BM-infused FSHR-null females compared with control mutant females (31). Whereas no data were provided with respect to donor cell tracking in recipient ovaries, the rescue of ovarian function resulting from FSHR deficiency argues strongly for generation of BM-derived (wild type, FSHR expressing) granulosa cells in ovaries of the infused mutant females. It is also worthwhile mentioning that these outcomes agree with similar findings from experiments with male mice showing that transplanted BM-derived cells give rise to FSHR-expressing Sertoli cells in the testis (22).

Theca-Interstitial Stem Cells

As the reproductive biology community awaits the isolation of mammalian female GSC and granulosa stem cells, a very recent study has already accomplished this in the context of the other major follicular somatic component, the theca-interstitial cell. Although not as well studied as oocytes or granulosa cells, theca-interstitial cells serve diverse and fundamentally important roles in the ovary including androgen biosynthesis, paracrine cross talk with granulosa cells to ensure proper follicle development, and overall structural support of the follicle as it progresses to larger and more advanced stages of maturation (32). Using dispersed newborn mouse ovaries as starting material for serial culture experiments, Honda et al. (33) reported the isolation of relatively pure populations of colony-forming fibroblast-like cells that could be propagated long-term. After in vitro treatment with serum, LH and granulosa cell-conditioned medium, these cells took on characteristic features of mature theca-interstitial cells. Moreover, 2 wk after transplantation of putative theca-interstitial stem cells transgenic for expression of GFP into the ovaries of wild-type adult females, donor-derived cells were observed in both the inner and outer theca layers of growing and fully mature follicles (33). Hence, the successful isolation of what appear to be theca-interstitial stem cells may offer a new model to further explore paracrine interactions that occur between granulosa and theca-interstitial cells during follicular development. In addition, these cells may aid in efforts to understand the mechanisms responsible for ovarian disorders associated with excess androgen production.

Stem Cell Dysfunction and PCOS?

PCOS is the most common endocrine disorder in women. Although the actual etiology of PCOS remains unclear, it is characterized by a polycystic appearance of the ovaries, hyperandrogenism, and amenorrhea with chronic anovulation (34,35). In a recent study, Maciel et al. (36) reported that primary, secondary, and Graafian follicle numbers are all significantly elevated in ovaries of PCOS patients vs. controls. Interestingly, the most dramatic change was observed in primary follicle numbers, with almost 3-fold more primary follicles being detected in ovaries of women with PCOS. From these observations, Maciel et al. (36) logically concluded that the large increase in primary follicle numbers was due to either accelerated recruitment from the primordial follicle pool or reduced atresia of follicles that had already begun to grow. However, atretic preantral (primordial, primary, and secondary) follicles were not detected in any ovarian section analyzed (normal or PCOS). These findings suggest that the incidence of follicle atresia at these early stages of development is extremely low, if occurring at all (36). Regarding the other possible explanation, accelerated recruitment out of the resting primordial follicle pool should result in less total primordial follicles being present in ovaries of women with PCOS. This, however, was also not observed. In fact, the number of primordial follicles in ovaries of PCOS patients was actually 30% higher than controls (36). One is therefore left wondering how substantial increases in primary, secondary, and Graafian follicle numbers occur in ovaries of women with PCOS if accelerated recruitment of primordial follicles and reduced atresia are not apparent. Should claims of oogenesis in adult human ovaries (37,38,39), like those reported for adult rodent (3,4,5,6,7,11,40,41,42,43,44,45,46) and nonhuman primate (47) ovaries, be confirmed, the possibility that PCOS involves an abnormally high rate of postnatal oocyte and follicle production would be reasonable to evaluate. Similarly, the potential role of the newly discovered theca-interstitial stem cells discussed earlier in PCOS might deserve some consideration as well, given the central importance of this particular cell lineage to the PCOS phenotype.

An Emerging Role for Stem-like Cells in Ovarian Cancer

It is estimated that in this year alone over 21,500 women in the United States will be diagnosed with ovarian cancer and more than 15,500 women will succumb to it (48; see also http://seer.cancer.gov), making this disease the most lethal gynecological cancer. The high mortality rate of those diagnosed with ovarian cancer is due to several factors. These include a current inability to detect the disease at early stages when it would be most treatable, the high rate of disease recurrence, and the fact the recurrent disease is often resistant to subsequent rounds of chemotherapy (49,50). Moreover, studies discussed below suggest that ovarian cancer may arise from and recur due to a rare population of stem-like cells that maintain their tumorigenic potential after cytotoxic therapy.

A hypothesized role for such putative cancer stem cells (CSC), also referred to as tumor-initiating cells, in cancer development is not unique to the ovary. In fact, reports of tumor-initiating stem cells in hematological and nongynecologic solid cancers have been available for years (51,52,53,54,55). And although support grows each year for the concept that abnormal stem-like cells contribute to the development of many types of cancer, it is important to stress that the existence of true CSC remains a topic of debate (56,57). Nevertheless, similar to other solid tumors, clonogenic cells that are capable of self-renewal, express markers of pluripotency, and generate differentiated progeny in vitro and in vivo have been isolated from human epithelial ovarian cancers (58). It has also been postulated that putative ovarian CSC possess an altered mitochondrial phenotype that confers a change in function favorable to tumorigenesis (59).

Recently, Szotek et al. (60) reported the isolation of putative mouse ovarian CSC by capitalizing on past observations that many types of stem cells use a multidrug resistance (MDR) pump to rid themselves of chemicals, including nuclear dyes. This property facilitates fluorescence-activated cell sorting of those rare cells capable of nuclear dye exclusion, which have been termed side-population (SP) cells (61,62). This in turn has led to the finding that SP cells exhibit many stem cell-like properties (63,64,65). Furthermore, SP cells lose their ability to exclude nuclear dyes in response to treatment with verapamil, a potent inhibitor of MDR-1 protein pump activity (61,62). Accordingly, Szotek et al. (60) identified a rare population of verapamil-sensitive SP cells in mouse ovarian cancer cell lines that has clonogenic properties in vitro and forms tumors in vivo. Furthermore, these cells show enhanced chemo-resistance in vitro. In contrast, non-SP cells derived from the same cancer cell lines do not exhibit clonogenic or tumor-forming properties. In this same study, SP cell fractions were also isolated from human ovarian cancer ascites and cell lines, although the ability of these cells to generate tumors in vivo was not verified (60).

Other more circumstantial evidence further supports a role for CSC in ovarian cancer. First, the high rate of chemo-resistant disease recurrence is in keeping with two known properties of stem cells: quiescence (which would render CSC resistant to cytotoxic drugs that target mitotic cells) and elevated MDR pump activity (which would allow CSC to remove cytotoxic drugs before significant intracellular damage could be inflicted). Second, ovarian cancer presents multiple histological subtypes, including the more common serous and the less common endometrioid, mucinous, and clear cell cancers (49). These subtypes are defined by a histological resemblance of the tumor to normal gynecologic tissues. Serous is similar in appearance to the oviduct, whereas endometrioid and mucinous resemble the uterus (endometrium) and cervix, respectively (49). Thus, it is possible that the diversity in histological phenotype associated with ovarian cancer hints at either an inherent or acquired plasticity of these cells or their derivation from a common but more primitive stem-like cell. However, the burden remains to unequivocally establish that CSC exist and contribute to human ovarian cancer, and to then delineate the signaling pathways that regulate ovarian CSC activity. If accomplished, these findings could lead to the development of new therapeutic strategies that specifically target ovarian CSC. This in turn may improve the long-term outcome of treatments for this devastating disease.

Conclusions

Stem cell biology and mammalian female reproductive biology have been intertwined ever since the discovery that that pluripotent cells could be isolated from the inner cell mass of preimplantation embryos more than 25 yr ago (66,67), if not even decades earlier when stem cells were first isolated from a germ cell tumor (68). This relationship was further cemented by experiments in the late 1990s that demonstrated the feasibility of cloning genetically identical animals through somatic cell nuclear transfer (SCNT) (69). These experiments revealed that mature eggs possess the capacity to re-reprogram nuclei of differentiated adult somatic cells back to a pluripotent state (70). However, the bond between stem cell biology and reproductive biology has traditionally been one born more out of necessity (ESC derivation or SCNT requires an oocyte) rather than one of investigative interest into how stem cells may influence reproduction. In light of the recent work highlighted above, this relationship is on the verge of a major shift that will directly benefit the field of mammalian reproductive biology. Even though the promise of what stem cells may offer in the context of improving fertility, extending reproductive organ function or combating gynecologic diseases is alluring, the work discussed in this minireview paints only a preliminary picture that will require many more years of study before we can fully grasp the significance of stem cells in reproductive biology and medicine. Nevertheless, the important first steps have been taken, and exciting new insights into the ability of stem cells to generate oocytes, granulosa cells and theca-interstitial cells, as well as the role that CSC may play in the development of ovarian cancer, are already available. As these stories continue to unfold, we are confident that the discipline of female reproductive biology will break its traditional role of simply serving as a source of material for the derivation of stem cells or SCNT. Instead, the ovary will assume its place as a major model system for the study of how stem cells contribute to adult organ development, homeostasis, aging, and disease.

Acknowledgments

We would like to thank the many postdoctoral trainees who contributed to the work conducted by the authors discussed herein.

Footnotes

Work conducted in the authors’ laboratories discussed herein was supported by the National Institutes of Health (R01-AG024999 and R37-AG012279 to J.L.T.; R01-CA98333 to B.R.R.), Advanced Medical Research Foundation, Shulsky Philanthropic Fund, Rosenberg Philanthropic Fund, and Vincent Memorial Research Funds.

Disclosure Statement: The authors have nothing to disclose.

First Published Online June 12, 2008

Abbreviations: BM, Bone marrow; CSC, cancer stem cell; ESC, embryonic stem cell; FSHR, FSH receptor; GFP, green fluorescent protein; GSC, germline stem cell; MDR, multidrug resistance; PB, peripheral blood; PCOS, polycystic ovary syndrome; PGC, primordial germ cell; SCNT, somatic cell nuclear transfer; SP, side-population (cells).

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