Ovarian regeneration: The potential for stem cell contribution in the postnatal ovary to sustained endocrine function

https://doi.org/10.1016/j.mce.2016.10.012Get rights and content

Highlights

  • Aging results in a decline in the endocrine function of the ovary.

  • Stem cell-based therapies may one day sustain or reverse age-related ovarian failure.

  • Therapies would require somatic granulosa or granulosa-like cells with steroidogenic capacity.

Abstract

The endocrine function of the ovary is dependent upon the ovarian follicle, which on a cellular basis consists of an oocyte surrounded by adjacent somatic cells responsible for generating sex steroid hormones and maintenance of hormonal stasis with the hypothalamic-pituitary axis. As females age, both fertility and the endocrine function of the ovary decline due to waning follicle numbers as well as aging-related cellular dysfunction. Although there is currently no cure for ovarian failure and endocrine disruption, recent advances in ovarian biology centered on ovarian stem cell and progenitor cell populations have brought the prospects of cell- or tissue-based therapeutic strategies closer to fruition. Herein, we review the relative contributions of ovarian stem cells to ovarian function during the reproductive lifespan, and postulate steps toward the development of ovarian stem cell-based approaches to advance fertility treatments, and also importantly to provide a physiological long-term means of endocrine support.

Introduction

In female mammals, fertility and endocrine function rely on a tightly regulated synchronicity within the hypothalamic-pituitary-gonadal (HPG) axis, in which the ovary serves as both the primary source of sex steroid hormones and germ cells (oocytes) required to maintain hormonal stasis and fertility throughout the reproductive lifespan. Predominantly localized to the outer cortex, the ovarian follicles serve as the functional units of the ovaries and consist of an oocyte surrounded by granulosa cells or their precursors, enclosed within an extracellular matrix (ECM)-rich basement membrane, composed of a species- and developmental stage-specific combination of predominantly laminins and collagens (Berkholtz et al., 2006, Heeren et al., 2015, Hummitsch et al., 2013). In rodents it has been demonstrated that the majority of the pregranulosa cells enclosed within primordial follicles in the ovarian cortex are non-proliferative, however mitotically active pregranulosa cells are found within follicles of the medulla, which are likely part of the primordial pool active prior to sexual maturity (Hirshfield and DeSanti, 1995). Following a process of ‘follicle activation’ of quiescent primordial follicles, the granulosa cells transition from squamous to cuboidal and mitotically activate, and a theca cell layer is recruited to surround the basement membrane (Skinner, 2005). In growing follicles, the ovarian granulosa and theca cells work in concert to respond to circulating levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary to generate the sex steroids (i.e. estradiol and progesterone), acting through the FSH receptor (FSHR) and LH receptor (LHR), respectively.

In recent years both germline stem cells, termed ‘female germline stem cells’ (fGSC) or ‘oogonial stem cells’ (OSCs), and somatic ovarian stem cells or progenitors have been reported, generating a renewed enthusiasm for the exploration of strategies to promote ovarian regeneration and/or sustained ovarian function (reviewed in Woods and Tilly, 2015a, Grieve et al., 2015, Silvestris et al., 2015). However, despite the identification of ovarian stem cell and progenitor populations along with evidence to support that adult ovaries are amenable to follicle renewal during the reproductive lifespan, ovarian failure remains inevitable due to pathological conditions such as polycystic ovarian syndrome (PCOS) or depletion of follicles as a consequence of surgical ablation, exposure to environmental toxicants or chemotherapeutic agents, or as a result of age. As a major outcome of ovarian failure (in addition to infertility), steroid biosynthesis ceases and the ability of the ovary to feedback to the hypothalamus via inhibin and estradiol is lost. Consequently, circulating levels of FSH (followed by LH) rise sharply in women with menopause, and the pathological conditions associated with ovarian failure ensue. Accordingly, strategies to improve fertility, as well as delay or prevent the endocrine-related symptoms associated with menopause will require a greater understanding of ovarian function and the properties that govern the renewal and regeneration of multiple ovarian cell types. Herein we review germline and somatic stem cell populations in the ovary, a role for pluripotent stem cell-derived somatic cells, and the potential for these cells to maintain ovarian function during the reproductive lifespan, and prospective utility for therapeutics as efforts to extend fertility and prevent or delay menopause come closer to fruition.

Section snippets

Ovarian germ cells: primordial germ cells (PGCs) and oogonial stem cells (OSCs) as distinct precursors to oocytes

It has traditionally been accepted that most female mammals, unlike males, or other vertebrate or invertebrate females, are endowed at birth with a non-renewable pool of oocytes, of which a species-specific number will be selected for ovulation throughout the reproductive lifespan until the pool is exhausted (reviewed in Woods and Tilly, 2013c). However, more recent data supports ovarian function and oocyte biology as having a greater degree of plasticity than previously thought. While the

Granulosa cells: origin and plasticity

Granulosa cells, which are direct descendants of the quiescent pre-granulosa cells within primordial follicles, participate in bidirectional communication with oocytes throughout follicular maturation (reviewed extensively in Kidder and Mhawi, 2002), and, as the source of ovarian derived estrogen in women, are critical components of endocrine function. Although the properties of steroid biosynthesis and HPG feedback have been intensely studied and are well characterized (Maggi et al., 2016,

Origin of theca cells

Following follicle activation and subsequent granulosa cell proliferation, theca cells are recruited and organized around the growing follicle where they provide structural support, contain the blood supply, and eventually generate the requisite androgens for conversion to estrogen in the granulosa cells in response to LH (reviewed by Young and McNeilly, 2010). Theca cells are thought to be actively recruited to the growing follicle by granulosa cells, and in turn, granulosa cells likely

Ovarian replacement as a putative therapeutic for loss of endocrine function in ovaries

Ovarian aging occurs relatively early in the chronological lifespan of women and has been the subject of scientific inquiry for decades. To this end, researchers have employed the use of ‘heterochronic’ transplantations to evaluate ovarian aging in a systemic context. Early work demonstrated that placement of a ‘young’ mouse ovary into an ovariectomized ‘old’ mouse restored estrus, although it failed to restore fertility completely (Krohn, 1962). Later work expanded this experimental design and

Conclusion

Although the use of elective ovarian cryopreservation and transplantation for the purpose of sustaining fertility has been subject to ethical debate, utilization as a therapeutic intervention for menopause to improve quality of life and healthy aging remains an intriguing possibility. However, clinical data for reversal of age-associated menopause from ovarian transplants have not been published and the availability of viable patient autologous tissue would be a likely limiting factor, as

Competing financial interests

Dori C. Woods declares interest in intellectual property described in U.S. Patent 8,642,329 and U.S. Patent 8,647,869, and is a recipient of a corporate-sponsored research award from OvaScience, Inc. (Waltham, MA). Jonathan L. Tilly discloses interest in intellectual property described in U.S. Patent 7,195,775, U.S. Patent 7,850,984, U. S. Patent 7,955,846, U.S. Patent 8,642,329, U.S. Patent 8,647,869, and U.S. Patent 8,652,840, and is a scientific cofounder and a current member of the

Acknowledgments

A Method to Extend Research in Time (MERIT) Award from the National Institute on Aging (NIH R37-AG012279), and a grant from the Glenn Foundation for Medical Research, supported work conducted by the authors discussed herein.

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