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Review
. 2013 Jan;31(1):24-32.
doi: 10.1055/s-0032-1331794. Epub 2013 Jan 17.

An Evolutionary Perspective on Adult Female Germline Stem Cell Function From Flies to Humans

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Free PMC article
Review

An Evolutionary Perspective on Adult Female Germline Stem Cell Function From Flies to Humans

Dori C Woods et al. Semin Reprod Med. .
Free PMC article

Abstract

The concept that oogenesis continues into reproductive life has been well established in nonmammalian species. Recent studies of mice and women indicate that oocyte formation is also not, as traditionally believed, restricted to the fetal or perinatal periods. Analogous to de novo oocyte formation in flies and fish, newly formed oocytes in adult mammalian ovaries arise from germline stem cells (GSCs) or, more specifically, oogonial stem cells (OSCs). Studies of mice have confirmed that isolated OSCs, once delivered back into adult ovaries, are capable of generating fully functional eggs that fertilize to produce healthy embryos and offspring. Parallel studies of OSCs recently purified from ovaries of reproductive-age women indicate that these cells closely resemble their mouse ovary-derived counterparts, although the fertilization competency of oocytes generated by human OSCs awaits clarification. Despite the ability of OSCs to produce new oocytes during adulthood, oogenesis will still ultimately cease with age, contributing to ovarian failure. The causal mechanisms behind these events in mammals are unknown, but studies of flies have revealed that GSC niche dysfunction plays a critical role in age-related oogenic failure. Such insights derived from evaluation of nonmammalian species, in which postnatal oogenesis has been studied in depth, may aid in development of new strategies to alleviate ovarian failure and infertility in mammals.

Conflict of interest statement

Competing Financial Interests

Dori Woods declares interest as a scientific consultant for OvaScience, Inc. (Cambridge, MA). Jonathan Tilly declares interest in intellectual property described in U.S. Patent 7,955,846 and is a cofounder of OvaScience, Inc.

Figures

Figure 1
Figure 1
Mathematical decay curve depicting the rate of oocyte loss from ovaries of young adult rhesus monkeys. Past work from Vermande-Van Eck published in 1956 reported that female rhesus monkeys at or just after sexual maturation (~4 years of age) possess ~58,000 oocyte-containing follicles per ovary, with atresia occurring at an incidence of 4.5% and clearance of atretic follicles completed within 14 days. Plotting these three variables in a mathematical decay curve, in the absence of any new oocyte input, predicts that >90% of the oocytes present at puberty will be eliminated by the time these females reach 6 years of age and <500 oocytes will remain at 8 years of age. Such an outcome is highly discordant with the fact that female rhesus monkeys exhibit ovarian function and natural fertility at ≤20 years of age. The most logical explanation for this observation is that the loss of oocytes through follicular atresia is partly offset by de novo oogenesis and folliculogenesis during adulthood, to allow maintenance of ovarian function through 20 to 25 years of age.
Figure 2
Figure 2
Personal correspondence from Gertrude Vermande (Van Eck) following publication of our paper in 2004, which challenged a principal dogma in the field of reproduction by concluding that oogonial stem cells exist in adult mouse ovaries and actively contribute to oocyte and follicular renewal. This example serves as a reminder of the importance of historical observations to the interpretation of more contemporary studies.
Figure 3
Figure 3
Comparison of mammalian gametogenesis and germline stem cell function in the gonads of adult males and adult females. In most if not all studies, spermatogonial stem cells (SSCs) are isolated as a mix of type A dark (Ad) and type A pale (Ap) spermatogonia. Once isolated, SSCs can be stably expanded ex vivo, although the in vitro generation of haploid (1n) cells from cultured SSCs of any species has not yet been reported. Functionality of SSCs is classically assessed through intratesticular transplantation protocols, in which transplanted SSCs carrying a traceable marker gene repopulate chemotherapy-damaged seminiferous tubules to produce fertilization-competent spermatozoa with the donor cell haplotype. In females, oogonial stem cells (OSCs) isolated from adult mouse and human ovaries can also be stably expanded ex vivo, although little is currently known of the intermediate stages of germ cells formed as OSCs undergo expansion and ultimately differentiation through meiosis. Accordingly, possible OSC progenitors A and B have been depicted by drawing parallels to SSC biology. In addition to evidence of stable ex vivo expansion, the generation of haploid germ cells in cultures of mouse and human OSCs has also been reported. In studies comparable with those used to test SSC functionality, transplantation of OSCs carrying green fluorescent protein (GFP) as a traceable marker gene into adult wild-type mouse ovaries, with or without prior chemotherapy conditioning, results in the formation of GFP-positive oocytes that mature, ovulate, and fertilize to produce viable embryos and offspring.

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