Fate of the initial follicle pool: Empirical and mathematical evidence supporting its sufficiency for adult fertility

Abstract

The importance of the initial follicle pool in fertility in female adult mammals has recently been debated. Utilizing a mathematical model of the dynamics of follicle progression (primordial to primary to secondary), we examined whether the initial follicle pool is sufficient for adult fertility through reproductive senescence in CD1 mice. Follicles in each stage were counted from postnatal day 6 through 12 months and data were fit to a series of first-order differential equations representing two mechanisms: an initial pool of primordial follicles as the only follicle source (fixed pool model), or an initial primordial follicle pool supplemented by germline stem cells (stem cell model). The fixed pool model fit the experimental data, accurately representing the maximum observed primary follicle number reached by 4-6 months of age. Although no germline stem cells could be identified by SSEA-1 immunostaining, the stem cell model was tested using a range of de novo primordial follicle production rates. The stem cell model failed to describe the observed decreases in follicles over time and did not parallel the accumulation and subsequent reduction in primary follicles during the early fertile lifespan of the mouse. Our results agree with established dogma that the initial endowment of ovarian follicles is not supplemented by an appreciable number of stem cells; rather, it is sufficient to ensure the fertility needs of the adult mouse.

Life-long in vivo cell-lineage tracing shows that no oogenesis originates from putative germline stem cells in adult mice

“…In contrast to these reports, other recent reports have provided evidence that adult oogenesis and the so-called GSCs do not exist and have questioned the above-mentioned findings (8)(9)(10)(11)(12). For example, by tracing the proliferation of cultured Ddx4-positive cells in vitro, a recent study from our group reported that no mitotically active GSCs exist in the postnatal mouse ovary (10).…”

Ovarian stem cells: From basic to clinical applications

“…The dynamics of the follicle population were simulated according to two distinct models: a fixed pool model and a stem cell model in the mouse ovary. The fixed pool model accurately reflected the experimental decrease in follicle numbers and allowed the authors to refute the concept of GSC replenishment in the adult ovary [18] . Johnson's assumption that busulfan was only toxic to GSCs and does not kill primordial follicles was questioned by two groups [16,17] .…”

“…Following the publication of this landmark article, Johnson et al [1] were confronted by criticism and skepticism [16][17][18][19][20] . The main criticisms were related to the subjectivity of the scoring, the tissue fixation protocol, the mathematical model used to calculate the follicular dynamics, the toxicity of busulfan to follicles, the capacity of BrdU-MVH-double-positive cells for oocyte Ozakpinar OB et al .…”

“…Johnson et al [1] were criticized for applying the rate of follicle disappearance from the CBA/Ca mouse strain, reported as a fast-depleting strain, in comparison to the C57Bl/6 strain [16] . To verify Johnson et al [1] 's results, Bristol-Gould et al [18] proposed examining whether the initial population of follicles was sufficient to support fertility in adulthood by using a mathematical model of the dynamics of follicle progression. These authors counted the follicles in each stage from postnatal day 6 through to 12 mo in mice.…”

Qualitative modelling via constraint programming

“…Empirical data is scarce for primordial follicles [46], is calculated by inference for primary follicles [30], and simply does not exist for secondary follicles [19]. As a direct result of these limitations, two entirely different and contradictory compartmental models have been published in the literature [6,18]. A third research group investigating the same cell dynamics but with its own empirical data and modelling assumptions would be highly likely to produce a third quantitative model being fundamentally different to those already published.…”