Germline Stem Cells and Follicular Renewal in the Postnatal Mammalian Ovary

Abstract

Up to now, the accepted wisdom was that, unlike males who retain germline stem cells (GSCs) through their adult lives, oocyte production in females of most mammalian species ceases before birth. Females therefore are born with a fixed pool of GSCs, or oocytes, all of them arrested in meiosis. The ovarian follicles are oocytes enclosed by somatic cells. The oocyte reserve in human females is exhausted at approximately the fifth decade of life, inducing menopause. Directly contradicting these views, the investigators have found that juvenile and adult mouse ovaries have mitotically active germ cells that continuously replenish the pool of follicles. A study of mouse ovaries, based on analyses of healthy quiescent and early growing follicle numbers, showed that approximately one third of the peak endowment of immature follicles was lost by young adulthood. In contrast to previous studies in mammals, a parallel study of atretic (degenerating) follicles showed that atresia increased markedly by days 30 to 40, reaching a peak of more than 1200 dying follicles per ovary that continued well into reproductive life (Fig. 1). There was a clear discordance between changes in numbers of nonatretic follicles and the corresponding incidence of atresia in the postnatal mammalian ovary. Histologic studies demonstrated large ovoid cells that resembled germ cells of the fetal mouse ovary; they were found in the surface epithelial cell layer covering the ovary. Immunohistochemical studies affirmed that these cells were of a germline lineage. Immunostaining confirmed the presence of germ cells in varying stages of meiosis. The investigators identified genes whose expression is necessary for replicating germ cells to produce oocytes for follicle formation in postnatal life. In studies with busulphan, a germ-cell toxicant, exposed ovaries had fewer than 5% of the primordial follicle pool present in control animals. The rate of follicle loss was very close to that expected from previously reported data. Finally, ovarian fragments taken from wild-type mice were grafted into the ovaries of transgenic female siblings after removing approximately half of the host’s ovary. The transgenic germ cells infiltrated the grafted tissue and initiated folliculogenesis with the resident wild-type somatic cells. These observations suggest that GSCs are present in the postnatal mouse ovary. The findings have therapeutic potential for expanding the follicle reserve so as to postpone normal or premature ovarian failure.Fig. 1: Postnatal ovarian germ-cell dynamics. (A and B) Numbers of nonatretic (A) and atretic (B) primordial and total immature (primordial, primary, small preantral) follicles in mouse ovaries during postnatal development (B, total immature follicles; mean ± standard error, n = 3–4 mice per age group). (C) Incidence of primordial and primary follicle atresia in ovaries exposed to DMBA on day 25 postpartum (mean ± standard error, n = 4–5 mice per time point). (D) Comparison of nonatretic and atretic immature follicle numbers in C57BL/6, CD1, and AKR/J strains of mice (mean ± standard error, n = 3–5 mice per age group). Reproduced with permission. Nature 2004;428:145–150. Copyright © 2004, Nature Publishing Group. All rights reserved.