Of Mice and (wo)Men: Purified Oogonial Stem Cells from Mouse and Human Ovaries

Abstract

When it comes to reproducing, James Brown summed up the human experience: This is a man’s world. Women produce a limited number of viable eggs (probably considerably fewer than 400) and become reproductively senescent in the forth or fifth decade of life. In contrast, men produce millions of sperm per day, with little evidence of age-related decline, and can father offspring into their seventh decade and beyond—if they can find willing mates. Universal agreement exists that a germline stem cell population in the testis makes continuous sperm production possible. The existence of a corresponding stem germ cell population in the ovary, however, has been the subject of intense debate. The latest chapter in this debate was recently published online in Nature Medicine [1]. What makes this paper especially noteworthy is that it provides the first evidence that isolation techniques used to obtain putative oogonial stem cells (OSCs) from the mouse ovary can be used to isolate similar cells from human ovaries. The findings are the result of collaborative studies between investigators at Harvard and at Saitama Medical Center in Japan. The Harvard group includes Jonathan Tilly, whose laboratory challenged the ‘‘central dogma’’ of reproductive biology—that all eggs produced by the mammalian ovary initiate oogenesis during fetal development—with a paper in 2004 reporting OSCs in the mouse ovary [2]. In males, spermatogonial stem cells (SSCs) at the basement membrane of the seminiferous tubules divide to replenish their numbers and give rise to progenitor spermatogonia that provide the steady supply of new spermatocytes required for continuous sperm production. The SSC population is thought to be small in number, making up 0.03% of the total testicular cell population in adult mice [3]. Techniques for the isolation and in vitro expansion of SSCs have been developed, and the litmus test of the putative SSC cells obtained—their capacity to regenerate continual sperm production following transplantation into a recipient testis—has been firmly established [4, 5]. Despite a flurry of research, the existence of the female germline stem cell counterpart—OSCs—has remained controversial. White et al. [1] expand our understanding of OSCs with the demonstration that a population of mitotically active cells can be isolated from both mouse and human ovarian tissue by cell sorting using an antibody that recognizes the Cterminal portion of DDX4, a germ cell-specific RNA helicase. The isolated cells express genes known to be restricted to germ cells, and like male SSCs, these appear to be a rare type (an estimated 0.014% of the ovarian cell population). Interestingly, in contrast to the male, where isolated SSCs form colonies of actively dividing cells after several days in culture [6–9], from 10 to 12 wk (mouse) and from 4 to 8 wk (human) of culture were required to obtain actively dividing OSC colonies. This smacks of in vitro transformation, raising concern about whether the population of cells that exists in the ovary are