Implications and Current Limitations of Oogenesis from Female Germline or Oogonial Stem Cells in Adult Mammalian Ovaries

Abstract

A now large body of evidence supports the existence of mitotically active germ cells in postnatal ovaries of diverse mammalian species, including humans. This opens the possibility that adult stem cells naturally committed to a germline fate could be leveraged for the production of female gametes outside of the body. The functional properties of these cells, referred to as female germline or oogonial stem cells (OSCs), in ovaries of women have recently been tested in various ways, including a very recent investigation of the differentiation capacity of human OSCs at a single cell level. The exciting insights gained from these experiments, coupled with other data derived from intraovarian transplantation and genetic tracing analyses in animal models that have established the capacity of OSCs to generate healthy eggs, embryos and offspring, should drive constructive discussions in this relatively new field to further exploring the value of these cells to the study, and potential management, of human female fertility. Here, we provide a brief history of the discovery and characterization of OSCs in mammals, as well as of the in-vivo significance of postnatal oogenesis to adult ovarian function. We then highlight several key observations made recently on the biology of OSCs, and integrate this information into a broader discussion of the potential value and limitations of these adult stem cells to achieving a greater understanding of human female gametogenesis in vivo and in vitro.

Ovary does harbor stem cells - size of the cells matter!

“…Presence of smaller-sized cells (supposedly the VSELs) was recently confirmed in mice [6] and human [7,8] ovaries by other groups as well and more than 20 groups have now independently reported VSELs in multiple adult tissues [9]. VSELs in mouse ovaries express pluripotent [OCT-4A, SOX-2, NANOG, SSEA-1 (SSEA-4 in humans)] and primordial germ cells [STELLA, FRAGILIS] specific markers whereas OSCs express cytoplasmic OCT-4B, SCA-1 (CD133 in humans), DDX-4 (MVH) and other markers.…”

“…Ovarian VSELs undergo rare asymmetrical cell divisions to self-renew and give rise to the OSCs which in turn undergo symmetrical cell divisions and clonal expansion to form germ cell nests before undergoing meiosis and differentiating into oocytes and this process is regulated by FSH [2,11]. Ovarian stem cells have been reported to differentiate in vitro into oocytes [12,13], birth of mouse pups [6] and their role in ovarian cancers has also been demonstrated [14]. Initial data is also published to support neo-oogenesis in adult ovaries in vivo from the stem cells [15][16][17].…”

“…DDX-4 is expressed on the OSCs/germ cells [6] and getting its expression on the perivascular cells by Wagner's group [1] is suggestive of non-specific binding and technical issues. A careful study of the methodology by Wagner's group [1] makes it very evident that the ovarian stem cells were unknowingly discarded while processing samples for single-cell RNA-seq and this could explain their negative results.…”

Premature ovarian insufficiency: an International Menopause Society White Paper

“…The possible existence of such cells in the postnatal mammalian ovary was suggested in two papers published in 2004 150 and 2012 151 , which attracted enormous controversy 152 . Subsequently, however, a number of research groups have provided further evidence that such cells, often termed 'oogonial stem cells' (OSCs), can indeed be identified and isolated from the postnatal mammalian ovary in a number of species including the human 153,154 .…”

Estrogen regulation of germline stem cell differentiation as a mechanism contributing to female reproductive aging

“…The cells obtained were extensively characterized for germline identity and oocyte-forming capacity [24], with outcomes that have since been independently confirmed by at least three other labs [35][36][37][38]. Consequently, several OSC-based technologies for potentially improving reproductive health and fertility are currently being explored [39][40][41][42][43], one of which entered clinical study with positive early outcomes reported for women seeking pregnancy through assisted reproduction [41,44,45]. However, other studies claiming to counter this now large body of work on mammalian OSCs have also been published [46][47][48][49], which in turn have been questioned by subsequent experiments identifying significant issues with the approaches taken [27,[50][51][52].…”