Heterogeneity of Stem Cells in the Ovary

Every organ in the body is thought to harbor two populations of stem cells, including the quiescent and the actively dividing, that leads to heterogeneity among them. It is generally believed that the ovary harbors a fixed number of follicles at birth that differentiate during fetal development from the primordial germ cells. The numbers of follicles decrease by age, leading to menopause. However, in 2004, it was suggested that ovary may harbor stem cells that are possibly involved in the formation of new follicles throughout reproductive life. Research over little more than a decade shows that ovarian stem cells include a quiescent population of very small embryonic-like stem cells (VSELs) and slightly bigger, actively dividing ovarian stem cells (OSCs). This heterogeneity among ovarian stem cells is similar to the presence of VSELs along with spermatogonial stem cells (SSCs) in the testis or hematopoietic stem cells (HSCs) in the hematopoietic system. VSELs express embryonic markers, including nuclear OCT-4, and are lodged in the ovary surface epithelium (OSE). Ovarian VSELs undergo asymmetric cell division to self-renew and give rise to OSCs that in turn undergo symmetric cell divisions and clonal expansion (germ cell nest) followed by meiosis to form an oocyte that gets assembled as a primordial follicle. Both VSELs and OSCs also express receptors for follicle-stimulating hormone (FSHR) and are directly activated by FSH to undergo neo-oogenesis and primordial follicle assembly. Whether stimulation of ovaries by FSH in Infertility Clinics activates the stem cells leading to the formation of multiple follicles needs further investigation. Epithelial cells lining the surface of ovary provide a niche to the stem cells under normal circumstances and undergo epithelial-mesenchymal transition (EMT) to form granulosa cells for primordial follicle assembly. Compromised function of the epithelial cells with age possibly leads to inability of stem cells to form follicles, leading to menopause. More than 90% of ovarian cancers arise in the OSE, possibly due to excessive self-renewal of VSELs. Altered biology of the OSE cells results in the formation of myofibroblasts by EMT and may provide a cancerous niche that supports excessive expansion of the stem cells lodged in the OSE, leading to ovarian cancer. Ovarian cancer cells express markers like OCT-4 and FSHR, which are also expressed by the VSELs lodged in the OSE, whereas the epithelial cells are distinctly negative for the same. Lot more research is required in the field to gain further understanding of ovarian stem cell biology.