The ovarian stem cell controversy: do they exist and what do they mean?
A female’s ability to reproduce has always been viewed as a race against time. The notion that females have a fixed reserve of eggs is deeply integrated into both medical and social literature. (1) In a sense, we view the ovary as this dwindling candle, and menopause as the gust of wind that puts the light out.
Jonathan Tilly at Harvard Medical School is challenging this scientific dogma. Dr. Tilly and his team have discovered specialized stem cells in the ovaries of female mice—both young and adult. These cells have the ability to produce new and immature eggs, analogous to the repetitive nature of sperm. (4) Meaning, if a female’s reproductive ability was in fact a candle, these stem cells are capable of adding more wax!
The ovarian reserve.
The ovarian reserve is the number of healthy, immature eggs in the ovaries. Although it’s widely accepted that this reserve depletes as female age increases, the discovery of stem cells in mice ovaries challenges this finite characteristic.
Stem cells are cells with the capacity to differentiate into other specialized cells. (5) The female mice were found to hold oogonial stem cells (OSCs). OSCs are known as egg precursor cells and are similar to spermatogonial stem cells found in males. (6) OSCs produce oocytes (a developing egg), while spermatogonial stem cells support the generation of sperm. (7)
Oogenesis: the development of eggs.
Oogenesis is when oocytes form and develop with meiosis or cell division. After oogenesis, the cell is ready for fertilization. This process was known to end after puberty; during this stage, follicle-stimulating hormone (FSH) stimulates the growth of multiple oocytes. (8) The dogma of female reproductive biology asserts that these oocyte populations do not increase. (9)
Neo-oogenesis: replenishing the ovarian reserve.
Neo-oogenesis challenges this idea and refers to the mechanism by which ovarian cells can actually renew their ovarian reserve. The possibility of ovarian reserve renewal is quite controversial. (8) And since we adore controversy, let’s dive into the study that started this all!
The groundbreaking experiment.
Dr. Tilly and his team conducted an experiment where the researchers transplanted normal ovarian tissues into mice. These mice had been genetically modified to express a certain green fluorescent protein, GFP, in their ovaries. If oocyte populations were finite at birth, there would be no fluorescence in the ovaries. Any fluorescing ovaries had to have developed post-transplantation. To the researchers’ surprise, upon examination, they found the fluorescing eggs enveloped by the transplanted ovary tissues. This meant that these eggs grew post-transplant. If the ovarian reserve was really fixed at birth, this wouldn’t be possible. (10, 11)
It’s important to keep in mind that many researchers remain skeptical of Dr. Tilly’s findings. (12) Other experiments do not show evidence of ovarian stem cells or a repletive ability in the ovarian reserve. Single-cell analysis techniques of all cells in female ovarian tissue were unable to identify any ovarian stem cells. (13) Another study mathematically demonstrates that the number of non-growing follicles is inversely proportional to age. This illustrates a natural decline rather than a continuous generation of eggs, through a mechanism such as stem cells. (14)
Even if ovarian stem cells aren’t what Dr. Tilly and his team found, the repletive properties identified in their experiment give hope. This discovery could have quite fascinating implications such as:
Ovarian stem cell harvesting and storage. Cells could be stored for later use, such as to generate new eggs when necessary. This could preserve fertility in older women. (1, 15) Research with mice and humans has shown eggs, from GFP-producing cells, when fertilized, were able to create embryos with a GFP marker. (15)
Ovarian tissue implants for hormonal function. Ovarian tissue could be grown in a laboratory setting, then be implanted back into a female body. This could aid in the restoration of hormonal function, such as estrogen production. Furthermore, cancer survivors or females with Turner syndrome can have their ovarian tissue restored if their hormonal function is compromised. (1)
Delaying natural menopause. Ovarian stem cells may also be used to postpone menopause through the replenishment of the ovarian reserve. (1, 16) Treatment with bone marrow-derived mesenchymal stem cells (BMSCs) has been shown to treat premature ovarian failure. In the study, two women were injected with BMSCs and demonstrated increased ovarian reserve, elevated estrogen levels, resumption of menses, and improved menopausal symptoms. (17)
It is traditionally believed that women are born with a fixed ovarian reserve that diminishes with age. Dr. Tilly and his team at Harvard Medical School have challenged this long-held belief with the discovery of ovarian stem cells in the ovaries of female mice.
These stem cells hold the potential to generate new eggs, similar to the continuous production of sperm in males.
This finding remains controversial, as other experiments have failed to identify ovarian stem cells or continuous egg generation.
If true, the repletive properties of ovarian stem cells could enhance fertility and menopausal therapies.