Women may not be born with a limited number of eggs after all. The discovery of stem cells tucked away in human ovaries suggests that new eggs are actually produced throughout life. The finding could pave the way for new fertility treatments.
and his colleagues at Massachusetts General Hospital first challenged the idea that mammals are born with a limited supply of eggs back in 2004, when they found evidence for ovarian stem cells in mice.
The surprise came when Tilly鈥檚 team looked carefully at the number of oocytes 鈥� cells that develop into fertilisable eggs 鈥� in the ovary. Because total oocyte numbers drop throughout life, it was assumed that these cells were continually dying off.
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However, within the period it took for total cell numbers to drop by 500, the team viewed 1500 cells dying, suggesting that new cells were being made at the same time. Further investigation identified ovarian cells that appeared to be capable of producing new oocytes (Nature, ).
Many in the field remained sceptical. 鈥淭here were a lot of vocal critics,鈥� says Tilly. 鈥淭hey said it was absolute hogwash and wouldn鈥檛 amount to anything.鈥� Undeterred, Tilly鈥檚 group set out to look for similar cells in human ovaries. Through a collaboration with in Japan, the group were able to analyse unwanted ovaries leftover from gender-reassignment operations.
Major breakthrough
The team started by looking in the ovarian tissue for a protein specific to egg cells that could allow them to identify these cells amongst the many that are present in ovarian tissue. They noted that, early in the development of an egg cell, this protein is expressed on the cell鈥檚 outer membrane, before it gets pulled into the cell during development.
The team isolated cells expressing this protein on their surface by tagging the protein itself with a fluorescent marker. They then introduced a gene to make the cells glow green. When the group placed their fluorescent cells back into human ovarian tissue grafted under the skin of a mouse, they found that the cells were able to form multiple new immature eggs.
The finding of such stem-cell-like cells is being hailed as a major breakthrough by gynaecologists, including at New York Medical College in Valhalla. Oktay hopes the cells could be stimulated to replenish dwindling egg numbers in older women, or in those who experience premature ovarian failure.
IVF hope
Tilly is optimistic that his technique could also be used to enhance in vitro fertilisation 鈥� a procedure that involves extracting eggs from women with fertility problems, fertilising them, and implanting the resulting embryos back into the body.
His group was only able to grow early-stage oocytes, too young to be used in IVF, because the mouse is too small a creature to develop mature human eggs. However, Tilly is set to join forces with at the University of Edinburgh, UK, who has found a way to mature early oocytes to a more advanced developmental stage outside of a body.
By harnessing these stem cells rather than the eggs themselves, the groups could cut a lot of the hassle from the IVF process. Repeated, costly rounds of hormone therapy coupled with egg extraction 鈥� which tends to supply around 7 eggs at a time 鈥� could be avoided, for a start.
Instead, Tilly reckons all the eggs a person could ever need for IVF could be developed from one small piece of ovary, which can be removed in a simple laparoscopic operation. 鈥淔rom a 3-millimetre piece of tissue we can get 100 [stem] cells,鈥� he says. 鈥淲e can make a million of those cells in culture and each has the potential to make an oocyte.鈥�
Egg rejuvenation
There could also be benefits for women undergoing chemotherapy, which can leave them infertile. Currently, ovarian tissue is extracted and frozen before chemotherapy is started, so that it can be thawed and re-implanted once the woman has recovered.
However, there is a risk that cancerous cells could remain in the tissue, says Telfer. 鈥淚f we could get the [stem] cells from the tissue and culture them to the egg stage, then we could just implant an embryo rather than the whole tissue,鈥� she says.
What鈥檚 more, the stem cells could also be used to rejuvenate old eggs. Typically, older eggs are more prone to accumulating genetic errors. It is thought that a lack of energy might be responsible for their failure to divide properly, resulting in the abnormal numbers of chromosomes behind Down鈥檚 syndrome and other disorders.
Energy boost
Rejuvenating old eggs was partly realised in the late 1990s, when a clinic at the Institute for Reproductive Medicine and Science of Saint Barnabus in New Jersey, tried a new approach to IVF in women who had been through repeated, failed attempts. The idea was to inject fluid from young, donated eggs into the older women鈥檚 eggs along with their partners鈥� sperm.
At first the outcome seemed almost too good to believe 鈥� the 27 couples who tried the procedure gave birth to a total of 17 children. It was thought that the younger mitochondria floating around in the younger fluid could provide sufficient energy for error-free cell division (Human Reproduction Update, ).
However, because mitochondria carry maternal DNA, the children technically had three genetic parents. And because children normally only inherit mitochondrial DNA from their mother, no one knew what would happen when this DNA came from two sources.
Young for old
Concerns grew when the clinic found that two of the fetuses had developed Turner鈥檚 syndrome 鈥� a disorder resulting from missing parts of sex chromosomes. The wrote letters to the clinic advising that it put a halt to the procedure.
Tilly and his team reckon they can get around the problems faced by these early attempts by . 鈥淪tem cells stay young throughout life, and so will have young mitochondria,鈥� says Tilly.
鈥淲e could isolate the stem cells鈥� mitochondria and inject them into the same woman鈥檚 older eggs. It鈥檚 an adaptation of the old, disastrous protocol that could deliver clinical benefit.鈥� The team has partnered with , which is set to launch a clinical trial this year.
at the Center for Human Reproduction in New York City, says that the stem cells have a lot of exciting potential. 鈥淚t鈥檚 a beautiful piece of work,鈥� he says.
Journal reference: , DOI: 10.1038/nm.2669
