DOGMA states that women are born with all the eggs they will ever have. Now, the discovery of stem cells tucked away in human ovaries suggests that new eggs are actually produced throughout life. The finding could lead to limitless eggs for IVF treatments, and the rejuvenation of older eggs, boosting the chances for women to have children later in life.
Jonathan Tilly and colleagues at Massachusetts General Hospital in Boston 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’s team looked carefully at the number of oocytes – cells that develop into viable eggs – 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. “There were a lot of vocal critics,” says Tilly. “They said it was absolute hogwash and wouldn’t amount to anything.” Undeterred, Tilly’s group set out to look for similar cells in human ovaries. Through a collaboration with Saitama Medical University in Japan, the group was able to analyse unwanted ovaries leftover from gender-reassignment operations.
The team started by targeting a protein specific to egg cells in the ovarian tissue that allowed them to identify these cells among the many that are in the tissue. They noted that, early in the development of an egg cell, this protein is expressed on the cell’s 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 (Nature Medicine, ).
The finding of such stem-cell-like cells is being hailed as a major breakthrough by gynaecologists, including Kutluk Oktay 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.
Tilly is optimistic that his technique could also be used to enhance IVF – 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 Evelyn Telfer at the University of Edinburgh, UK, who has found a way to mature early oocytes to a more advanced developmental stage in the lab.
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 – which tends to supply around 7 eggs at a time – 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. “From a 3-millimetre piece of tissue we can get 100 [stem] cells,” he says. “We can make a million of those cells in culture and each has the potential to make an oocyte.”
“From a 3-millimetre piece of ovary we can make a million stem cells, each of which could make an egg”
Everlasting youth
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. “If 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,” she says.
What’s 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 cellular energy might be responsible for their failure to divide properly, resulting in the abnormal numbers of chromosomes behind Down’s syndrome and other disorders.
“The stem cells could be used to rejuvenate old eggs so that they are not prone to genetic errors”
The rejuvenation of 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’s eggs along with their partners’ sperm.
At first the outcome seemed almost too good to believe – 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 as children normally only inherit mitochondrial DNA from their mother, no one knew what would happen when this DNA came from two sources.
Concerns grew when the clinic found that two of the fetuses had developed Turner’s syndrome – a disorder resulting from missing parts of sex chromosomes. The US Food and Drug Administration wrote 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 harnessing an older woman’s own mitochondria from her ovarian stem cells. “Stem cells stay young throughout life, and so will have young mitochondria,” says Tilly. “We could isolate the stem cells’ mitochondria and inject them into the same woman’s older eggs. It’s an adaptation of the old, disastrous protocol that could deliver clinical benefit.”
The team has partnered with OvaScience, which is set to launch a clinical trial this year. “The trial represents the first fruits of [Tilly’s] research,” says Oktay.
Norbert Gleicher at the Center for Human Reproduction in New York City says that the stem cells have a lot of exciting potential. “It’s a beautiful piece of work,” he says.
Origins of ‘miracle’ pregnancies
Some seemingly miraculous pregnancies might be explained by the identification of stem cells in human ovaries.
Kutluk Oktay at New York Medical College in Valhalla recalls one young woman who was going through tough chemotherapy treatment for a cancer of the white blood cells. Because such treatments often destroy fertility, Oktay removed and froze one of the woman’s ovaries before she started her therapy.
The therapy was a success but left her infertile. “Blood tests confirmed that she was in menopause,” says Oktay. Indeed, after two years of having sex without contraception, no pregnancy occurred.
When the woman wanted to pursue having children, Oktay thawed and implanted some of her ovarian tissue under the skin of her abdomen with the idea of letting oocytes develop for later collection for use in IVF. Oktay was trialling this less invasive implantation procedure in order to keep an eye on the tissue in case it contained cancer cells.
Remarkably, within a month, the woman was pregnant. It didn’t stop there. “She had three babies, pretty much one after the other,” says Oktay.
Oktay has seen similar outcomes in several other women. Exactly how the pregnancies came about is something of a mystery, but the newly discovered stem cells may provide an explanation. Stem cells in the remaining ovary could somehow be resilient to the chemotherapy, says Oktay. In that case, signals from the healthy ovarian tissue may have restarted egg production.
Or stem cells preserved in the healthy tissue might have been behind the production of the healthy, fertilisable eggs. It is possible that these cells travelled in the circulation on a homing mission to the remaining ovary, says Oktay.