In research that could have far-reaching implications for female fertility, U.S. scientists have isolated stem cells from human ovarian tissue that give rise to what appear to be normal egg cells.
The finding, published Sunday in the journal Nature Medicine, builds on earlier landmark papers by the Boston researchers, which suggest that female mammals continue producing egg cells, known as oocytes, into adulthood.
Since 2004, the scientists at Massachusetts General Hospital have produced a series of papers based on work in laboratory mice, which challenge the long-held belief that female mammals are born with a finite number of eggs that run out at a certain point in the life cycle.
The team was able to isolate stem cells from ovarian tissue taken from mice, from which they grew fully functional egg cells in the lab, which could then be fertilized and even produce healthy offspring.
"The primary objective of the current study was to prove that oocyte-producing stem cells do, in fact, exist in the ovaries of women during reproductive life, which we feel this study demonstrates very clearly," said lead author Jonathan Tilly, director of the Vincent Center for Reproductive Biology at Massachusetts General.
In their experiments, the team isolated the stem cells from ovarian tissue that had been removed from women in their 20s and early 30s.
When put in culture dishes in the lab, these stem cells gave rise to cells with the characteristic features of oocytes, including the physical appearance and gene expression patterns of those seen inside human ovaries.
"They spontaneously generate eggs in the dish," Tilly said in a phone interview, noting that they proliferate so well that a small number of stem cells could easily spawn a million egg cells in the lab.
The researchers next took stem cells they had genetically manipulated to glow green and injected them into snippets of human ovarian tissue. These prepared tissue bits were then grafted beneath the skin of specially bred mice, which have no immune system that can cause rejection of human tissue.
Within two weeks, researchers discovered the implanted ovarian tissue in the mice contained numerous immature human follicles with egg cells that originated from the injected stem cells. Follicles are small sacs within the ovary which contain maturing eggs.
Tilly said they knew the eggs cells had arisen from the injected stem cells "because they were all green."
Among the many potential clinical applications the researchers are exploring is whether these stem cells could produce oocytes that could play a role in in-vitro fertilization, as well as other applications to improve the outcomes of IVF and other infertility treatments.
"Can we use these cells for fertility reasons to maximize the opportunity for patients who are experiencing infertility to have different options available to them to have a genetically matched child?" asked Tilly.
"I think it's a fairly good possibility that at some point in the not-too-distant future there will be clinical protocols developed using some aspect of these cells or their properties that will have a significant impact on human reproduction."
Among them is the idea of extracting structures responsible for energy production in cells — called mitochondria — from the stem cells and injecting them into a woman's eggs at the time of in-vitro fertilization, with the hope of boosting the chances of conception and a successful birth.
But Tilly said another idea is to see whether these ovarian stem cells could be used to delay menopause — and the myriad health effects that can develop as women age.
"I've always been intrigued by the prospects of what if you could slow the rate at which the egg cell pool goes away and end up keeping an ovary functioning long past its normal time of failure," he said.
"With these egg stem cells, it raises the prospect that by harnessing the power of those cells, perhaps we can control the rate at which that precious reserve of egg cells is depleted and maybe even delay it ... And if you could achieve that, what would happen? Would we truly see a benefit or would there be unforeseen bad effects?"
More than a decade ago, Tilly's lab created a mouse through genetic manipulation that did not experience ovarian failure with age and was able to maintain an adequate reservoir of eggs.
"So it didn't undergo the equivalent of menopause," he said, or "mouseopause" as the scientists have dubbed it.
While normal mice as they reach old age experience health problems similar to those of postmenopausal women — including declining eyesight and hearing, hair loss, osteoporosis, diminished cognitive function and reduced muscle mass — these genetically modified mice did not. Nor did they have an increased risk of cancer.
So could these stem cells one day be used as the basis for an anti-aging treatment?
"There would be some pretty significant health benefits that would come out of it," said Tilly, if that were the case.
Even though every aspect of the human oocyte-producing stem cells have so far matched what the researchers have found in their mouse equivalents, Tilly conceded that "mouse is mouse — and perhaps human will be different."
"We don't know" if eggs generated from human ovarian stem cells will be normal and healthy, he said. "We will have to be very careful if and when we get to that stage."