Men typically produce working sperm as long as they live, but most textbooks say female mammals are born with all the egg cells, or oocytes, they will ever have. Since 2004, however, reproductive biologist Jonathan Tilly of Massachusetts General Hospital in Boston has challenged that conventional wisdom, arguing that in mice—and perhaps also in humans—there must be an ongoing source of new eggs. Today, Tilly and his colleagues report isolating rare cells in ovarian tissue from adult women that can grow in lab dishes and form immature oocytes. The potential egg stem cells could help scientists devise new ways to help rescue the fertility of women who have to undergo cancer treatments or who suffer from premature menopause. The debate over renewable eggs, however, is far from over.
Since the 1950s, reproductive biologists have thought that egg production ends about halfway through mammalian fetal development. A baby girl, for example, is born with an estimated 1 million oocytes. Starting at puberty, those oocytes mature at a rate of about 1000 per menstrual cycle. (Only one of those matured eggs is released into the fallopian tubes each cycle.) And once the oocyte supply runs low, menopause begins. But in 2004, Tilly and his colleagues published data that challenged that idea. They found that in mice, too many oocytes die during each menstrual cycle to sustain the supply of eggs for the animal's lifetime fertility. New eggs, presumably from an unidentified stem cell, must be coming from somewhere, they proposed. Other researchers dismissed the team's conclusions, saying the team had drastically overestimated the rate of oocyte death.
In 2009, however, Tilly's idea that adult animals can produce new oocytes got a boost from researchers in China. Biologist Ji Wu and his colleagues at Shanghai Jiao Tong University reported that they had isolated "female germline stem cells" from adult mouse ovaries. To prove their case, the team even genetically modified the putative stem cells so that they produced green fluorescent protein (GFP) and then injected them into the ovaries of sterilized mice. After the treatment, those females gave birth to pups that glowed green, demonstrating that the injected cells had given rise to mature oocytes.
It was not clear, however, whether similar egg stem cells existed in human ovaries—or what the cells' role might be in normal fertility and reproduction. In their paper published today in Nature Medicine, Tilly and his colleagues report that they have refined Wu's cell-collection methods and fished out similar cells from human ovary tissue. Tilly's colleague Yasushi Takai, who works at the Saitama Medical Center in Japan, was able to collect ovarian tissue from six women who had sex reassignment surgery. The women were healthy and young—between 22 and 33 years old—and all agreed to have their tissue used for the project.
The cells, which Tilly calls oogonial stem cells (OSCs), are very rare—only about 1 out of 10,000 ovarian cells. The OSCs grew quickly in the lab, and under certain conditions they spontaneously formed cells that visually and molecularly resemble oocytes. To find out how the cells would behave in an ovary, the scientists injected OSCs engineered to make GFP into a piece of donated human ovarian tissue and then implanted the tissue under the skin of a mouse. When they looked at the grafts 1 and 2 weeks later, they found immature follicles—the ovarian structure in which fertile eggs develop—with green oocytes at their center.
Finding a human version of the cells Wu isolated is "very exciting," says Evelyn Telfer, who studies oocyte development at the University of Edinburgh in the United Kingdom. "As an egg biologist, I'm juiced about this," says David Albertini of the University of Kansas Medical Center in Kansas City.
The oocyte cells that grew from the human OSCs were far too immature to be fertilized, Tilly notes. And attempting such an in vitro fertilization experiment would need special ethical oversight, he says. He and Telfer have plans to collaborate to see whether her techniques for maturing oocytes in vitro might work with OSC-derived cells. In the United Kingdom, scientists can apply for a license to conduct fertilization experiments with human cells. Whether the stem cells themselves could be a source of fertile oocytes grown in the lab is doubtful, Albertini says. He points out that expanding cells in culture almost always causes cells to accumulate potentially harmful mutations.
Both Telfer and Albertini caution that the current experiments don't address what, if any, role the apparent stem cells might play in normal ovaries. But both say that studying the cells in the lab could help researchers better understand the mysteries of the oocyte. "I think it's a great model," Albertini says. "It could help us move toward understanding how these incredible cells [oocytes] are born and how they develop."
Tilly holds a patent on the human egg stem cells, and he has started a biotech company to explore possible ways to use the cells to help improve fertility treatments. He says researchers at the company will screen for compounds that encourage the cells' growth and development, and they will test whether compounds in the cells might be able to boost the fertility of aged eggs.
Correction: The item has been updated to reflect the correct number of oocytes at birth. It is roughly 400,000 per ovary, not 400,000 total as stated in the original.