For 70 years, the biological dogma held that women are born with a fixed supply of eggs depleted by menopause. Stem cell research in mouse, bovine, primate, and human ovaries now challenges it
For 70 years, the biological dogma held that women are born with a fixed supply of eggs depleted by menopause. Stem cell research in mouse, bovine, primate, and human ovaries now challenges it
Since the early 2000s, biologist Jonathan Tilly has been finding cells in adult ovaries capable of forming new eggs. In 2017, a genetic label placed on such cells in mice showed that eggs arising in adulthood could be fertilized and produce healthy offspring. A July 3 article in Scientific American reported the story: one skeptic changed her position after working with Tilly, while others dispute the method itself.
The idea that ovaries might replenish their egg supply was first proposed in the 1920s. In the mid-twentieth century, British zoologist Solly Zuckerman counted eggs in animals of different ages, found no new cells, and concluded that ovaries are unable to produce them. For 70 years that remained the only accepted answer.
In 2004, biologist Jonathan Tilly (Northeastern University) published a calculation in Nature that contradicted the dogma. Eggs in the ovary die continuously through a process called follicular atresia. If the supply were never replenished, the rate of depletion would match the rate of cell death. In practice, depletion was considerably slower, meaning new eggs were forming in the ovary. Tilly proposed that oogonial stem cells (OSCs) were responsible, by analogy with spermatogonial stem cells in the testes.
In 2009, such cells were first isolated from mouse ovaries; in 2012, from human ovaries. Antibodies and transplantation provided only indirect evidence: it remained unclear whether the cells themselves were viable and whether they could independently mature into eggs. Tilly's laboratory obtained rigorous proof in 2017: a genetic label placed on cells entering meiosis in adult female mice showed that labeled eggs produced viable offspring through the grandchild generation. Regenerative capacity declined with age: in young mice, roughly 1,500 cells were restored over three weeks; in middle-aged mice, roughly 600; in old mice, none.
Evelyn Telfer, head of reproductive biology at the University of Edinburgh, was a skeptic until she began working with Tilly on human ovarian tissue. Some of the cells, she told Scientific American, "transformed" and formed structures resembling follicles, where eggs mature. She explains: "You are part of a scientific community with certain views, and if you go against them, it is hard to get funding." Aaron Hsueh of Stanford University questions the antibodies used to isolate these cells; Tilly responds that the antibodies are commercially available and that his critics ignore nearly a hundred studies published since 2004.
In 2023, the same laboratory identified why stem cells stop replenishing the supply with age: developmental genes are silenced, and the cells lose their capacity to form eggs. The same was found in human ovarian tissue.
"The house has fallen into disrepair... the environment in which the cells exist no longer supports their function properly," says Tilly, comparing the ovary to a house and the stem cells to its occupants, who can remain in place even after menopause.
With age, the tissue surrounding the eggs becomes more fibrotic, Telfer adds, disrupting the signals the cells need. In mice and rats, that fibrosis has already been traced to a single molecule: the protein IL-11 drives collagen accumulation in ovarian tissue, and blocking it partially restored fertility, suggesting that the dilapidated house can sometimes be repaired. Tilly has already isolated "dormant" OSCs from ovarian tissue of women who went through menopause decades ago; the result is unpublished, but the laboratory is trying to determine whether these cells can be reawakened.