The tiny clump of mouse cells didn’t look like an ovary. For one thing, it was much smaller, microscopic. And instead of being attached to a uterus it was floating in a test tube. And yet, from within the pocket of cells, oocytes began to form, then grow, maturing into eggs. Later, when some of these eggs would get fertilized and gestate all the way to healthy, fertile, newborn mice, this feat would be made all the more astonishing by the fact that the “ovarioids” that had made them were produced entirely from stem cells.
The experiment, published Thursday in Science, marks the first time that researchers have overcome a key hurdle in the hunt for achieving one of reproductive medicine’s wilder ideas: in vitro gametogenesis, or IVG. Sperm and eggs are gametes, and until recently, the only way to make them was inside a testes or an ovary. IVG promises a new possibility — producing them in test tubes from stem cells, which scientists can easily create from skin and other cells.
Researchers said the advance will make it easier to study causes of infertility, and could lead to treatments in people, though that is likely still decades of exploratory work away. But the research suggests it may someday be possible for women who’ve lost reproductive function, either due to cell failure or cancer treatment, to have more eggs made for them in a lab. It also raises other reproductive possibilities — same-sex couples, for example, could both be genetic parents to their children — and could spark a debate about how the technology should be used.
The study was led by IVG pioneer Katsuhiko Hayashi of Kyushu University in Japan. In 2011, his lab was the first to produce functional mouse sperm from stem cells. In 2016, they got another scientific first when they used stem cells to produce functional eggs in mice. But in order to get the eggs to develop properly, his team had to incubate their stem-cell-derived primordial egg cells with fresh ovarian tissues taken from mice. Without these support cells, the egg doesn’t get the signals it needs to mature.
But this process isn’t exactly compatible with the ultimate goal of moving the technology into humans. “It’s a kind of bottleneck, because it’s really difficult to get these kinds of tissues for animals other than the mouse,” said Hayashi.
So his team spent the last five years figuring out the molecular recipe for recreating this ovarian support tissue. With that in hand, they nudged mouse embryonic stem cells into these supporting cells. And when combined with the primordial egg cells, they gave rise to viable, egg-producing ovarioids.
“It’s a very serious piece of work,” said Richard Anderson, chair of clinical reproductive science at the University of Edinburgh, who was not involved in the study. “This group has done a lot of impressive things leading up to this, but this latest paper really completes the in vitro gametogenesis story by doing it in a completely stem-cell-derived way.”
Hayashi’s team is now working on repeating the advance in marmosets. They’ve also begun collaborating with another Japanese research group led by Mitinori Saitou, who has produced human primordial egg cells from stem cells. Hayashi expects they could have fully mature stem-cell-derived eggs within a decade. “However, the issue is the quality of the in-vitro oocyte,” he said. “That could take a long, long time to verify.”
Still, it’s not too soon for governments to start thinking about how IVG might be regulated. Bioethicists have raised concerns that the easy mass production of eggs and sperm could lead to all types of novel legal and social conundrums. Should there be limits placed on how many embryos a person can make from their own cells? Are existing legal frameworks for defining parenthood compatible with the age of IVG?
“I suspect that if it does start to show feasibility in humans, there’s going to be a lot of pressure from various groups — same-sex couples, those with infertility issues — to have access to this technology before society grapples with its implications, said Megan Allyse, a Mayo Clinic bioethicist who specializes in emerging reproductive technologies. “The concern about this kind of research is that once you prove it’s possible, the next question everybody asks is not ‘should we use it?’ Or ‘do we have a need for it?’ It’s ‘how are we going to use it?’”