In an advance that could lead to new fertility treatments, researchers have coaxed immature human egg cells to fully develop in the lab for the first time. Still unclear is whether the resulting eggs, which reached maturity in just 22 days, compared with 5 months in the body, are normal and whether they can combine with sperm to make a healthy embryo.
The feat nonetheless is "extraordinarily important," says Kyle Orwig, a stem cell biologist at the Magee-Womens Research Institute at the University of Pittsburgh in Pennsylvania who was not involved in the new work. "It has real potential for application," he adds. "We already have the patients."
Those patients include women who have gone through chemotherapy, which can damage eggs and cause infertility. Girls with cancer who haven't hit puberty don't yet produce mature eggs that can be frozen, so some choose to preserve a small piece of ovarian tissue, which can later be placed back in the body to start making eggs. But that's a risky choice in some cases, because the transplant could reintroduce the cancer with the cells. If the new process is perfected, these women could instead rely on the tissue they saved as girls to generate eggs for in vitro fertilization.
That ovarian tissue bears clusters of cells known as primordial follicles, which surround immature precursors to egg cells. As these follicles gradually enlarge and mature, the egg precursors undergo their own maturation process inside. After puberty, the follicles rupture—one per month—to release a mature egg to be fertilized.
So far, different research teams have run only a few legs of this developmental relay in the lab. In 2008, reproductive biologist Evelyn Telfer and colleagues at the University of Edinburgh managed the first half. They started with primordial follicles from ovarian tissue and nourished them into a semideveloped state. Then in 2015, a group at Northwestern University in Chicago, Illinois, ran the final leg. They created mature eggs from partially developed follicles.
In the new work, Telfer and her collaborators completed the whole developmental cycle. They took small samples from the ovaries of 10 women undergoing elective caesarian sections, and isolated 87 follicles, which they let develop in a soup of nutrients. Then came a new step: They carefully extracted the fragile, immature eggs and some surrounding cells from the follicles, and allowed them to further mature on a special membrane in the presence of more growth-supporting proteins. In the end, just nine of these eggs passed the final test for maturity—they were able to divide and halve their chromosomes so they were ready to join with sperm during fertilization, the researchers reported online 30 January in Molecular Human Reproduction.
The laboratory process may be inefficient, but it's a thrilling first step, Telfer says. "We had no great expectations. To see at least one [egg reaching maturity], we thought, ‘Wow, that's actually quite incredible.'"
But others aren't yet ready to declare this a victory. The paper doesn't include any genetic analysis of the final eggs that confirms they are healthy, notes Mitinori Saitou, a stem cell biologist at Kyoto University in Japan whose team developed methods to create mouse egg cells from embryonic or reprogrammed stem cells. He's concerned that the shortened maturation process in the lab can't possibly mirror development that naturally takes place over months. And the details of the final chromosome-halving division give him pause. Normally, a smaller cell called a polar body pinches off from the egg. In the new experiments, the polar bodies were abnormally large, which to Saitou suggests that the egg hasn't matured properly. "The final products they got are clearly abnormal," he says. "Even if what they report is true, there are a lot of things that should be improved."
Telfer suggests that the eggs reach maturity faster because many inhibitory signals from the body are absent. Neither the speedy results nor the large polar bodies necessarily point to problems with the eggs, she says. Still, her team is working on improvements to the process, and also hopes—with approval from the United Kingdom's Human Fertilisation and Embryology Authority—to try fertilizing the lab-matured eggs to create human embryos. Any such embryos would just be studied during their early development for now—there are no plans yet to try to create a pregnancy with them.
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