In a potential methods breakthrough, stem cell biologists grew mouse embryos for five-and-a-half days in vitro, longer than ever before. Appearing recently in Nature, the study unveils new protocols and equipment, including a temperature-and-pressure-controlled incubator that enabled the coauthors to push the boundaries of embryo culture in the lab. Long-lived laboratory mouse embryos could be a revolutionary tool to study development and possibly to pinpoint when and how disorders arise.
Within a mouse’s 20-day gestation period, the coauthors focused on the critical window between days 5 and 11 when organs begin to form. They collected the embryos, as translucent cylinders of stem cells, from the mother’s uterus on day 5, then grew them through the process of tissue formation and organ differentiation. The findings are exciting both for the length of time the embryos survived and for the developmental process captured, says senior author Jacob Hanna at the Weizmann Institute of Science, in Rehovot, Israel.
This is the first mammal model to open a window onto the process from stem cell differentiation to organ formation in the lab. It will enable all sorts of new experiments, Hanna says—for example introducing viruses such as Zika, to learn how exactly they harm the fetus. “It’s not only about being able to grow [mouse] embryos,” Hanna says, “but being able to manipulate them.”
Typically researchers grow mouse post-implantation embryos for maybe one day in vitro, according to Hanna. Determined to extend this apparent time limit, he and coauthors built an incubation system from scratch to control the concentrations of oxygen, carbon dioxide, temperature, and pressure surrounding each embryo. The coauthors also used new recipes for growth medium, including blood serum from rats and humans that was rich in glucose and other nutrients. The embryos survived on this glucose-rich fluid, taking up nutrients by diffusion, until they reached a centimeter in size. At that point, the fetal mice became too large to rely on diffusion, could no longer supply blood to their hearts without a connection to the mother, and died on day 11.
“The next question is: What about day 11 to birth?” says stem cell biologist Jun Wu at the University of Texas Southwestern Medical Center in Dallas. One long-term goal is to grow a mouse fetus from fertilization all the way to birth at day 20. Test tube embryogenesis still generally relies on a mother to carry the pregnancy to birth. This recent work is the longest developmental biologists have been able to grow an early embryo outside of a mother, Wu says. Other research has grown lamb fetuses from mid-late gestation to birth, he notes.
Wu recently published a separate Nature study revealing a new type of blastoid based on human rather than mouse cells, a model structure that mimics the preimplantation blastocyst stage of the human embryo when the fetus is a ball-like structure of stem cells with a central cavity. If Hanna’s methods for growing mouse embryos could be applied to Wu’s blastoids for multiple days, the technique could open a new window on early human development, he says.
Future research will likely use mouse embryos to study many aspects of development, especially insights into what goes wrong due to mutations or environmental conditions, Hanna says. Many years from now there’s a chance that these methods could help women have children without the need for a uterus, Wu and Hanna both note. “I’d call it sci-fi at this stage,” Wu cautions. “I don’t think it’ll happen anytime soon.”
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