‘Suspended’ mouse embryos open new research paths to reproduction, cancer and more

Blue stem cells
UCSF researchers discovered the mTOR inhibitors may put stem cells in a state of suspended animation.

Scientists at the University of California at San Francisco were studying an emerging class of experimental cancer drugs called mTOR inhibitors when they made a surprising discovery. They were able to use the drugs to put mouse embryos in a state of suspended animation—a period of hibernation that was stable and lasted for up to four weeks. When they removed the mTOR inhibitors and implanted the embryos back into the mother, they developed into normal mice.

“To put it in perspective, mouse pregnancies only last about 20 days, so the 30-day-old ‘paused’ embryos we were seeing would have been pups approaching weaning already if they’d been allowed to develop normally,” said lead author Miguel Ramalho-Santos, an associate professor of obstetrics/gynecology and reproductive sciences at UCSF in a press release from the university. The research was published online in the journal Nature.

The scientists were able to demonstrate that blocking mTOR in the early embryos, or blastocysts, put them into a dormant stage that mimics “diapause,” which is a naturally occurring delayed pregnancy that many species exhibit when they’re lacking food or other vital resources. “mTOR is this beautiful regulator of developmental timing that works by being a nutrient sensor,” Ramalho-Santos said. “It doesn’t just drive cells into growing willy-nilly; it tunes cell growth based on the level of nutrients that are available in the environment.”

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The UCSF team showed that mTOR inhibitors can also suspend the development of mouse embryonic stem cells. The drugs appear to work by suppressing gene activity, and there were clues that the state of suspended animation might be able to be extended beyond 30 days.

The discovery could advance a range of scientific pursuits, from regenerative medicine to reproduction to cancer treatment. It could be a boon particularly to the field of assisted reproduction, which has been hampered by the tendency of blastocysts to rapidly degrade. Using mTOR inhibitors to put embryos into a dormant stage rather than freezing them might boost the success rate and give doctors time to test them for genetic disorders, the UCSF scientists believe.

As for the implications of the research on mTOR development in cancer, Ramalho-Santos urges caution. The UCSF results suggest that the drugs may leave behind dormant cancer cells, which could come back to life after the therapy is stopped. That may require using the drugs in combination with other medicines to ensure all of the cancer is eradicated, he said.

The mTOR pathway has long been of interest in the oncology community. An analog of the mTOR inhibitor rapamycin is approved to treat renal cell carcinoma, and several other drugs that act on the same pathway are being examined in other tumor types. Last year, a global research team discovered genetic mutations in follicular lymphoma that activate mTOR, potentially providing a new treatment target.

Although it wasn’t their intention to explore the role of mTOR inhibition in pausing embryo development, the UCSF team is excited to follow the science and see if it may lead to new ways of preserving stem cells and using them for regenerative medicine. “We weren’t trying to model aging or test cancer therapies or develop better techniques for tissue regeneration or organ transplantation,” Ramalho-Santos said. “None of that was in our mind, but our experiments told us we were on to something we had to understand, and we couldn’t ignore where they led.”

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