Researchers have found a way to pause the development of early mouse embryos for up to a month in the lab, a finding with potential implications for assisted reproduction, regenerative medicine, aging, and even cancer, the authors say.

The new study -- published in Nature -- involved experiments with pre-implantation mouse embryos, called blastocysts. The researchers found that drugs that inhibit the activity a master regulator of cell growth called mTOR can put these early embryos into a stable and reversible state of suspended animation.

"Normally, blastocysts only last a day or two, max, in the lab. But blastocysts treated with mTOR inhibitors could survive up to 4 weeks," said the study's lead author.

They showed that paused embryos could quickly resume normal growth when mTOR inhibiters were removed, and developed into healthy mice if implanted back into a recipient mother.

The discovery was a surprise to the researchers, who had intended to study how mTOR-inhibiting drugs slow cell growth in blastocysts, not to find a way to put the embryos into hibernation: "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 the author.

Further experiments demonstrated that cultured mouse embryonic stem cells - which are derived from the blastocyst-stage embryo - can also be put into suspended animation by mTOR inhibitors. The drugs appear to act by reducing gene activity across much of the genome, the team found, with the exception of a handful of so-called "repressor" genes that themselves may act to inhibit gene activity. The researchers tested a number of different mTOR inhibitors and found that the most effective was a new synthetic drug called Rapa-Link that was recently developed at UCSF.

The researchers believe that it should be possible to extend the suspended animation for much longer than the thirty days observed in the present study, author said: "Our dormant blastocysts are eventually dying when they run out of some essential metabolite within them. If we could supply those limiting nutrients in the culture medium, we should be able to sustain them even longer. We just don't know exactly what they need yet."

Researchers demonstrated that the dormant state they were able to induce in blastocysts by blocking mTOR was almost identical to the natural ability of mice to pause a pregnancy in its early stages. This temporary stasis, called diapause, occurs in species across the animal kingdom, and in mammals from mice to wallabies, it typically allows mothers to delay pregnancy when food is scarce or they are otherwise stressed.

It makes sense that mTOR would be involved in the process of diapause, author said: "mTOR is this beautiful regulator of developmental timing that works by being a nutrient sensor. 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."

It is an open question whether humans also have the ability to pause pregnancies at the blastocyst stage, author said, because the time from fertilization to implantation is hard to measure in humans. However, anecdotal accounts from practitioners of in vitro fertilization of unusually long pregnancies and mismatches between the timing of artificial embryo transfer and the resulting pregnancy suggest that humans too may have the ability to delay implantation of fertilized embryos in some circumstances.

http://www.ucsf.edu/news/2016/11/405016/researchers-put-mouse-embryos-suspended-animation

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature20578.html