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Mouse embryos put in suspended animation for weeks

Inhibiting a molecular path lets mouse blastocysts survive for weeks in the lab. Researchers have found a way to pause the development of early mouse embryos for up to a month in the lab. The finding has potential implications for assisted reproduction, regenerative medicine, aging and even cancers.


The new study — published online November 23, 2016 in Nature — involved experiments with pre-implantation mouse embryos, called blastocysts. The University of California San Francisco (UCSF) 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.


mTOR is also known as rapamycin, a member of a family of protein kinases, and a protein that in humans is encoded by the MTOR gene.


It is the core of two distinct protein complexes, mTOR complex 1 and mTOR complex 2. These complexes regulate different cell processes: mTOR complex1 (mTORC1) regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR complex 2 (mTORC2), promotes activation of insulin receptors and insulin-like growth factor 1 receptors. mTORC2 is also implicated in the control and maintenance of the actin cytoskeleton — the filament structures in the cytoplasm maintaining cell shape. Wikipedia

"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, Aydan Bulut-Karslioglu PhD, a post-doctoral researcher in the lab of senior author Miguel Ramalho-Santos PhD, who is an associate professor of obstetrics/gynecology and reproductive sciences at UCSF.


Bulut-Karslioglu and colleagues found that paused embryos could quickly resume normal growth when mTOR inhibiters were removed, developing 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.


"It was completely surprising. We were standing around in the tissue culture room, scratching our heads, and saying wow, what do we make of this?" said Ramalho-Santos, who is a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research. "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."

Further experiments demonstrated that cultured mouse embryonic stem cells — 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, with the exception of a handful of "repressor" genes that may also act inhibit gene activity. Researchers tested many different mTOR inhibitors. The most effective was a new synthetic drug called Rapa-Link recently developed at UCSF by the lab of Kevan Shokat, PhD.


Researchers believe it should be possible to extend the time of suspended animation much longer than the thirty days observed in the present study. Bulut-Karslioglu: "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."


Drug-induced dormancy mimics natural pausing of pregnancy that occurs in stressed mice.

Bulut-Karslioglu and colleagues demonstrated the dormant state they induced in blastocysts by blocking mTOR — was almost identical to the natural ability of mice to pause a pregnancy in its early stages.

Temporary stasis, called diapause, occurs in species across the animal kingdom. In mammals from mice to wallabies. It allows mothers to delay pregnancy when food is scarce. Or if they are otherwise stressed.


"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," says Ramalho-Santos.

It is an open question whether humans also have the ability to pause pregnancies at the blastocyst stage, adds Bulut-Karslioglu. Principally because the time from fertilization to implantation is hard to measure in humans. Anecdotal accounts from in-vitro fertilization practitioners tell of unusually long pregnancies and mismatches between timing of artificial embryo transfer and the resulting pregnancy — suggesting humans may also have the ability to delay implantation of fertilized embryos.

The new research could have a big impact on the field of assisted reproduction, where practitioners are currently limited by the rapid degradation of embryos once they reach the blastocyst stage. Putting blastocysts into suspended animation may avoid the compromise of freezing embryos and give practitioners more time to test fertilized blastocysts for genetic defects before implanting them, Bulut-Karslioglu said.


mTOR inhibitors are already in clinical trials to treat certain forms of cancer, but the new results suggest a potential danger of this approach.


Ramalho-Santos explains: "Our results suggest that mTOR inhibitors may well slow cancer growth and shrink tumors, but could leave behind these dormant cancer stem cells that could go back to spreading after therapy is interrupted. You might use a second or third line of drugs specifically to kill off those remaining dormant cells."

The authors are eager to explore whether mTOR inhibitors and related downstream biochemical pathways can drive stem cells into a dormant state at later stages of development, which could have major implications efforts to repair or replace ailing organs in the field of regenerative medicine. The authors add that their findings also have potential implications in aging research.

mTOR inhibitors have already been shown to extend the lives of mice and other animals, an outcome which the authors believe might result partly from preserving more youthful stem cells.


"This is a great example of the power of basic science. We weren't looking for ways to pause blastocyst development or mimic diapause. We weren't trying to model aging or test cancer therapies or develop better techniques for tissue regeneration or organ transplantation. 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."

Miguel Ramalho-Santos  PhD, Associate Professor, Obstetrics and Gynecology and Reproductive Sciences, University of California San Franciso, California USA


Abstract
Cultured pluripotent stem cells are a cornerstone of regenerative medicine owing to their ability to give rise to all cell types of the body. Although pluripotent stem cells can be propagated indefinitely in vitro, pluripotency is paradoxically a transient state in vivo, lasting 2–3 days around the time of blastocyst implantation1. The exception to this rule is embryonic diapause, a reversible state of suspended development triggered by unfavourable conditions2. Diapause is a physiological reproductive strategy widely employed across the animal kingdom, including in mammals, but its regulation remains poorly understood. Here we report that the partial inhibition of mechanistic target of rapamycin (mTOR), a major nutrient sensor and promoter of growth3, induces reversible pausing of mouse blastocyst development and allows their prolonged culture ex vivo. Paused blastocysts remain pluripotent and competent—able to give rise to embryonic stem (ES) cells and live, fertile mice. We show that both naturally diapaused blastocysts in vivo and paused blastocysts ex vivo display pronounced reductions in mTOR activity, translation, histone modifications associated with gene activity and transcription. Pausing can be induced directly in cultured ES cells and sustained for weeks without appreciable cell death or deviations from cell cycle distributions. We show that paused ES cells display a remarkable global suppression of transcription, maintain a gene expression signature of diapaused blastocysts and remain pluripotent. These results uncover a new pluripotent stem cell state corresponding to the epiblast of the diapaused blastocyst and indicate that mTOR regulates developmental timing at the peri-implantation stage. Our findings have implications in the fields of assisted reproduction, regenerative medicine, cancer, metabolic disorders and ageing.

Additional authors on the paper are Steffen Biechele, PhD, and Trisha A. Macrae, of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, and Diabetes Center at UCSF; Hu Jin, Miroslav Hejna, PhD, and Jun S. Song, PhD, of the Carl R. Woese Institute for Genomic Biology at the University of Illinois, Urbana-Champaign; and Marina Gertsenstein, PhD, of the Centre for Phenogenomics in Toronto.

This research was supported by grants from the National Institutes of Health (5P30CA082103, P30DK063720, R01CA163336, R01OD012204, R01GM113014) and the National Science Foundation (1442504). The authors declare no competing financial interests.

About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit http://www.ucsf.edu/news.

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Nov 30, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



“Normally, blastocysts only last a day or two, max, in the lab. But blastocysts treated with mTOR inhibitors could survive up to four weeks,” says Aydan Bulut-Karslioglu PhD, from the lab of
Miguel Ramalho-Santos PhD, Associate professor of Obstetrics/Gynecology and
Reproductive Sciences, UCSF.

Image Credit:
Miguel Ramalho-Santos lab UCSF, California USA


 


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