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Mouse embryos put in suspended animation for weeks
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.
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.
"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.
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."
"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.
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.
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.
“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