Inhibition of mTOR induces a paused pluripotent state
Open accessAbstract
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 implantation. The exception to this rule is embryonic diapause, a reversible state of suspended development triggered by unfavourable conditions. 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 growth, 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.
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Similar intermediate states have been described during embryonic development, where cells enter a paused, pluripotent state in response to environmental stress.
“Similar intermediate states have been described during embryonic development, where cells enter a paused, pluripotent state in response to environmental stress.62”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [62]
Of the 131 cells that undergo apoptosis in C. elegans, the great majority (105) are neurons.
“For example, of the 131 cells that undergo apoptosis in C. elegans, the great majority (105) are neurons, thus highlighting the importance of PCD for CNS development.22”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [22]
The Methods section, “Analysis of Apoptosis” (page unavailable), describes an assay in mouse embryonic stem cells, not cell death in C. elegans. Searches for the 131-cell and 105-neuron counts and for C. elegans neuronal cell death found no passage in our copy addressing the claim. (LLM, conf=0.77)
Experimental — accuracy not yet measuredLysosomes are important in apoptosis, a form of programmed cell death requisite for appropriate development of the mammalian nervous system.
“Lysosomes are also important in apoptosis, a form of programmed cell death (PCD) that is requisite for the appropriate development of the mammalian nervous system.21,22.”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [22]
The Methods section describes an apoptosis assay in embryonic stem cells, and Extended Data Figures 2 and 4 discuss apoptosis and an autophagy/lysosomal inhibitor in blastocysts. Neither passage addresses whether lysosomes are important in apoptosis or whether apoptosis is required for mammalian nervous-system development; searches for those connections found no supporting passage in our copy. Page numbers were not provided. (LLM, conf=0.76)
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- Authors
- Bulut-Karslioglu, A., Biechele, S., Jin, H., Macrae, T. A., Hejna, M., Gertsenstein, M., Song, J. S., & Ramalho-Santos, M.
- Affiliations
- University of California, San Francisco (US)
- University of Illinois Urbana-Champaign (US)
- Toronto Centre for Phenogenomics (CA)
- Venue
- Nature
- Published
- 2016-11-23
- Volume
- 540
- Issue
- 7631
- Pages
- 119-123
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5143278
- OpenAlex
- W2553053943
- Cited by
- 283
- References
- 39
- Citations by year
- 2026: 17 · 2025: 40 · 2024: 37 · 2023: 32 · 2022: 32 · 2021: 42 · 2020: 23 · 2019: 27 · 2018: 17 · 2017: 14 · 2016: 2
- FWCI
- 10.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation
- National Institutes of Health (R01OD012204)
- University of California, San Francisco
- National Cancer Institute (P30CA082103, R01CA163336)
- National Institute of General Medical Sciences (R01GM113014)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063720)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- mTOR inhibition, delayed implantation, blastocyst development, pluripotency, epiblast, embryonic stem cells, long-term culture, transcriptional repression, histone modifications, peri-implantation development, developmental timing, assisted reproduction, regenerative medicine, rapamycin, mouse embryo, translational regulation, nutrient sensing
- MeSH terms
- Mouse Embryonic Stem Cells, Animals, Blastocyst, Cells, Cultured, Female, Germ Layers, Histones, Male, Transcription, Genetic, Protein Biosynthesis, Down-Regulation, Pluripotent Stem Cells, Embryonic Development, Mice, TOR Serine-Threonine Kinases, In Vitro Techniques
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