Human Naive Pluripotency Attained by Transient Inhibition of Mtor
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ABSTRACT:
PROVIDER: PRJNA517616 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8501520_1.fastq.gz | Fastqsanger.gz | |||
| SRR8501520_2.fastq.gz | Fastqsanger.gz | |||
| SRR8501530_1.fastq.gz | Fastqsanger.gz | |||
| SRR8501530_2.fastq.gz | Fastqsanger.gz | |||
| SRR8501540_1.fastq.gz | Fastqsanger.gz |
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Project description:Mouse embryonic stem cells (mESCs) are in naive pluripotency that represents the ground state of development, from which all cells in the mouse embryo are derived. In contrast, human embryonic stem cells (hESCs) are in a primed state of pluripotency with many different properties. Despite intense efforts to generate naive human pluripotent stem cells (hPSCs), it has not been possible to derive naive hPSCs without relying on transgene overexpression or chemicals. Here, we show that a transient treatment with Torin1, a selective inhibitor of mTOR, converted hPSCs from primed to naive pluripotency. The naive hPSCs were maintained in the same condition as mESCs in defined media with 2iLI (MEK inhibitor, GSK3b inhibitor, LIF and Insulin). Like mESCs, they exhibited high clonal efficiency, rapid cell proliferation, active mitochondrial respiration, X chromosome activation, DNA hypomethylation, and transcriptomes similar to those of human blastocysts than primed hESCs. Most importantly, the naive hPSCs significantly contributed to mouse embryos when transferred to mouse blastocysts. mTor inhibition induced nuclear translocation of TFE3, a critical transcription factor at the interplay of autophagy and pluripotency. TFE3 with mutated nuclear localization signal blocked the conversion from primed to naive pluripotency. It appears that by mimicking diapause at the cellular level, naive pluripotency in human can be readily attained from primed hPSCs, thus establishing the unified ground state of pluripotency in mammals.
2020-05-13 | GSE102031 | GEO
Project description:Mouse embryonic stem cells (mESCs) are in naive pluripotency that represents the ground state of development, from which all cells in the mouse embryo are derived. In contrast, human embryonic stem cells (hESCs) are in a primed state of pluripotency with many different properties. Despite intense efforts to generate naive human pluripotent stem cells (hPSCs), it has not been possible to derive naive hPSCs without relying on transgene overexpression or chemicals. Here, we show that a transient treatment with Torin1, a selective inhibitor of mTOR, converted hPSCs from primed to naive pluripotency. The naive hPSCs were maintained in the same condition as mESCs in defined media with 2iLI (MEK inhibitor, GSK3b inhibitor, LIF and Insulin). Like mESCs, they exhibited high clonal efficiency, rapid cell proliferation, active mitochondrial respiration, X chromosome activation, DNA hypomethylation, and transcriptomes similar to those of human blastocysts than primed hESCs. Most importantly, the naive hPSCs significantly contributed to mouse embryos when transferred to mouse blastocysts. mTor inhibition induced nuclear translocation of TFE3, a critical transcription factor at the interplay of autophagy and pluripotency. TFE3 with mutated nuclear localization signal blocked the conversion from primed to naive pluripotency. It appears that by mimicking diapause at the cellular level, naive pluripotency in human can be readily attained from primed hPSCs, thus establishing the unified ground state of pluripotency in mammals.
2020-05-13 | GSE87452 | GEO
Project description:The ability to support blastocyst chimera formation is the most critical property of naïve pluripotent stem cells (PSCs). Transient inhibition of mTOR converts human PSCs from primed to naive state. Naïve human PSCs cultured in 2iLI robustly incorporate into mouse embryonic development after injected to mouse blastocysts.
2020-05-13 | GSE125813 | GEO
Project description:Human Naive Pluripotency Attained by Transient Inhibition of mTor
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Project description:Human Naive Pluripotency Attained by Transient Inhibition of mTOR
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Project description:Pluripotency can be maintained in the naïve state through manipulation of ERK and WNT signalling (2i), shielding embryonic stem cells (ESCs) from inductive cues. Alternatively, inhibiting CDK8/19 (CDK8/19i), a repressor of the Mediator co-activator complex, directly stimulates super-enhancer activity, and was recently shown to stabilize cells in a functional state that resembles naïve pluripotency. Naïve ESCs exhibit important epigenetic, transcriptional and metabolic features. However, our understanding on how these regulatory layers are inter-connected to promote the naive state is in progress. To fill this gap, here we used mass spectrometry to describe the dynamic molecular events (i.e. phosphoproteome, proteome and metabolome) executed by 2i and CDK8/19i, as they transition cell identity into naïve pluripotency. We observed rapid proteomic reprogramming, revealing widespread commonalities, and some important differences, between these two approaches, suggesting a largely over-lapping mechanism. CDK8/19i acts directly on the control of the transcriptional machinery, which elicits a rapid and direct activation of key identity genes including those that maintain the naïve program. Additional molecular changes in 2i are achieved by phosphorylation of critical downstream effectors that reinforce the naïve transcriptional circuitry while repressing factors from the more-differentiated formative and primed states. Comparing transcriptomic and proteomic changes, we found that post-transcriptional de-repression is a major feature of naïve pluripotency conferred by both 2i and CDK8/19i, and this may support the enhanced mitochondrial capacity of naive cells. Furthermore, at the level of metabolome, while 2i- and CDK8/19i-treated cells share similar aspects in one-carbon metabolism and beta-oxidation, in other regards they are divergent, a feature which may explain their differences in DNA methylation. These datasets provide a valuable resource for exploring the molecular mechanisms underlying pluripotency and cell identity transitions.
2021-02-10 | PXD018694 | Pride
Project description:Transient mTOR inhibition rescues 4-1BB-CAR-Tregs from tonic signal-induced dysfunction
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Project description:Pluripotent stem cells (PSCs) can transition between cell states in vitro, closely reflecting developmental changes in the early embryo. PSCs can be stabilized in their naive state by blocking extracellular differentiation stimuli, particularly FGF5 MEK signaling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF-MEK-signaling. Mechanistically, chemical inhibition of CDK8 and CDK19 kinases (CDK8/19i) removes their ability to repress the Mediator complex at enhancers. Thus CDK8/19i increases Mediator-driven recruitment of RNA Pol II to promoters and enhancers. This efficiently stabilizes the naive transcriptional program, and confers resistance to enhancer perturbation by BRD4 inhibition. Moreover, naive pluripotency during embryonic development coincides with reduction in CDK8/19. We conclude that global hyperactivation of enhancers drives naive pluripotency, and this can be captured in-vitro by inhibiting extracellular FGF-MEK-signaling, or downstream, by CDK8/19i. These principles may apply to other contexts of cellular plasticity.
2020-02-26 | GSE127186 | GEO
Project description:IRF1 in exit from naive pluripotency
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Project description:Effects of mTOR inhibition on the phenotypes of spleen naive CD4+ T (TN) cells.
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