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Pluripotency takes a Pause for Thought!

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Review of “Inhibition of mTOR induces a paused pluripotent state” from Nature by Stuart P. Atkinson

A new study from the laboratory of Miguel Ramalho-Santos (University of California, San Francisco, USA) has made us, and pluripotency, pause for thought! Specifically, the enterprising team has discovered a means to artificially induce mouse embryonic diapause, a reversible state of suspended development [1], and has revealed details of the new paused pluripotent state of diapaused blastocyst cells. Bulut-Karslioglu et al believe that their new findings, published in Nature, may have implications for assisted reproduction, regenerative medicine, aging, and cancer [2].

So don’t pause, read on!

Unfavorable growth conditions can prompt diapause [1] and so, the authors first assessed if they could artificially induce blastocyst diapause and create a “paused” pluripotent state by inhibiting growth pathways. Of the pathways tested, inhibition of the mTOR pathway, which senses and integrates nutritional and environmental cues, extended blastocyst survival in ex vivo culture (up to 9-12 days). Interestingly, paused blastocysts still gave rise to fully pluripotent embryonic stem cells (ESCs) (after 7 days) and produced live-born, fertile mice (4-5 days)! Within this paused state, cells of the blastocyst displayed multiple alterations, including enhanced autophagy, reduced protein synthesis, reduced nascent transcription, and the formation of a repressive chromatin environment. 

Excitingly, the study also extended pausing via mTOR inhibition to cultured ESCs, which remained viable for weeks without significant cell death but displayed a slowed cell cycle and a dampened global transcriptional profile. Encouragingly, following the withdrawal of mTOR inhibition, ESCs contributed to high-grade germline-transmitting mouse chimeras, so confirming their in vivo developmental potential.

So what does this mTOR-mediated pluripotency “pause for thought” bring to the game? Other than allowing for the genetic and molecular dissection of embryonic diapause, the authors suggest that mTOR inhibition may allow the “suspended animation” of assisted reproduction embryos, instead of harmful freezing cycles, and allow time for genetic testing. Furthermore, paused blastocysts and ESCs may allow us to model aging, test cancer therapies, and develop techniques for tissue regeneration/organ transplantation.

References

  1. Fenelon JC, Banerjee A, and Murphy BD. Embryonic diapause: development on hold. Int J Dev Biol 2014;58:163-174.
  2. Bulut-Karslioglu A, Biechele S, Jin H, et al. Inhibition of mTOR induces a paused pluripotent state. Nature 2016;540:119-123.