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2016 ; 540
(7631
): 119-123
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Inhibition of mTOR induces a paused pluripotent state
#MMPMID27880763
Bulut-Karslioglu A
; Biechele S
; Jin H
; Macrae TA
; Hejna M
; Gertsenstein M
; Song JS
; Ramalho-Santos M
Nature
2016[Dec]; 540
(7631
): 119-123
PMID27880763
show ga
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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