Inhibition of mTOR induces a paused pluripotent state.
Inhibition of mTOR induces a paused pluripotent state.
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DOI：
10.1038/nature20578
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发表时间：
2016-12-01
期刊：
影响因子：
64.8
通讯作者：
Ramalho-Santos, Miguel
中科院分区：
文献类型：
--
作者：
Bulut-Karslioglu, Aydan;Biechele, Steffen;Jin, Hu;Macrae, Trisha A.;Hejna, Miroslav;Gertsenstein, Marina;Song, Jun S.;Ramalho-Santos, Miguel
培养的多能干细胞是再生医学的基石，因为它们能够产生身体的所有细胞类型。虽然多能干细胞在体外可以无限增殖，但多能性在体内是一种短暂的状态，大约在胚泡植入时持续2-3天。这一规则的例外是胚胎滞育，这是一种由不利条件引发的可逆的暂停发育状态。滞育是动物界广泛采用的一种生理生殖策略，包括哺乳动物，但对其调控仍知之甚少。在这里，我们报告了雷帕霉素（mTOR），一个主要的营养传感器和生长促进剂的机械目标的部分抑制，诱导小鼠囊胚发育的可逆暂停，并允许其延长cultureex vivo。暂停的胚泡保持多能性和能力，能够产生胚胎干细胞（ES）和活的、有生育能力的小鼠。我们发现，无论是自然滞育blastocystsin vivo和暂停blastocystsex vivo显示明显减少mTOR活性，翻译，组蛋白修饰与基因活性和转录。在培养的ES细胞中可以直接诱导暂停，并持续数周而没有明显的细胞死亡或偏离细胞周期分布。我们发现，暂停ES细胞显示出显着的全球转录抑制，保持滞育囊胚的基因表达签名，并保持多能性。这些结果揭示了一种新的多能干细胞状态，对应于滞育胚泡的上胚层，并表明mTOR调节围植入期的发育时机。我们的发现在辅助生殖、再生医学、癌症、代谢紊乱和衰老等领域都有意义。
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 indefinitelyin vitro, pluripotency is paradoxically a transient statein 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 cultureex 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 blastocystsin vivoand paused blastocystsex vivodisplay 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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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
23.9
作者：
Nichols, Jennifer;Smith, Austin
通讯作者：
Smith, Austin
囊胚的整体蛋白质组学分析揭示了控制小鼠胚胎滞育和植入重新激活的关键分子机制
影响因子：
3.6
作者：
Fu, Zheng;Wang, Bingyan;Wang, Haibin
通讯作者：
Wang, Haibin
DOI：
10.1007/bf00637187
发表时间：
1991-01-01
期刊：
ROUXS ARCHIVES OF DEVELOPMENTAL BIOLOGY
影响因子：
--
作者：
AZIZ, M;ALEXANDRE, H
通讯作者：
ALEXANDRE, H
影响因子：
9.5
作者：
Lazar, Cosmin;Meganck, Stijn;Nowe, Ann
通讯作者：
Nowe, Ann