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Metabolic characterization of a paused-like pluripotent state.
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2020-04-06 , DOI: 10.1016/j.bbagen.2020.129612
Maria Inês Sousa 1 , Bibiana Correia 2 , Ana Sofia Rodrigues 2 , João Ramalho-Santos 1
Affiliation  

Embryonic diapause is a conserved reproductive strategy in which development arrests at the blastocyst phase. Recently mammalian target of rapamycin (mTOR) inhibition was shown to induce diapause on mouse blastocysts and a paused-like state on mouse embryonic stem cells (mESCs). In this work, we aimed to further characterize this new paused-pluripotent state, focusing on its glycolytic and oxidative metabolic function. We therefore exposed mESCs, to the mTOR inhibitor INK-128 and evaluated proliferation, pluripotency status and energy-related metabolism, as well as the mTOR inhibition status and translational function. Unexpectedly, in our hands INK-128 did not inhibit the phosphorylation of mTOR or its downstream targets after 48 h. Accordingly, no alterations on protein translational function were observed. Nonetheless, INK-128 could still successfully induce a paused-like state in naïve mESCs regardless of their culturing conditions, by greatly slowing proliferation without affecting pluripotency status. This effect was more prevalent in 2i cultured cells. Interestingly, in this paused-like state, mESCs present a glucose-related hypometabolic profile, which is a hallmark of diapaused blastocysts, with decreased glycolytic and oxidative metabolism and decreased nutrient uptake. Despite the lack of mTOR inhibition and translational suppression, INK-128 still induced a paused-like pluripotent state through cell cycle and metabolic modulation, rather than by translational suppression, suggesting more than one avenue for this type of pluripotent phenotype.

中文翻译:

暂停样多能状态的代谢表征。

胚胎滞育是一种保守的生殖策略,其中发育在囊胚期停止。最近,哺乳动物的雷帕霉素靶蛋白 (mTOR) 抑制被证明可诱导小鼠胚泡滞育和小鼠胚胎干细胞 (mESCs) 的暂停样状态。在这项工作中,我们旨在进一步表征这种新的暂停多能状态,重点关注其糖酵解和氧化代谢功能。因此,我们将 mESCs 暴露于 mTOR 抑制剂 INK-128 并评估增殖、多能性状态和能量相关代谢,以及 mTOR 抑制状态和翻译功能。出乎意料的是,在我们手中,INK-128 在 48 小时后并没有抑制 mTOR 或其下游靶标的磷酸化。因此,没有观察到蛋白质翻译功能的改变。尽管如此,无论培养条件如何,INK-128 仍然可以通过在不影响多能性状态的情况下大大减缓增殖,成功地诱导幼稚 mESCs 中的暂停状态。这种效应在 2i 培养的细胞中更为普遍。有趣的是,在这种暂停状态下,mESCs 呈现出与葡萄糖相关的低代谢特征,这是滞育囊胚的标志,糖酵解和氧化代谢减少,营养吸收减少。尽管缺乏 mTOR 抑制和翻译抑制,INK-128 仍然通过细胞周期和代谢调节而不是通过翻译抑制诱导暂停样多能状态,这表明这种类型的多能表型不止一种途径。通过大大减缓增殖而不影响多能性状态。这种效应在 2i 培养的细胞中更为普遍。有趣的是,在这种暂停状态下,mESCs 呈现出与葡萄糖相关的低代谢特征,这是滞育囊胚的标志,糖酵解和氧化代谢减少,营养吸收减少。尽管缺乏 mTOR 抑制和翻译抑制,INK-128 仍然通过细胞周期和代谢调节而不是通过翻译抑制诱导暂停样多能状态,这表明这种类型的多能表型不止一种途径。通过大大减缓增殖而不影响多能性状态。这种效应在 2i 培养的细胞中更为普遍。有趣的是,在这种暂停状态下,mESCs 呈现出与葡萄糖相关的低代谢特征,这是滞育囊胚的标志,糖酵解和氧化代谢减少,营养吸收减少。尽管缺乏 mTOR 抑制和翻译抑制,INK-128 仍然通过细胞周期和代谢调节而不是通过翻译抑制诱导暂停样多能状态,这表明这种类型的多能表型不止一种途径。这是滞育囊胚的标志,糖酵解和氧化代谢减少,营养吸收减少。尽管缺乏 mTOR 抑制和翻译抑制,INK-128 仍然通过细胞周期和代谢调节而不是通过翻译抑制诱导暂停样多能状态,这表明这种类型的多能表型不止一种途径。这是滞育囊胚的标志,糖酵解和氧化代谢减少,营养吸收减少。尽管缺乏 mTOR 抑制和翻译抑制,INK-128 仍然通过细胞周期和代谢调节而不是通过翻译抑制诱导暂停样多能状态,这表明这种类型的多能表型不止一种途径。
更新日期:2020-04-20
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