【原】α-酮戊二酸加速启动的人多能干细胞的初始分化

α-Ketoglutarate Accelerates the Initial Differentiation of Primed Human Pluripotent Stem Cell

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|核心内容：

多能干细胞(PSCs)可以从特定培养条件下建立的原始或更多分化、启动、多潜能状态自我更新或分化。

细胞内α-酮戊二酸(α-KG)浓度的增加有利于幼鼠胚胎干细胞(MESCs)的自我更新。

αKG或αKG/琥珀酸水平对人PSCs和小鼠上皮干细胞分化的影响尚不清楚。

我们检测了启动的hPSCs和EpiSCs，发现αKG或αKG/琥珀酸比值的增加加速，而琥珀酸水平的升高延迟了启动的PSC的分化。

αKG已被证明可以抑制线粒体ATP合成酶，并调节表观基因组修饰的双加氧酶。

线粒体解偶联不妨碍αKG加速启动的PSC分化。

取而代之的是，αKG诱导和琥珀酸化受损的PSCs的整体组蛋白和脱氧核糖核酸去甲基化。

这些数据支持αKG促进自我更新或分化，取决于多能性状态。

原文摘要：

Pluripotent stem cells (PSCs) can self-renew or differentiate from naive or more differentiated, primed, pluripotent states established by specific culture conditions. Increased intracellular α-ketoglutarate (αKG) was shown to favor self-renewal in naive mouse embryonic stem cells (mESCs). The effect of αKG or αKG/succinate levels on differentiation from primed human PSCs (hPSCs) or mouse epiblast stem cells (EpiSCs) remains unknown. We examined primed hPSCs and EpiSCs and show that increased αKG or αKG-to-succinate ratios accelerate, and elevated succinate levels delay, primed PSC differentiation. αKG has been shown to inhibit the mitochondrial ATP synthase and to regulate epigenome-modifying dioxygenase enzymes. Mitochondrial uncoupling did not impede αKG-accelerated primed PSC differentiation. Instead, αKG induced, and succinate impaired, global histone and DNA demethylation in primed PSCs. The data support αKG promotion of self-renewal or differentiation depending on the pluripotent state.

#αKG就像一个催化加速剂，naive细胞就像在原地转圈圈，αKG只能让细胞原地转得更快，可以巩固保持原地不动的状态。但是primed细胞已经做出命运决定，αKG当然会加速该决定。

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参考文献：http:///backend/ptpmcrender.fcgi?accid=PMC5023506&blobtype=pdf

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