α-Ketoglutarate Accelerates the Initial Differentiation of Primed Human Pluripotent Stem Cells.
α-Ketoglutarate Accelerates the Initial Differentiation of Primed Human Pluripotent Stem Cells.
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DOI：
10.1016/j.cmet.2016.07.002
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发表时间：
2016-09-13
期刊：
影响因子：
29
通讯作者：
Teitell MA
中科院分区：
文献类型：
--
作者：
TeSlaa T;Chaikovsky AC;Lipchina I;Escobar SL;Hochedlinger K;Huang J;Graeber TG;Braas D;Teitell MA
多能干细胞（PSC）可以自我更新或从幼稚或通过特定培养条件建立的更分化、引发的多能状态分化。细胞内α-酮戊二酸（αKG）的增加有利于幼稚小鼠胚胎干细胞（mESC）的自我更新。αKG或αKG/琥珀酸水平对从致敏的人PSC（hPSC）或小鼠上胚层干细胞（EpiSC）分化的影响仍然未知。我们检查了引发的hPSC和EpiSC，并显示增加的αKG或αKG/琥珀酸盐比率加速引发的PSC分化，并且升高的琥珀酸盐水平延迟引发的PSC分化。已证明αKG抑制线粒体ATP合酶并调节表观基因组修饰双加氧酶。线粒体解偶联并不阻碍α KG加速的引发PSC分化。相反，αKG诱导，琥珀酸受损，整体组蛋白和DNA去甲基化在引发的PSC。数据支持αKG促进自我更新或分化，这取决于多能状态。α-酮戊二酸（αKG）是去甲基化反应的重要辅助因子，有助于维持幼稚多能干细胞。TeSlaa等人表明，在多能性的后期阶段，αKG可以促进早期分化，强调细胞环境和潜在的细胞成熟阶段可以改变αKG的作用。
Pluripotent stem cells (PSCs) can self-renew or differentiate from naïve or more differentiated, primed, pluripotent states established by specific culture conditions. Increased intracellular α-ketoglutarate (αKG) was shown to favor self-renewal in naïve 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/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. α-ketoglutarate (αKG) is an important cofactor for demethylation reactions that helps to maintain naive pluripotent stem cells. TeSlaa et al. show that at later stages of pluripotency, αKG can promote early differentiation, highlighting that the cellular context and potentially the stage of cellular maturity can alter the effect of αKG.
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影响因子：
16.8
作者：
Leitch, Harry G.;McEwen, Kirsten R.;Turp, Aleksandra;Encheva, Vesela;Carroll, Tom;Grabole, Nils;Mansfield, William;Nashun, Buhe;Knezovich, Jaysen G.;Smith, Austin;Surani, M. Azim;Hajkova, Petra
通讯作者：
Hajkova, Petra
影响因子：
64.5
作者：
Kaelin WG Jr;McKnight SL
通讯作者：
McKnight SL
DOI：
10.1126/science.1226603
发表时间：
2013-01-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Shyh-Chang N;Locasale JW;Lyssiotis CA;Zheng Y;Teo RY;Ratanasirintrawoot S;Zhang J;Onder T;Unternaehrer JJ;Zhu H;Asara JM;Daley GQ;Cantley LC
通讯作者：
Cantley LC
影响因子：
29
作者：
Thai M;Graham NA;Braas D;Nehil M;Komisopoulou E;Kurdistani SK;McCormick F;Graeber TG;Christofk HR
通讯作者：
Christofk HR
影响因子：
56.9
作者：
Thomson, JA;Itskovitz-Eldor, J;Jones, JM
通讯作者：
Jones, JM