Vitamin C and l-Proline Antagonistic Effects Capture Alternative States in the Pluripotency Continuum.
Vitamin C and l-Proline Antagonistic Effects Capture Alternative States in the Pluripotency Continuum.
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DOI：
10.1016/j.stemcr.2016.11.011
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发表时间：
2017-01-10
影响因子：
5.9
通讯作者：
Minchiotti G
中科院分区：
文献类型：
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作者：
D'Aniello C;Habibi E;Cermola F;Paris D;Russo F;Fiorenzano A;Di Napoli G;Melck DJ;Cobellis G;Angelini C;Fico A;Blelloch R;Motta A;Stunnenberg HG;De Cesare D;Patriarca EJ;Minchiotti G
代谢产物和辅因子正在成为细胞可塑性和重编程的关键调节因子，它们在多能性控制中的作用刚刚被发现。在这里，我们提供了前所未有的证据表明，胚胎干细胞（ESC）的多能性依赖于两种生理代谢产物的相对水平，即抗坏血酸（维生素C，VitC）和l-脯氨酸（l-Pro），这影响了全球DNA甲基化，转录谱和能量代谢。具体而言，虽然高VitC/l-Pro比率将ESC推向幼稚状态，但相反的条件（l-Pro过量）捕获完全可逆的早期致敏多能状态，这取决于自分泌成纤维细胞生长因子和转化生长因子β信号传导途径。我们的研究结果强调了代谢物的可用性在控制从幼稚到启动状态的多能性连续体中的关键作用。整体DNA甲基化由ESC中的l-Pro和VitC可用性调节l-Pro和VitC相对水平诱导幼稚和可逆的启动多能性高l-Pro/低VitC水平诱导ESC中的代谢重编程l-Pro诱导并维持ESC中的自分泌FGF和TGF-β信号传导在这篇文章中，Minchiotti，De Cesare及其同事表明，两种生理代谢物，维生素C和l-脯氨酸，将ESC导向幼稚或可逆的多能性启动状态，置于幼稚/2 i和FGF/激活素状态之间，并突出了代谢-表观遗传串扰在发育连续体中的关键作用。
Metabolites and cofactors are emerging as key regulators of cell plasticity and reprogramming, and their role in the control of pluripotency is just being discovered. Here we provide unprecedented evidence that embryonic stem cell (ESC) pluripotency relies on the relative levels of two physiological metabolites, namely ascorbic acid (vitamin C, VitC) and l-proline (l-Pro), which affect global DNA methylation, transcriptional profile, and energy metabolism. Specifically, while a high VitC/l-Pro ratio drives ESCs toward a naive state, the opposite condition (l-Pro excess) captures a fully reversible early primed pluripotent state, which depends on autocrine fibroblast growth factor and transforming growth factor β signaling pathways. Our findings highlight the pivotal role of metabolites availability in controlling the pluripotency continuum from naive to primed states. Global DNA methylation is modulated by l-Pro and VitC availability in ESCs l-Pro and VitC relative levels induce naive and reversible primed pluripotency High l-Pro/low VitC levels induce metabolic reprogramming in ESCs l-Pro induces and sustains autocrine FGF and TGF-β signaling in ESCs In this article, Minchiotti, De Cesare, and colleagues show that the relative levels of two physiological metabolites, vitamin C and l-proline, direct ESCs toward naive or reversible primed states of pluripotency, placed between the naive/2i and FGF/activin states, and highlight a pivotal role of metabolic-epigenetic crosstalk in the developmental continuum.