Department of Molecular Biology and Scripps Center for Mass Spectrometry, The Scripps Research Institute, La Jolla, California, USA.
Nat Chem Biol. 2010 Jun;6(6):411-7. doi: 10.1038/nchembio.364. Epub 2010 May 2.
Metabolites offer an important unexplored complementary approach to understanding the pluripotency of stem cells. Using MS-based metabolomics, we show that embryonic stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. By monitoring the reduced and oxidized glutathione ratio as well as ascorbic acid levels, we demonstrate that the stem cell redox status is regulated during differentiation. On the basis of the oxidative biochemistry of the unsaturated metabolites, we experimentally manipulated specific pathways in embryonic stem cells while monitoring the effects on differentiation. Inhibition of the eicosanoid signaling pathway promoted pluripotency and maintained levels of unsaturated fatty acids. In contrast, downstream oxidized metabolites (for example, neuroprotectin D1) and substrates of pro-oxidative reactions (for example, acyl-carnitines), promoted neuronal and cardiac differentiation. We postulate that the highly unsaturated metabolome sustained by stem cells allows them to differentiate in response to in vivo oxidative processes such as inflammation.
代谢物为理解干细胞的多能性提供了一种重要的、尚未开发的补充方法。我们使用基于 MS 的代谢组学方法表明,胚胎干细胞的特征是具有高度不饱和结构的丰富代谢物,其水平在分化时降低。通过监测还原型和氧化型谷胱甘肽的比例以及抗坏血酸水平,我们证明了干细胞的氧化还原状态在分化过程中受到调节。基于不饱和代谢物的氧化生物化学,我们在监测对分化影响的同时,在胚胎干细胞中实验性地操纵特定途径。抑制类二十烷酸信号通路可促进多能性并维持不饱和脂肪酸的水平。相比之下,下游氧化代谢物(例如神经保护素 D1)和促氧化反应的底物(例如酰基辅酶 A)促进神经元和心脏分化。我们假设,由干细胞维持的高度不饱和代谢组使它们能够响应体内氧化过程(如炎症)进行分化。