Phospholipid remodeling is critical for stem cell pluripotency by facilitating mesenchymal-to-epithelial transition
Phospholipid remodeling is critical for stem cell pluripotency by facilitating mesenchymal-to-epithelial transition
复制标题
磷脂重塑通过促进间充质到上皮的转变对于干细胞多能性至关重要
DOI：
10.1126/sciadv.aax7525
复制
发表时间：
2019-11-01
期刊：
影响因子：
13.6
通讯作者：
Liu, Xingguo
中科院分区：
文献类型：
--
作者：
Wu, Yi;Chen, Keshi;Liu, Xingguo
代谢重编程已经成为细胞命运决定的关键调节器。葡萄糖和氨基酸代谢的作用已被广泛记录，而多能性中的脂质代谢在很大程度上仍未被探索。使用高覆盖率的脂质组学方法，我们揭示了在重编程过程中发生的磷脂的动态变化，并表明在重编程的早期阶段需要用于磷脂酰乙醇胺（PE）合成的CDP-乙醇胺（CDP-Etn）途径。从机制上讲，CDP-Etn途径以Pebp 1依赖性方式抑制NF-κ B信号传导和间充质基因，而不影响自噬，从而加速间充质向上皮转化（MET）并增强重编程。此外，PE与Pebp 1的结合增强了Pebp 1与IKK α/β的相互作用，并降低了IKK α/β的磷酸化。CDP-Etn-Pebp 1轴与肝细胞分化中的EMT/MET相关，表明Etn/PE是广谱MET/EMT调节代谢物。总的来说，我们的研究揭示了磷脂，细胞迁移和多能性之间不可预见的联系，并强调了磷脂在细胞命运转变中的重要性。
Metabolic reprogramming has emerged as a key regulator of cell fate decisions. Roles of glucose and amino acid metabolism have been extensively documented, whereas lipid metabolism in pluripotency remains largely unexplored. Using a high-coverage lipidomics approach, we reveal dynamic changes in phospholipids occurring during reprogramming and show that the CDP-ethanolamine (CDP-Etn) pathway for phosphatidylethanolamine (PE) synthesis is required at the early stage of reprogramming. Mechanistically, the CDP-Etn pathway inhibits NF-kappa B signaling and mesenchymal genes in a Pebp1-dependent manner, without affecting autophagy, resulting in accelerated mesenchymal-to-epithelial transition (MET) and enhanced reprogramming. Furthermore, PE binding to Pebp1 enhances the interaction of Pebp1 with IKK alpha/beta and reduces the phosphorylation of IKK alpha/beta. The CDP-Etn-Pebp1 axis is associated with EMT/MET in hepatocyte differentiation, indicating that Etn/PE is a broad-spectrum MET/EMT-regulating metabolite. Collectively, our study reveals an unforeseen connection between phospholipids, cell migration, and pluripotency and highlights the importance of phospholipids in cell fate transitions.