PDF(Pubmed)
Abstract：
Pluripotent embryonic stem cells (ESCs) can develop into any cell type in the body. Yet, the regulatory mechanisms that govern cell fate decisions during embryogenesis remain largely unknown. We now demonstrate that mouse ESCs (mESCs) display large natural variations in mitochondrial reactive oxygen species (mitoROS) levels that individualize their nuclear redox state, H3K4me3 landscape, and cell fate. While mESCs with high mitoROS levels (mitoROSHIGH) differentiate toward mesendoderm and form the primitive streak during gastrulation, mESCs, which generate less ROS, choose the alternative neuroectodermal fate. Temporal studies demonstrated that mesendodermal (ME) specification of mitoROSHIGH mESCs is mediated by a Nrf2-controlled switch in the nuclear redox state, triggered by the accumulation of redox-sensitive H3K4me3 marks, and executed by a hitherto unknown ROS-dependent activation process of the Wnt signaling pathway. In summary, our study explains how ESC heterogeneity is generated and used by individual cells to decide between distinct cellular fates.
摘要：
多能胚胎干细胞（ESC）可以在体内发育成任何细胞类型。然而，在胚胎发生过程中，控制细胞命运决定的调节机制仍然未知。我们现在证明，小鼠ESCs（mESCs）在线粒体活性氧（mitoROS）水平上表现出很大的自然变化，从而个性化其核氧化还原状态。H3K4me3景观，细胞命运虽然mESCs具有高mitoROS水平（mitoROSHIGH）向中内胚层分化并在原肠胚形成过程中形成原始条纹，mESC,产生较少的ROS，选择替代的神经外胚层命运。时间研究表明，mitoROSHIGHmESCs的中内胚层（ME）规范是由核氧化还原态的Nrf2控制的开关介导的，由氧化还原敏感型H3K4me3标记的积累引发，并通过迄今为止未知的ROS依赖性Wnt信号通路激活过程执行。总之,我们的研究解释了ESC异质性是如何产生的，并被单个细胞用来决定不同的细胞命运。
