Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, MI, USA.
Dev Cell. 2024 Aug 19;59(16):2118-2133.e8. doi: 10.1016/j.devcel.2024.07.008. Epub 2024 Aug 5.
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 (mitoROS) 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 mitoROS 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.
多能胚胎干细胞 (ESCs) 可发育为体内任何细胞类型。然而，胚胎发生过程中控制细胞命运决定的调控机制在很大程度上仍不清楚。我们现在证明，小鼠 ESCs（mESCs）显示出线粒体活性氧（mitoROS）水平的巨大自然变化，使它们的核还原状态、H3K4me3 景观和细胞命运个体化。虽然具有高 mitoROS 水平（mitoROS）的 mESCs 在原肠胚形成期间向中胚层和原始条纹分化，但产生较少 ROS 的 mESCs 选择替代的神经外胚层命运。时间研究表明，mitoROS mESCs 的中胚层（ME）特化是由核还原状态的 Nrf2 控制的开关介导的，该开关由积累的氧化还原敏感的 H3K4me3 标记触发，并通过以前未知的 ROS 依赖的 Wnt 信号通路激活过程执行。总之，我们的研究解释了 ESC 异质性如何被单个细胞产生和利用，以决定不同的细胞命运。
