Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
Stem Cell Reports. 2023 Jun 13;18(6):1295-1307. doi: 10.1016/j.stemcr.2023.04.008. Epub 2023 May 18.
Signaling is central in cell fate regulation, and relevant information is encoded in its activity over time (i.e., dynamics). However, simultaneous dynamics quantification of several pathways in single mammalian stem cells has not yet been accomplished. Here we generate mouse embryonic stem cell (ESC) lines simultaneously expressing fluorescent reporters for ERK, AKT, and STAT3 signaling activity, which all control pluripotency. We quantify their single-cell dynamics combinations in response to different self-renewal stimuli and find striking heterogeneity for all pathways, some dependent on cell cycle but not pluripotency states, even in ESC populations currently assumed to be highly homogeneous. Pathways are mostly independently regulated, but some context-dependent correlations exist. These quantifications reveal surprising single-cell heterogeneity in the important cell fate control layer of signaling dynamics combinations and raise fundamental questions about the role of signaling in (stem) cell fate control.
信号转导在细胞命运调控中至关重要，相关信息编码在其随时间的活性变化（即动态）中。然而，目前尚未实现对单个哺乳动物干细胞中几种途径的同时动态定量。在这里，我们生成了同时表达 ERK、AKT 和 STAT3 信号活性荧光报告基因的小鼠胚胎干细胞 (ESC) 系，这些基因都控制着多能性。我们定量分析了它们对不同自我更新刺激的单细胞动力学组合，并发现所有途径都存在显著的异质性，其中一些途径依赖于细胞周期而不依赖于多能状态，即使在当前被认为高度均一的 ESC 群体中也是如此。途径大多是独立调控的，但也存在一些依赖于上下文的相关性。这些定量分析揭示了信号转导动力学组合这一重要细胞命运控制层中的惊人单细胞异质性，并提出了关于信号在（干细胞）细胞命运控制中的作用的基本问题。
