Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge, UK.
Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
Cell Stem Cell. 2019 Sep 5;25(3):388-406.e8. doi: 10.1016/j.stem.2019.07.009. Epub 2019 Aug 15.
Understanding how cell identity transitions occur and whether there are multiple paths between the same beginning and end states are questions of wide interest. Here we show that acquisition of naive pluripotency can follow transcriptionally and mechanistically distinct routes. Starting from post-implantation epiblast stem cells (EpiSCs), one route advances through a mesodermal state prior to naive pluripotency induction, whereas another transiently resembles the early inner cell mass and correspondingly gains greater developmental potency. These routes utilize distinct signaling networks and transcription factors but subsequently converge on the same naive endpoint, showing surprising flexibility in mechanisms underlying identity transitions and suggesting that naive pluripotency is a multidimensional attractor state. These route differences are reconciled by precise expression of Oct4 as a unifying, essential, and sufficient feature. We propose that fine-tuned regulation of this "transition factor" underpins multidimensional access to naive pluripotency, offering a conceptual framework for understanding cell identity transitions.
了解细胞身份转变是如何发生的，以及相同的起点和终点状态之间是否存在多种路径，这是一个广泛关注的问题。在这里，我们表明，获得原始多能性可以通过转录和机制上不同的途径来实现。从着床后胚胎外胚层干细胞（EpiSCs）开始，一条途径在诱导原始多能性之前先通过中胚层状态，而另一条途径则短暂地类似于早期内细胞团，并相应地获得更大的发育潜能。这些途径利用不同的信号网络和转录因子，但随后都汇聚到相同的原始终点，这表明在身份转变的机制中存在惊人的灵活性，并表明原始多能性是一个多维吸引态。这些途径差异通过 Oct4 的精确表达得到调和，Oct4 是一个统一的、必不可少的和充分的特征。我们提出，对这个“过渡因子”的精细调控为多维进入原始多能性提供了基础，为理解细胞身份转变提供了一个概念框架。
