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Single Cell Analysis Reveals the Stochastic Phase of Reprogramming to Pluripotency Is an Ordered Probabilistic Process

机译：单细胞分析揭示了重编程为多能性的随机阶段是一个有序的概率过程

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Despite years of research, the reprogramming of human somatic cells to pluripotency remains a slow, inefficient process, and a detailed mechanistic understanding of reprogramming remains elusive. Current models suggest reprogramming to pluripotency occurs in two-phases: a prolonged stochastic phase followed by a rapid deterministic phase. In this paradigm, the early stochastic phase is marked by the random and gradual expression of pluripotency genes and is thought to be a major rate-limiting step in the successful generation of induced Pluripotent Stem Cells (iPSCs). Recent evidence suggests that the epigenetic landscape of the somatic cell is gradually reset during a period known as the stochastic phase, but it is known neither how this occurs nor what rate-limiting steps control progress through the stochastic phase. A precise understanding of gene expression dynamics in the stochastic phase is required in order to answer these questions. Moreover, a precise model of this complex process will enable the measurement and mechanistic dissection of treatments that enhance the rate or efficiency of reprogramming to pluripotency. Here we use single-cell transcript profiling, FACS and mathematical modeling to show that the stochastic phase is an ordered probabilistic process with independent gene-specific dynamics. We also show that partially reprogrammed cells infected with OSKM follow two trajectories: a productive trajectory toward increasingly ESC-like expression profiles or an alternative trajectory leading away from both the fibroblast and ESC state. These two pathways are distinguished by the coordinated expression of a small group of chromatin modifiers in the productive trajectory, supporting the notion that chromatin remodeling is essential for successful reprogramming. These are the first results to show that the stochastic phase of reprogramming in human fibroblasts is an ordered, probabilistic process with gene-specific dynamics and to provide a precise mathematical framework describing the dynamics of pluripotency gene expression during reprogramming by OSKM.
机译：尽管进行了多年的研究，但是将人类体细胞重编程为多能性仍然是一个缓慢，低效的过程，并且对重编程的详细机械理解仍然难以捉摸。当前模型表明，重编程到多能性的过程分为两个阶段：长时间的随机阶段，然后是快速的确定性阶段。在这种范式中，早期随机阶段的特征是多能性基因的随机和逐步表达，被认为是成功诱导多能干细胞（iPSC）产生的主要限速步骤。最近的证据表明，在称为随机阶段的过程中，体细胞的表观遗传格局逐渐复位，但是既不知道这种情况如何发生，也不知道有什么限速步骤控制整个随机阶段的进展。为了回答这些问题，需要对随机阶段的基因表达动态有一个精确的了解。此外，这个复杂过程的精确模型将能够对治疗进行测量和机械解剖，从而提高重编程为多能性的速度或效率。在这里，我们使用单细胞转录谱分析，FACS和数学建模来表明随机阶段是一个有序的概率过程，具有独立的基因特异性动力学。我们还显示，感染OSKM的部分重编程细胞遵循两个轨迹：朝向越来越像ESC的表达谱的生产轨迹，或者远离成纤维细胞和ESC状态的替代轨迹。这两个途径的区别在于生产轨迹中一小群染色质修饰剂的协同表达，支持了染色质重塑对于成功重编程至关重要的观点。这些是第一个显示人类成纤维细胞重编程的随机阶段是有序的，具有基因特异性动态的概率过程，并提供了一个精确的数学框架来描述OSKM重编程过程中多能性基因表达动态的第一个结果。

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