Optimal-Transport Analysis of Single-Cell Gene Expression Identifies Developmental Trajectories in Reprogramming
Optimal-Transport Analysis of Single-Cell Gene Expression Identifies Developmental Trajectories in Reprogramming
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DOI：
10.1016/j.cell.2019.01.006
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发表时间：
2019-02-07
期刊：
影响因子：
64.5
通讯作者：
Lander, Eric S.
中科院分区：
文献类型：
--
作者：
Schiebinger, Geoffrey;Shu, Jian;Lander, Eric S.
理解在发育过程中指导分化的分子程序是一项重大挑战。在此，我们引入Waddington - OT，这是一种研究发育时间进程的方法，用于推断祖先 - 后代的命运，并对其背后的调控程序进行建模。我们应用该方法从315,000个单细胞RNA测序（scRNA - seq）图谱中重建重编程的全貌，这些图谱是在18天内每隔半天收集一次的。结果显示出比以往所描述的更广泛的发育程序。细胞逐渐呈现出终末基质状态或间充质 - 上皮转化状态。后者产生与多能性、胚外和神经细胞相关的细胞群，每个细胞群都包含多个更精细的亚群。分析预测了影响命运的转录因子和旁分泌信号，并且实验验证了转录因子Obox6和细胞因子GDF9可提高重编程效率。我们的方法阐明了重编程的过程和结果，并提供了一个适用于生物学中各种时间进程的框架。
Understanding the molecular programs that guide differentiation during development is a major challenge. Here, we introduce Waddington-OT, an approach for studying developmental time courses to infer ancestor-descendant fates and model the regulatory programs that underlie them. We apply the method to reconstruct the landscape of reprogramming from 315,000 single-cell RNA sequencing (scRNA-seq) profiles, collected at half-day intervals across 18 days. The results reveal a wider range of developmental programs than previously characterized. Cells gradually adopt either a terminal stromal state or a nnesenchymal-to-epithelial transition state. The latter gives rise to populations related to pluripotent, extra-embryonic, and neural cells, with each harboring multiple finer subpopulations. The analysis predicts transcription factors and paracrine signals that affect fates and experiments validate that the TF Obox6 and the cytokine GDF9 enhance reprogramming efficiency. Our approach sheds light on the process and outcome of reprogramming and provides a framework applicable to diverse temporal processes in biology.