Department of Mathematics, The NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, California, United States of America.
Department of Mathematics, University of California, Riverside, Riverside, California, United States of America.
PLoS Comput Biol. 2021 Mar 8;17(3):e1008571. doi: 10.1371/journal.pcbi.1008571. eCollection 2021 Mar.
During early mammalian embryo development, a small number of cells make robust fate decisions at particular spatial locations in a tight time window to form inner cell mass (ICM), and later epiblast (Epi) and primitive endoderm (PE). While recent single-cell transcriptomics data allows scrutinization of heterogeneity of individual cells, consistent spatial and temporal mechanisms the early embryo utilize to robustly form the Epi/PE layers from ICM remain elusive. Here we build a multiscale three-dimensional model for mammalian embryo to recapitulate the observed patterning process from zygote to late blastocyst. By integrating the spatiotemporal information reconstructed from multiple single-cell transcriptomic datasets, the data-informed modeling analysis suggests two major processes critical to the formation of Epi/PE layers: a selective cell-cell adhesion mechanism (via EphA4/EphrinB2) for fate-location coordination and a temporal attenuation mechanism of cell signaling (via Fgf). Spatial imaging data and distinct subsets of single-cell gene expression data are then used to validate the predictions. Together, our study provides a multiscale framework that incorporates single-cell gene expression datasets to analyze gene regulations, cell-cell communications, and physical interactions among cells in complex geometries at single-cell resolution, with direct application to late-stage development of embryogenesis.
在哺乳动物胚胎早期发育过程中，一小部分细胞在特定的空间位置和短暂的时间窗口内做出强有力的命运决定，形成内细胞团（ICM），然后形成上胚层（Epi）和原始内胚层（PE）。尽管最近的单细胞转录组学数据允许对单个细胞的异质性进行仔细研究，但早期胚胎利用一致的时空机制来从 ICM 中强有力地形成 Epi/PE 层的机制仍然难以捉摸。在这里，我们构建了一个多尺度的三维模型，以重现从受精卵到晚期囊胚的观察到的模式形成过程。通过整合来自多个单细胞转录组数据集的时空信息，数据驱动的建模分析表明，有两个主要过程对 Epi/PE 层的形成至关重要：一种是用于命运-位置协调的选择性细胞-细胞粘附机制（通过 EphA4/EphrinB2），另一种是细胞信号传导的时间衰减机制（通过 Fgf）。然后，使用空间成像数据和单细胞基因表达数据的不同子集来验证预测。总之，我们的研究提供了一个多尺度框架，该框架将单细胞基因表达数据集纳入其中，以分析基因调控、细胞间通讯以及在单细胞分辨率下复杂几何形状中的细胞间物理相互作用，可直接应用于胚胎发生的晚期发育。
