The cellular complexity and scale of the early liver have constrained analyses examining its emergence during organogenesis. To circumvent these issues, we analyzed 45,334 single-cell transcriptomes from embryonic day (E)7.5, when endoderm progenitors are specified, to E10.5 liver, when liver parenchymal and non-parenchymal cell lineages emerge. Our data detail divergence of vascular and sinusoidal endothelia, including a distinct transcriptional profile for sinusoidal endothelial specification by E8.75. We characterize two distinct mesothelial cell types as well as early hepatic stellate cells and reveal distinct spatiotemporal distributions for these populations. We capture transcriptional profiles for hepatoblast specification and migration, including the emergence of a hepatomesenchymal cell type and evidence for hepatoblast collective cell migration. Further, we identify cell-cell interactions during the organization of the primitive sinusoid. This study provides a comprehensive atlas of liver lineage establishment from the endoderm and mesoderm through to the organization of the primitive sinusoid at single-cell resolution.

早期肝脏的细胞复杂性和规模限制了对其在器官发生过程中出现的分析。为了解决这些问题，我们分析了从胚胎 (E)7.5 天（内胚层祖细胞被指定）到 E10.5 肝脏（肝实质和非实质细胞谱系出现）的 45,334 个单细胞转录组。我们的数据详细说明了血管和正弦内皮细胞的差异，包括 E8.75 的正弦内皮规范的独特转录谱。我们表征了两种不同的间皮细胞类型以及早期肝星状细胞，并揭示了这些群体的不同时空分布。我们捕获肝母细胞规范和迁移的转录谱，包括肝间充质细胞类型的出现和肝母细胞集体细胞迁移的证据。此外，我们还确定了原始正弦波组织过程中细胞与细胞之间的相互作用。这项研究以单细胞分辨率提供了从内胚层和中胚层到原始血窦组织的肝谱系建立的综合图谱。