Single-cell RNA-seq analysis unveils a prevalent epithelial/mesenchymal hybrid state during mouse organogenesis

Background: Organogenesis is crucial for proper organ formation during mammalian embryonic development. However, the similarities and shared features between different organs and the cellular heterogeneity during this process at single-cell resolution remain elusive. Results: We perform single-cell RNA sequencing analysis of 1,916 individual cells from eight organs and tissues of E9.5 to E11.5 mouse embryos, namely, the forebrain, hindbrain, skin, heart, somite, lung, liver, and intestine. Based on the regulatory activities rather than the expression patterns, all cells analyzed can be well classified into four major groups with epithelial, mesodermal, hematopoietic and neuronal identities. For different organs within the same group, the similarities and differences of their features and developmental paths are revealed and reconstructed. Conclusions: We identify mutual interactions between epithelial and mesenchymal cells and detect epithelial cells with prevalent mesenchymal features during organogenesis, which are similar to the features of intermediate epithelial/mesenchymal cells during tumorigenesis. The comprehensive transcriptome at single-cell resolution profiled in our study paves the way for future mechanistic studies of the gene- regulatory networks governing mammalian organogenesis. Here, we performed single-cell RNA sequencing (RNA-Seq) analysis of 1,916 individual cells from eight organs and tissues of E9.5 to E11.5 mouse embryos, including the forebrain, hindbrain, skin, heart, somite, lung, liver, and intestine.研究背景：器官发生（organogenesis）在哺乳动物胚胎发育过程中对于器官的正常形成至关重要。然而，不同器官之间的相似性与共有特征，以及该过程中单细胞分辨率下的细胞异质性，仍尚未得到清晰阐释。 研究结果：我们对胚胎期9.5至11.5天的小鼠胚胎的8种器官与组织中的1916个单个细胞开展了单细胞RNA测序（single-cell RNA sequencing）分析，所涉组织分别为前脑、后脑、皮肤、心脏、体节、肺、肝脏与肠道。本研究基于调控活性而非基因表达模式，可将所有分析细胞精准划分为四大类群，分别具备上皮、中胚层、造血及神经元细胞身份特征。针对同一类群内的不同器官，我们揭示并重构了其特征与发育路径的异同。 研究结论：我们鉴定出上皮细胞与间充质细胞之间的相互调控作用，并检测到器官发生过程中普遍存在具有间充质特征的上皮细胞，该特征与肿瘤发生过程中的上皮/间充质中间态细胞特征相似。本研究获取的单细胞分辨率下的全面转录组数据，为后续解析调控哺乳动物器官发生的基因调控网络的机制研究铺平了道路。在此，我们再次对胚胎期9.5至11.5天的小鼠胚胎的8种器官与组织中的1916个单个细胞进行了单细胞RNA测序（RNA-Seq）分析，所涉组织包括前脑、后脑、皮肤、心脏、体节、肺、肝脏与肠道。