State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Omics Core, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Cell. 2020 Mar 19;180(6):1198-1211.e19. doi: 10.1016/j.cell.2020.02.048.
It has generally proven challenging to produce functional β cells in vitro. Here, we describe a previously unidentified protein C receptor positive (Procr) cell population in adult mouse pancreas through single-cell RNA sequencing (scRNA-seq). The cells reside in islets, do not express differentiation markers, and feature epithelial-to-mesenchymal transition characteristics. By genetic lineage tracing, Procr islet cells undergo clonal expansion and generate all four endocrine cell types during adult homeostasis. Sorted Procr cells, representing ∼1% of islet cells, can robustly form islet-like organoids when cultured at clonal density. Exponential expansion can be maintained over long periods by serial passaging, while differentiation can be induced at any time point in culture. β cells dominate in differentiated islet organoids, while α, δ, and PP cells occur at lower frequencies. The organoids are glucose-responsive and insulin-secreting. Upon transplantation in diabetic mice, these organoids reverse disease. These findings demonstrate that the adult mouse pancreatic islet contains a population of Procr endocrine progenitors.
在体外产生功能性β细胞一直具有挑战性。在这里，我们通过单细胞 RNA 测序（scRNA-seq）描述了成年小鼠胰腺中以前未被识别的蛋白 C 受体阳性（Procr）细胞群。这些细胞存在于胰岛中，不表达分化标志物，具有上皮-间充质转化特征。通过遗传谱系追踪，Procr 胰岛细胞在成年期稳态时经历克隆扩增并产生所有四种内分泌细胞类型。当以克隆密度培养时，分选的 Procr 细胞（代表胰岛细胞的约 1%）可以强有力地形成胰岛样类器官。通过连续传代可以长期维持指数扩增，而在培养的任何时间点都可以诱导分化。β细胞在分化的胰岛类器官中占主导地位，而α、δ 和 PP 细胞的频率较低。这些类器官对葡萄糖有反应且能分泌胰岛素。在糖尿病小鼠中移植这些类器官可逆转疾病。这些发现表明，成年小鼠胰腺胰岛中存在 Procr 内分泌祖细胞群。
