Department of Pathology, Division of Biological Sciences, and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Dev Cell. 2022 Feb 7;57(3):398-414.e5. doi: 10.1016/j.devcel.2022.01.004.
The postnatal development and maturation of the liver, the major metabolic organ, are inadequately understood. We have analyzed 52,834 single-cell transcriptomes and identified 31 cell types or states in mouse livers at postnatal days 1, 3, 7, 21, and 56. We observe unexpectedly high levels of hepatocyte heterogeneity in the developing liver and the progressive construction of the zonated metabolic functions from pericentral to periportal hepatocytes, which is orchestrated with the development of sinusoid endothelial, stellate, and Kupffer cells. Trajectory and gene regulatory analyses capture 36 transcription factors, including a circadian regulator, Bhlhe40, in programming liver development. Remarkably, we identified a special group of macrophages enriched at day 7 with a hybrid phenotype of macrophages and endothelial cells, which may regulate sinusoidal construction and Treg-cell function. This study provides a comprehensive atlas that covers all hepatic cell types and is instrumental for further dissection of liver development, metabolism, and disease.
肝脏作为主要的代谢器官，其产后发育和成熟尚未得到充分理解。我们分析了 52834 个单细胞转录组，鉴定了出生后第 1、3、7、21 和 56 天的小鼠肝脏中的 31 种细胞类型或状态。我们观察到发育中的肝脏中肝细胞的异质性水平出乎意料地高，并且从中央静脉周围的肝细胞到门周的肝细胞逐渐构建了具有分区代谢功能的结构，这与窦状内皮细胞、星状细胞和库普弗细胞的发育相协调。轨迹和基因调控分析捕获了 36 种转录因子，包括生物钟调节因子 Bhlhe40，它们参与了肝脏发育的编程。值得注意的是，我们在第 7 天发现了一群富含具有巨噬细胞和内皮细胞混合表型的特殊巨噬细胞，它们可能调节窦状结构和 Treg 细胞功能。本研究提供了一个全面的图谱，涵盖了所有的肝细胞类型，对于进一步解析肝脏发育、代谢和疾病具有重要作用。
