单细胞RNA测序揭示了肝纤维化过程中肝星状细胞和巨噬细胞的异质性和细胞间通讯。
Single-cell RNA sequencing reveals the heterogeneity and intercellular communication of hepatic stellate cells and macrophages during liver fibrosis.
发表日期：2023 Oct
作者：
Sheng Cheng, Yunhan Zou, Man Zhang, Shihao Bai, Kun Tao, Jiaoxiang Wu, Yi Shi, Yuelan Wu, Yinzhong Lu, Kunyan He, Peng Sun, Xianbin Su, Shangwei Hou, Bo Han
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
肝纤维化的失控和过度进展被认为是肝硬化和肝细胞癌的主要病理生理原因，目前尚无有效的抗纤维化治疗选择。肝细胞间通讯和细胞异质性参与了肝纤维化的进展，但细胞表型改变和相互调节的准确特性尚不清楚。在本研究中，我们对从正常和纤维化小鼠肝脏中分离的非实质细胞（NPC）进行了单细胞RNA测序。我们鉴定出八种主要细胞类型，包括内皮细胞、肝细胞、树突状细胞、B细胞、自然杀伤/ T细胞、肝星状细胞（HSCs）、胆管细胞和巨噬细胞，并揭示了巨噬细胞和HSCs在转录谱中的最大变异。对HSCs和巨噬细胞亚群及其配体-受体相互作用的进一步分析揭示了这两组细胞在肝纤维化中的高异质性特征和严密的调控网络。最后，我们发现了一个促纤维化的Thbs1+巨噬细胞亚群，在小鼠和人类纤维化肝中扩增，通过PI3K/AKT/mTOR信号通路激活HSCs。我们的研究结果解码了HSCs和巨噬细胞在单细胞水平上的异质性及其细胞间相互作用，可能为肝纤维化的潜在治疗策略提供了新的见解。
© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.
Uncontrolled and excessive progression of liver fibrosis is thought to be the prevalent pathophysiological cause of liver cirrhosis and hepatocellular cancer, and there are currently no effective antifibrotic therapeutic options available. Intercellular communication and cellular heterogeneity in the liver are involved in the progression of liver fibrosis, but the exact nature of the cellular phenotypic changes and patterns of interregulatory remain unclear. Here, we performed single-cell RNA sequencing on nonparenchymal cells (NPCs) isolated from normal and fibrotic mouse livers. We identified eight main types of cells, including endothelial cells, hepatocytes, dendritic cells, B cells, natural killer/T (NK/T) cells, hepatic stellate cells (HSCs), cholangiocytes and macrophages, and revealed that macrophages and HSCs exhibit the most variance in transcriptional profile. Further analyses of HSCs and macrophage subpopulations and ligand-receptor interaction revealed a high heterogeneity characterization and tightly interregulated network of these two groups of cells in liver fibrosis. Finally, we uncovered a profibrotic Thbs1+ macrophage subcluster, which expands in mouse and human fibrotic livers, activating HSCs via PI3K/AKT/mTOR signaling pathway. Our findings decode unanticipated insights into the heterogeneity of HSCs and macrophages and their intercellular crosstalk at a single-cell level, and may provide potential therapeutic strategies in liver fibrosis.© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.