Single‐cell RNA sequencing reveals the heterogeneity and intercellular communication of hepatic stellate cells and macrophages during liver fibrosis
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
Affiliations
Sheng Cheng
Department of General Surgery Tongren Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
Yunhan Zou
Department of Biochemistry and Molecular Cell Biology Shanghai Key Laboratory for Tumor Microenvironment and Inflammation Shanghai Jiao Tong University School of Medicine Shanghai China
Man Zhang
Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University Shanghai China
Shihao Bai
Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University Shanghai China
Kun Tao
Department of Pathology Tongren Hospital Shanghai Jiaotong University School of Medicine Shanghai China
Jiaoxiang Wu
Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology Hongqiao International Institute of Medicine Tongren Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
Yi Shi
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Bio‐X Institutes Shanghai Jiao Tong University Shanghai China
Yuelan Wu
Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology Hongqiao International Institute of Medicine Tongren Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
Yinzhong Lu
Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology Hongqiao International Institute of Medicine Tongren Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
Kunyan He
Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University Shanghai China
Peng Sun
Department of General Surgery Tongren Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
Xianbin Su
Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University Shanghai China
Shangwei Hou
Department of Anesthesiology Tongren Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
Bo Han
Department of General Surgery Tongren Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
Abstract 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.