肝星状细胞
肌成纤维细胞
纤维化
转录组
癌症研究
生物
细胞生物学
病理
医学
基因表达
内分泌学
基因
生物化学
作者
Wu Yang,Hanqing He,Tongtong Wang,Nan Su,Feng Zhang,Kai Jiang,Jing Zhu,Chonghe Zhang,Kongyan Niu,Luyue Wang,Xiaodong Yuan,Nan Li,Lingjie Li,Wei Wu,Junhao Hu
出处
期刊:Hepatology
[Wiley]
日期:2021-08-21
卷期号:74 (5): 2774-2790
被引量:75
摘要
HSCs and portal fibroblasts (PFs) are the major sources of collagen-producing myofibroblasts during liver fibrosis, depending on different etiologies. However, the mechanisms by which their dynamic gene expression directs the transition from the quiescent to the activated state-as well as their contributions to fibrotic myofibroblasts-remain unclear. Here, we analyze the activation of HSCs and PFs in CCL4 -induced and bile duct ligation-induced fibrosis mouse models, using single-cell RNA sequencing and lineage tracing.We demonstrate that HSCs, rather than PFs, undergo dramatic transcriptomic changes, with the sequential activation of inflammatory, migrative, and extracellular matrix-producing programs. The data also reveal that HSCs are the exclusive source of myofibroblasts in CCL4 -treated liver, while PFs are the major source of myofibroblasts in early cholestatic liver fibrosis. Single-cell and lineage-tracing analysis also uncovers differential gene-expression features between HSCs and PFs; for example, nitric oxide receptor soluble guanylate cyclase is exclusively expressed in HSCs, but not in PFs. The soluble guanylate cyclase stimulator Riociguat potently reduced liver fibrosis in CCL4 -treated livers but showed no therapeutic efficacy in bile duct ligation livers.This study provides a transcriptional roadmap for the activation of HSCs during liver fibrosis and yields comprehensive evidence that the differential transcriptomic features of HSCs and PFs, along with their relative contributions to liver fibrosis of different etiologies, should be considered in developing effective antifibrotic therapeutic strategies.
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