Abstract
Chinese Chronic liver injury leads to progressive liver fibrosis and ultimately cirrhosis, a major cause of morbidity and mortality worldwide. However, there are currently no effective anti-fibrotic therapies available, especially for late-stage patients, which is partly attributed to the major knowledge gap regarding liver cell heterogeneity and cell-specific responses in different fibrosis stages. To reveal the multicellular networks regulating mammalian liver fibrosis from mild to severe phenotypes, we generated a single-nucleus transcriptomic atlas encompassing 49 919 nuclei corresponding to all main liver cell types at different stages of murine carbon tetrachloride (CCl 4)-induced progressive liver fibrosis. Integrative analysis distinguished the sequential responses to injury of hepatocytes, hepatic stellate cells and endothelial cells. Moreover, we reconstructed cell-cell interactions and gene regulatory networks implicated in these processes. These integrative analyses uncovered previously overlooked aspects of hepatocyte proliferation exhaustion and disrupted pericentral metabolic functions, dysfunction for clearance by apoptosis of activated hepatic stellate cells, accumulation of pro-fibrotic signals, and the switch from an anti-angiogenic to a pro-angiogenic program during CCl 4-induced progressive liver fibrosis. Our dataset thus constitutes a useful resource for understanding the molecular basis of progressive liver fibrosis using a relevant animal model. 慢性肝损伤会带来进行性肝纤维化，并最终导致肝硬化，而肝硬化在全球范围内的发病率和死亡率一直居高不下。目前临床上依然缺乏有效治疗肝纤维化的方法，尤其是针对晚期患者。这一现状部分来自于我们对肝脏细胞的异质性以及不同纤维化阶段细胞特异性反应的认知还很有限。为了揭示哺乳动物肝纤维化过程中的多细胞调控网络，我们利用四氯化碳诱导的小鼠肝纤维化模型，构建了包含不同纤维化阶段、囊括所有主要肝脏细胞类型的总计49 919细胞核的单细胞核转录组图谱。整合数据分析首先区分出肝细胞、肝星状细胞和内皮细胞对损伤的相继反应，我们进一步重建了纤维化过程中的细胞间相互作用和基因调控网络。这些分析揭示了一系列以往被忽略的众多方面的变化细节，包括肝细胞增殖能力的耗竭、中心周围肝细胞代谢功能紊乱、肝星状细胞激活后的凋亡清除失调、促纤维化信号的累积以及从抗血管生成向促血管生成的转变。因此，我们的数据为深入理解肝纤维化进程中的分子基础提供了重要参考。.