Transcriptional Dynamics of Hepatic Sinusoid-Associated Cells After Liver Injury.
Transcriptional Dynamics of Hepatic Sinusoid-Associated Cells After Liver Injury.
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DOI：
10.1002/hep.31215
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Ravnskjaer K
中科院分区：
文献类型：
--
作者：
Terkelsen MK;Bendixen SM;Hansen D;Scott EAH;Moeller AF;Nielsen R;Mandrup S;Schlosser A;Andersen TL;Sorensen GL;Krag A;Natarajan KN;Detlefsen S;Dimke H;Ravnskjaer K
肝窦细胞是已知的对损伤的纤维化反应的参与者。激活的肝星状细胞（HSC）、肝窦内皮细胞和枯否细胞负责窦毛细血管化和窦周基质沉积，损害血管交换并增加晚期纤维化的风险。虽然整体发病机制是很好的理解，纤维化过程中细胞转换之间的功能关系才刚刚开始得到解决。在单细胞分辨率下，我们在这里探索了单个细胞类型的异质性，并剖析了它们在纤维发生过程中的转变和串扰。我们应用单细胞转录组学来绘制健康和损伤肝脏中窦状隙相关细胞的异质性，并重建了从周细胞到肌成纤维细胞的单系HSC轨迹。通过激活状态对每个正弦细胞群进行分层，我们预测了损伤后正弦通信的变化。对HSC轨迹的加权基因相关网络分析鉴定了核心基因，其表达被证明高度预测非酒精性脂肪性肝炎（NASH）患者的晚期纤维化。在损伤抑制基因模块的核心成员中，我们鉴定出质膜囊泡相关蛋白（PLVAP）是一种在小鼠和人HSC中大量表达的蛋白质。PLVAP表达在损伤后活化的HSC中受到抑制，因此可能定义HSC在调节微循环交换及其在慢性肝病中的分解中迄今未知的作用。我们的研究提供了哺乳动物肝脏药物诱导损伤的单细胞解析，并确定了可能在窦完整性中发挥重要作用的关键基因，以及作为人类NASH晚期纤维化的标志物。
Hepatic sinusoidal cells are known actors in the fibrogenic response to injury. Activated hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and Kupffer cells are responsible for sinusoidal capillarization and perisinusoidal matrix deposition, impairing vascular exchange and heightening the risk of advanced fibrosis. While the overall pathogenesis is well understood, functional relations between cellular transitions during fibrogenesis are only beginning to be resolved. At single‐cell resolution, we here explored the heterogeneity of individual cell types and dissected their transitions and crosstalk during fibrogenesis. We applied single‐cell transcriptomics to map the heterogeneity of sinusoid‐associated cells in healthy and injured livers and reconstructed the single‐lineage HSC trajectory from pericyte to myofibroblast. Stratifying each sinusoidal cell population by activation state, we projected shifts in sinusoidal communication upon injury. Weighted gene correlation network analysis of the HSC trajectory led to the identification of core genes whose expression proved highly predictive of advanced fibrosis in patients with nonalcoholic steatohepatitis (NASH). Among the core members of the injury‐repressed gene module, we identified plasmalemma vesicle–associated protein (PLVAP) as a protein amply expressed by mouse and human HSCs. PLVAP expression was suppressed in activated HSCs upon injury and may hence define hitherto unknown roles for HSCs in the regulation of microcirculatory exchange and its breakdown in chronic liver disease. Our study offers a single‐cell resolved account of drug‐induced injury of the mammalian liver and identifies key genes that may serve important roles in sinusoidal integrity and as markers of advanced fibrosis in human NASH.
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影响因子：
25.7
作者：
Marrone G;Shah VH;Gracia-Sancho J
通讯作者：
Gracia-Sancho J
影响因子：
3.7
作者：
Herrnberger L;Hennig R;Kremer W;Hellerbrand C;Goepferich A;Kalbitzer HR;Tamm ER
通讯作者：
Tamm ER
影响因子：
6
作者：
Krenkel, Oliver;Hundertmark, Jana;Tacke, Frank
通讯作者：
Tacke, Frank
影响因子：
4.1
作者：
Elsheikh, Elzafir;Younoszai, Zahra;Younossi, Zobair M.
通讯作者：
Younossi, Zobair M.
影响因子：
15.9
作者：
Geraud, Cyrill;Koch, Philipp-Sebastian;Goerdt, Sergij
通讯作者：
Goerdt, Sergij