首页|Cell atlas of CCl4-induced progressive liver fibrosis reveals stage-specific responses

Cell atlas of CCl4-induced progressive liver fibrosis reveals stage-specific responses

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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(CCl4)-induced progressive liver fibrosis.Integrative analysis distinguished the sequential responses to injury of hepatocytes,hepatic stellate cells and endothelial cells.Moreover,we reconstructed the 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 CCl4-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.

Liver fibrosisToxicitySingle-cell and single-nucleus RNA-sequencingHepatocytesHepatic stellate cellsAngiogenesisCell-cell interactionsGene regulatory networks

Peng-Cheng Guo、Jing Zuo、Ke-Ke Huang、Guang-Yao Lai、Xiao Zhang、Juan An、Jin-Xiu Li、Li Li、Liang Wu、Yi-Ting Lin、Dong-Ye Wang、Jiang-Shan Xu、Shi-Jie Hao、Yang Wang、Rong-Hai Li、Wen Ma、Yu-Mo Song、Chang Liu、Chuan-Yu Liu、Zhen Dai、Yan Xu、Amar Deep Sharma、Michael Ott、Qing Ou-Yang、Feng Huo、Rong Fan、Yong-Yin Li、Jin-Lin Hou、Giacomo Volpe、Long-Qi Liu、Miguel A.Esteban、Yi-Wei Lai

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State Key Laboratory for Zoonotic Diseases,Key Laboratory for Zoonosis Research of Ministry of Education,Institute of Zoonosis,College of Veterinary Medicine,Jilin University,Changchun,Jilin 130062,China

BGI-Hangzhou,Hangzhou,Zhejiang 310012,China

BGI-Shenzhen,Shenzhen,Guangdong 518083,China

Key Laboratory of Biological Targeting Diagnosis,Therapy and Rehabilitation of Guangdong Higher Education Institutes,Fifth Affiliated Hospital of Guangzhou Medical University,Guangzhou,Guangdong 510799,China

Laboratory of Integrative Biology,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou,Guangdong 510530,China

Joint School of Life Sciences,Guangzhou Institutes of Biomedicine and Health and Guangzhou Medical University,Guangzhou,Guangdong 510530,China

School of Life Sciences,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei,Anhui 230026,China

College of Life Sciences,University of Chinese Academy of Sciences,Beijing 100049,China

Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou,Guangdong 510530,China

Biotherapy Centre,Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong 510630,China

Department of Gastroenterology,Hepatology and Endocrinology,Hannover Medical School,Hannover 30625,Germany

Department of Hepatobiliary Surgery and Liver Transplant Center,General Hospital of Southern Theater Command,Guangzhou,Guangdong 510010,China

Department of Infectious Diseases,Nanfang Hospital,Southern Medical University,Guangdong Provincial Key Laboratory of Viral Hepatitis Research,Guangzhou,Guangdong 510515,China

Hematology and Cell Therapy Unit,IRCCS-Istituto Tumori'Giovanni Paolo Ⅱ',Bari 70124,Italy

Laboratory

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaGuangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research FoundationScience and Technology Program of GuangzhouScience and Technology Program of Guangzhou

3220068892068106U20A2015322115300502021B15151200752021A1515110180202201010408202201011037

2023

10.24272/j.issn.2095-8137.2023.031

动物学研究
中国科学院昆明动物研究所 中国动物学会

动物学研究

CSTPCDCSCD
影响因子：0.582
ISSN：0254-5853
年,卷(期)：2023.44(3)
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