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

Peng-Cheng Guo ¹Jing Zuo ²Ke-Ke Huang ³Guang-Yao Lai ⁴Xiao Zhang ¹Juan An ⁵Jin-Xiu Li ⁶Li Li ⁷Liang Wu ⁷Yi-Ting Lin ⁷Dong-Ye Wang ⁷Jiang-Shan Xu ²Shi-Jie Hao ⁶Yang Wang ²Rong-Hai Li ²Wen Ma ²Yu-Mo Song ²Chang Liu ²Chuan-Yu Liu ²Zhen Dai ⁸Yan Xu ⁹Amar Deep Sharma ¹⁰Michael Ott ¹⁰Qing Ou-Yang ¹¹Feng Huo ¹¹Rong Fan ¹²Yong-Yin Li ¹²Jin-Lin Hou ¹²Giacomo Volpe ¹³Long-Qi Liu ²Miguel A.Esteban ¹⁴Yi-Wei Lai²

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作者信息

1. 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
2. BGI-Hangzhou,Hangzhou,Zhejiang 310012,China;BGI-Shenzhen,Shenzhen,Guangdong 518083,China
3. 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
4. BGI-Hangzhou,Hangzhou,Zhejiang 310012,China;BGI-Shenzhen,Shenzhen,Guangdong 518083,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
5. BGI-Hangzhou,Hangzhou,Zhejiang 310012,China;BGI-Shenzhen,Shenzhen,Guangdong 518083,China;Laboratory of Integrative Biology,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,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
6. BGI-Hangzhou,Hangzhou,Zhejiang 310012,China;BGI-Shenzhen,Shenzhen,Guangdong 518083,China;College of Life Sciences,University of Chinese Academy of Sciences,Beijing 100049,China
7. Laboratory of Integrative Biology,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou,Guangdong 510530,China
8. Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou,Guangdong 510530,China
9. Biotherapy Centre,Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong 510630,China
10. Department of Gastroenterology,Hepatology and Endocrinology,Hannover Medical School,Hannover 30625,Germany
11. Department of Hepatobiliary Surgery and Liver Transplant Center,General Hospital of Southern Theater Command,Guangzhou,Guangdong 510010,China
12. Department of Infectious Diseases,Nanfang Hospital,Southern Medical University,Guangdong Provincial Key Laboratory of Viral Hepatitis Research,Guangzhou,Guangdong 510515,China
13. Hematology and Cell Therapy Unit,IRCCS-Istituto Tumori'Giovanni Paolo Ⅱ',Bari 70124,Italy
14. 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
折叠

Abstract

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.

Key words

Liver fibrosis/Toxicity/Single-cell and single-nucleus RNA-sequencing/Hepatocytes/Hepatic stellate cells/Angiogenesis/Cell-cell interactions/Gene regulatory networks

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基金项目

National Natural Science Foundation of China(32200688)

National Natural Science Foundation of China(92068106)

National Natural Science Foundation of China(U20A2015)

National Natural Science Foundation of China(32211530050)

Guangdong Basic and Applied Basic Research Foundation(2021B1515120075)

Guangdong Basic and Applied Basic Research Foundation(2021A1515110180)

Science and Technology Program of Guangzhou(202201010408)

Science and Technology Program of Guangzhou(202201011037)

出版年

2023

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

参考文献量70

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