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Spatial and functional links between cellular virological state and progression of liver fibrosis in chronic hepatitis B

Xiaonan Zhang, Danping Liu, Wei Lu, Ye Zheng, Min Wu, Jiahui Ding, Mingzhu Xu, Xiaohui Zhou, Yanling Feng, Zhanqing Zhang, Zhenghong Yuan
doi: https://doi.org/10.1101/2020.01.13.904201
Xiaonan Zhang
1Research Unit, Shanghai Public Health Clinical Center, Fudan University
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  • For correspondence: zhyuan@shmu.edu.cn doctorzzqsphc@163.com zhangxiaonan@shphc.org.cn
Danping Liu
3Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University
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Wei Lu
3Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University
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Ye Zheng
4Department of Clinical Pathology, Shanghai Public Health Clinical Center, Fudan University
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Min Wu
1Research Unit, Shanghai Public Health Clinical Center, Fudan University
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Jiahui Ding
2Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University
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Mingzhu Xu
1Research Unit, Shanghai Public Health Clinical Center, Fudan University
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Xiaohui Zhou
5Department of laboratory animal, Shanghai Public Health Clinical Center, Fudan University
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Yanling Feng
4Department of Clinical Pathology, Shanghai Public Health Clinical Center, Fudan University
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Zhanqing Zhang
3Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University
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  • For correspondence: zhyuan@shmu.edu.cn doctorzzqsphc@163.com zhangxiaonan@shphc.org.cn
Zhenghong Yuan
1Research Unit, Shanghai Public Health Clinical Center, Fudan University
2Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University
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  • For correspondence: zhyuan@shmu.edu.cn doctorzzqsphc@163.com zhangxiaonan@shphc.org.cn
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Abstract

Chronic Hepatitis B Virus (HBV) infection is strongly associated with the progression of liver fibrosis, cirrhosis and hepatocellular carcinoma. Despite intensive study, the detailed mechanisms leading to HBV induced liver disease have not been fully elucidated. Previously, we reported a mosaic distribution of viral antigens and nucleic acids at single-cell level in liver tissues of chronic hepatitis B (CHB) patients and proposed a ‘three-stage model’ of HBV infection in vivo. Here, we explored whether the different stages at cellular level is functionally linked with fibrogenesis. We observed a tight spatial relationship between the invasion of collagen fibers and transitions from S-rich to DNA-rich stage. While S-rich cells mainly localized within minimally fibrotic tissue, DNA-rich cells were often closely surrounded by a milieu of stiffened extracellular matrix (ECM). cDNA microarray and subsequent validation analyses revealed that S-rich cells manifested elevated ribosomal proteins and oxidative phosphorylation genes in a disease phase-dependent manner. On the other hand, DNA-rich cells exhibited gradually deteriorated expression of hepatocyte-specific antigen and transcriptional regulator in parallel with the progression of hepatic fibrosis. Finally, during fibrogenesis, inflammatory genes such as IP-10 were found to be expressed in both portal infiltrated cells and surrounding parenchymal cells which resulted in suppressed antigen expression. Taken together, we propose that liver inflammation and accompanying fibrogenesis is spatially and functionally linked with the transition of virological stages at cellular level. These transitions occur possibly due to an altered hepatocyte transcription profile in response to a transformed ECM environment. The collective viral and host activities shape the histological alterations and progression of liver disease during CHB infection.

Footnotes

  • Financial Support: National Science and Technology Major project of China (2017ZX10302201001005)

    National Natural Science Foundation (81671998, 81873962)

    Shanghai Science and Technology Commission (16411960100)

  • http://www.hepb-atlas.com/

  • Abbreviations

    HBV
    Hepatitis B Virus
    CHB
    chronic hepatitis B
    ECM
    extracellular matrix
    HepPar-1
    hepatocyte Paraffin 1
    HNF4a
    Hepatocyte nuclear factor 4 alpha
    (HBeAg)
    hepatitis B e antigen
    (cccDNA)
    covalently closed circular DNA
    IT
    immune tolerant
    IA
    immune active
    ENH
    hepatitis B e antigen negative hepatitis
    ISH
    in situ hybridization
    HSC
    hepatic stellate cells
    HBsAg
    Hepatitis B Surface Antigen
    AgNOR
    argyrophilic nucleolar organizer region
    IP-10
    Interferon gamma-induced protein 10
  • Copyright 
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    Posted January 14, 2020.
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    Spatial and functional links between cellular virological state and progression of liver fibrosis in chronic hepatitis B
    Xiaonan Zhang, Danping Liu, Wei Lu, Ye Zheng, Min Wu, Jiahui Ding, Mingzhu Xu, Xiaohui Zhou, Yanling Feng, Zhanqing Zhang, Zhenghong Yuan
    bioRxiv 2020.01.13.904201; doi: https://doi.org/10.1101/2020.01.13.904201
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    Spatial and functional links between cellular virological state and progression of liver fibrosis in chronic hepatitis B
    Xiaonan Zhang, Danping Liu, Wei Lu, Ye Zheng, Min Wu, Jiahui Ding, Mingzhu Xu, Xiaohui Zhou, Yanling Feng, Zhanqing Zhang, Zhenghong Yuan
    bioRxiv 2020.01.13.904201; doi: https://doi.org/10.1101/2020.01.13.904201

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