The histogenesis of regenerative nodules in human liver cirrhosis

Authors

  • Wey-Ran Lin,

    1. Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    2. Department of Gastroenterology and Hepatology, Chang Gung University College of Medicine, Taipei, Taiwan
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  • Siew-Na Lim,

    1. Centre for Neuroscience and Trauma, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    2. Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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  • Stuart A. C. McDonald,

    1. Histopathology Unit, London Research Institute, Cancer Research UK, London, UK
    2. Centre for Digestive Diseases, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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  • Trevor Graham,

    1. Histopathology Unit, London Research Institute, Cancer Research UK, London, UK
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  • Victoria L. Wright,

    1. Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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  • Claire L. Peplow,

    1. Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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  • Adam Humphries,

    1. Histopathology Unit, London Research Institute, Cancer Research UK, London, UK
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  • Hemant M. Kocher,

    1. Tumour Biology Laboratory, John Vane Science Centre, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London, UK
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  • Nicholas A. Wright,

    1. Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    2. Histopathology Unit, London Research Institute, Cancer Research UK, London, UK
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  • Amar P. Dhillon,

    1. Department of Histopathology, University College London Medical School, Royal Free Campus, London, UK
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  • Malcolm R. Alison

    Corresponding author
    1. Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    • Centre for Diabetes, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK
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    • fax: + 44 207 882 2186.


  • Potential conflict of interest: Nothing to report.

Abstract

Here, we investigate the clonality and cells of origin of regenerative nodules in human liver cirrhosis using mitochondrial DNA (mtDNA) mutations as markers of clonal expansion. Mutated cells are identified phenotypically by deficiency in the entirely mtDNA encoded cytochrome c oxidase (CCO) enzyme by histochemical and immunohistochemical methods. Nodules were classified as either CCO-deficient or CCO-positive, and among 526 nodules from 10 cases, 18% were homogeneously CCO-deficient, whereas only 3% had a mixed phenotype. From frozen sections, hepatocytes were laser-capture microdissected from several sites within individual CCO-deficient nodules. Mutations were identified by polymerase chain reaction sequencing of the entire mtDNA genome. In all cases except for one, the nodules were monoclonal in nature, possessing up to four common mutations in all hepatocytes in a given nodule. Moreover, the identification of identical mutations in hepatic progenitor cells abutting CCO-deficient nodules proves that nodules can have their origins from such cells. Conclusion: These data support a novel pathway for the monoclonal derivation of human cirrhotic regenerative nodules from hepatic progenitor cells. (HEPATOLOGY 2010;51:1017–1026.)

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