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The histogenesis of regenerative nodules in human liver cirrhosis
Author(s) -
Lin WeyRan,
Lim SiewNa,
McDonald Stuart A. C.,
Graham Trevor,
Wright Victoria L.,
Peplow Claire L.,
Humphries Adam,
Kocher Hemant M.,
Wright Nicholas A.,
Dhillon Amar P.,
Alison Malcolm R.
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23483
Subject(s) - histogenesis , cirrhosis , pathology , medicine , anatomy , gastroenterology , immunohistochemistry
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. (H EPATOLOGY 2010;51:1017–1026.)