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The histogenesis of regenerative nodules in human liver cirrhosis†
Article first published online: 30 NOV 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 51, Issue 3, pages 1017–1026, March 2010
How to Cite
Lin, W.-R., Lim, S.-N., McDonald, S. A. C., Graham, T., Wright, V. L., Peplow, C. L., Humphries, A., Kocher, H. M., Wright, N. A., Dhillon, A. P. and Alison, M. R. (2010), The histogenesis of regenerative nodules in human liver cirrhosis. Hepatology, 51: 1017–1026. doi: 10.1002/hep.23483
Potential conflict of interest: Nothing to report.
- Issue published online: 2 MAR 2010
- Article first published online: 30 NOV 2009
- Accepted manuscript online: 30 NOV 2009 12:00AM EST
- Manuscript Accepted: 27 OCT 2009
- Manuscript Received: 9 OCT 2009
- Chang Gung Memorial Hospital Taiwan. Grant Number: CMRPG370721
- Cancer Research UK
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.)