title: The histogenesis of regenerative nodules in human liver cirrhosis.
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.
  
  
  CONCLUSIONS
  These data support a novel pathway for the monoclonal derivation of human cirrhotic regenerative nodules from hepatic progenitor cells.
authors.affiliation: Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Wey-Ran
authors.initials: WR
authors.lastname: Lin
authors.forename: Siew-Na
authors.initials: SN
authors.lastname: Lim
authors.forename: Stuart A C
authors.initials: SA
authors.lastname: McDonald
authors.forename: Trevor
authors.initials: T
authors.lastname: Graham
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Wright
authors.forename: Claire L
authors.initials: CL
authors.lastname: Peplow
authors.forename: Adam
authors.initials: A
authors.lastname: Humphries
authors.forename: Hemant M
authors.initials: HM
authors.lastname: Kocher
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.forename: Amar P
authors.initials: AP
authors.lastname: Dhillon
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Alison
mesh_terms: D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration / Q000235:genetics