title: Liver regeneration signature in hepatitis B virus (HBV)-associated acute liver failure identified by gene expression profiling.
abstract: BACKGROUND
  The liver has inherent regenerative capacity via mitotic division of mature hepatocytes or, when the hepatic loss is massive or hepatocyte proliferation is impaired, through activation of hepatic stem/progenitor cells (HSPC). The dramatic clinical course of acute liver failure (ALF) has posed major limitations to investigating the molecular mechanisms of liver regeneration and the role of HSPC in this setting. We investigated the molecular mechanisms of liver regeneration in 4 patients who underwent liver transplantation for hepatitis B virus (HBV)-associated ALF.
  
  
  RESULTS
  Gene expression profiling of 17 liver specimens from the 4 ALF cases and individual specimens from 10 liver donors documented a distinct gene signature for ALF. However, unsupervised multidimensional scaling and hierarchical clustering identified two clusters of ALF that segregated according to histopathological severity massive hepatic necrosis (MHN; 2 patients) and submassive hepatic necrosis (SHN; 2 patients). We found that ALF is characterized by a strong HSPC gene signature, along with ductular reaction, both of which are more prominent in MHN. Interestingly, no evidence of further lineage differentiation was seen in MHN, whereas in SHN we detected cells with hepatocyte-like morphology. Strikingly, ALF was associated with a strong tumorigenesis gene signature. MHN had the greatest upregulation of stem cell genes (EpCAM, CK19, CK7), whereas the most up-regulated genes in SHN were related to cellular growth and proliferation. The extent of liver necrosis correlated with an overriding fibrogenesis gene signature, reflecting the wound-healing process.
  
  
  CONCLUSIONS
  Our data provide evidence for a distinct gene signature in HBV-associated ALF whose intensity is directly correlated with the histopathological severity. HSPC activation and fibrogenesis positively correlated with the extent of liver necrosis. Moreover, we detected a tumorigenesis gene signature in ALF, emphasizing the close relationship between liver regeneration and liver cancer.
authors.affiliation: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Oriel
authors.initials: O
authors.lastname: Nissim
authors.forename: Marta
authors.initials: M
authors.lastname: Melis
authors.forename: Giacomo
authors.initials: G
authors.lastname: Diaz
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.forename: Ashley
authors.initials: A
authors.lastname: Tice
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fantola
authors.forename: Fausto
authors.initials: F
authors.lastname: Zamboni
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
authors.forename: Patrizia
authors.initials: P
authors.lastname: Farci
mesh_terms: D000328:Adult; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015967:Gene Expression Regulation, Viral; D006509:Hepatitis B / Q000378:metabolism* / Q000821:virology*; D006515:Hepatitis B virus / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008103:Liver Cirrhosis; D017114:Liver Failure, Acute / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D013234:Stem Cells / Q000166:cytology