title: Treatment of acetaminophen-induced acute liver failure in the mouse with conditionally immortalized human hepatocytes.
abstract: OBJECTIVE
  Liver failure is a life threatening condition currently treated by palliative measures and, when applicable, organ transplantation. The use of a bioartificial organ capable of fulfilling the main functions of the liver would represent an attractive alternative. However, the shortage of suitable donor cells, and their limited growth ability have impeded the development of this strategy. We investigated whether lentiviral vectors allow for conditional immortalization of human hepatocytes and whether these immortalized hepatocytes could reverse lethal acute liver failure.
  
  
  METHODS
  We exposed primary human hepatocytes to Cre-excisable lentiviral vectors coding for SV40T Antigen, telomerase, and/or Bmi-1 and tested the functionality of the resulting cell lines. Therapeutic potential of immortalized hepatocytes were tested in a murine model of acetaminophen-induced hepatic injury.
  
  
  RESULTS
  The immortalized hepatocytes grew continuously yet were non-tumorigenic, stopped proliferating when exposed to Cre recombinase, and conserved defining properties of primary hepatocytes, including the ability to secrete liver-specific proteins and to detoxify drugs. The implantation of encapsulated immortalized human hepatocytes rescued mice from lethal doses of acetaminophen.
  
  
  CONCLUSIONS
  Lentiviral vectors represent tools of choice for immortalization of non-dividing primary cells, and lentivirally immortalized human hepatocytes are promising reagents for cell-based therapy of acute liver failure.
authors.affiliation: Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Tuan Huy
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Gang
authors.initials: G
authors.lastname: Mai
authors.forename: Peter
authors.initials: P
authors.lastname: Villiger
authors.forename: José
authors.initials: J
authors.lastname: Oberholzer
authors.forename: Patrick
authors.initials: P
authors.lastname: Salmon
authors.forename: Philippe
authors.initials: P
authors.lastname: Morel
authors.forename: Leo
authors.initials: L
authors.lastname: Bühler
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D002461:Cell Line, Transformed; D017690:Cell Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D005822:Genetic Vectors; D022781:Hepatocytes / Q000637:transplantation; D006801:Humans; D016086:Lentivirus; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000628:therapy*; D019164:Liver, Artificial; D051379:Mice
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen