title: Factors affecting hepatocyte isolation, engraftment, and replication in an in vivo model.
abstract: Human hepatocyte transplantation is an alternative treatment for acute liver failure and liver diseases involving enzyme deficiencies. Although it has been successfully applied in selected recipients, both isolation and transplantation outcomes have the potential to be improved by better donor selection. This study assessed the impact of various donor variables on isolation outcomes (yield and viability) and posttransplant engraftment, using the SCID/Alb-uPA (severe combined immunodeficient/urokinase type plasminogen activator under the control of an albumin promoter) human liver chimeric mouse model. Human hepatocytes were obtained from 90 human liver donor specimens and were transplanted into 3942 mice. Multivariate analysis revealed improved viability with younger donors (P = 0.038) as well as with shorter warm ischemic time (P = 0.012). Hepatocyte engraftment, assessed by the posttransplant level of serum human alpha1-antitrypsin, was improved with shorter warm ischemia time. Hepatocytes isolated from older donors (>or=60 years) had lower viability and posttransplant engraftment (P <or= 0.01). In conclusion, the selection of young donors (<60 years) and rapid liver specimen retrieval, allowing for shorter warm ischemia time, are key determinants for the success of both the isolation of high viability human hepatocytes and their subsequent posttransplantation capacity for engraftment and expansion.
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Kawahara
authors.forename: Christian
authors.initials: C
authors.lastname: Toso
authors.forename: Donna N
authors.initials: DN
authors.lastname: Douglas
authors.forename: Mahra
authors.initials: M
authors.lastname: Nourbakhsh
authors.forename: Jamie T
authors.initials: JT
authors.lastname: Lewis
authors.forename: David Lorne
authors.initials: DL
authors.lastname: Tyrrell
authors.forename: Garry A
authors.initials: GA
authors.lastname: Lund
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Churchill
authors.forename: Norman M
authors.initials: NM
authors.lastname: Kneteman
mesh_terms: D000367:Age Factors; D000368:Aged; D000418:Albumins / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology* / Q000637:transplantation*; D006801:Humans; D007511:Ischemia; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D015999:Multivariate Analysis; D011401:Promoter Regions, Genetic; D012038:Regeneration; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D000418:Albumins; D014568:Urokinase-Type Plasminogen Activator