title: Increased survival despite failure of transplanted human hepatocyte implantation into liver parenchyma of nude mice with repeated lethal Jo2-induced liver deficiency.
abstract: We recently found that rat hepatocyte transplantation was efficient (liver repopulation: 2.4%) in a sublethal nude mouse model (less than 33% mortality) of repeated liver injury generated using Jo2, a mouse-specific anti-Fas antibody, at sublethal dose of 250 µg/kg for 3 weeks. Genomic analysis of the livers revealed cell cycle blockade and an antiproliferative status of circadian genes, suggesting a selective advantage. By contrast, in the present study, freshly isolated human hepatocyte transplantation performed in the same mouse model resulted in implantation of less than 6,000 cells per liver (about 0.006% repopulation) in all animals. Genomic analysis of nude mouse livers revealed a lack of P21 upregulation, while a signature of stimulation of liver regeneration was observed, including upregulation of early response genes and upregulation of circadian genes. When we translated this sublethal model to a lethal model (65% mortality) by increasing the Jo2 repeated doses to 375 µg/kg, human hepatocyte engraftment was still very low; however, animal mortality was corrected by transplantation (only 20% mortality). Genomic findings in livers from the mice of the lethal Jo2 transplanted group were similar to those of the sublethal Jo2 transplanted group, that is, no selective advantage genomic signature and signature of mouse liver regeneration. In conclusion, transplanted human hepatocytes acted as if they modified nude mouse liver responses to Jo2 by stimulating liver regeneration, leading to an increased survival rate.
authors: EA 3921, IFR 133, Faculté de Médecine et de Pharmacie, Besançon, France.
authors: Isabelle
authors: I
authors: Vidal
authors: Nadège
authors: N
authors: Blanchard
authors: Marie-Pierre
authors: MP
authors: Chenard-Neu
authors: Philippe
authors: P
authors: Bachellier
authors: Bruno
authors: B
authors: Heyd
authors: Frank
authors: F
authors: Staedtler
authors: Martin
authors: M
authors: Schumacher
authors: Eliane
authors: E
authors: Alexandre
authors: Lysiane
authors: L
authors: Richert
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D016678:Genome; D022781:Hepatocytes / Q000166:cytology / Q000637:transplantation*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D025341:Principal Component Analysis; D012709:Serum Albumin / Q000378:metabolism; D016019:Survival Analysis; D014019:Tissue Donors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D019014:fas Receptor / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C491899:Fas protein, mouse; D019394:Ki-67 Antigen; D012709:Serum Albumin; D019014:fas Receptor