Increased survival despite failure of transplanted human hepatocyte implantation into liver parenchyma of Nude mice with repeated lethal Jo2 induced-liver deficiency
Author: Isabelle Vidal, Nadege Blanchard, Marie Pierre ChenardNeu, Philippe Bachellier, Bruno Heyd, Frank Staedtler, Martin Schumacher, Eliane Alexandre, Lysiane Richert
Source: Cell Transplantation
Publisher: Cognizant Communication Corporation
Abstract:We recently found that rat hepatocyte transplantation was efficient (liver repopulation: 2.4%)in a sub-lethal Nude mouse model (less than 33% mortality) of repeated liver injury by Jo2, amouse-specific anti-Fas antibody, at sub-lethal dose of 250 μg/kg for three weeks, genomicanalysis of the livers revealing a cell cycle blockade and anti-proliferative status of circadiangenes suggesting selective advantage. By contrast, in the present study, freshly isolatedhuman hepatocyte transplantation, performed in the same mouse model, resulted inimplantation less than 6000 cells per liver (about 0.006% of repopulation) in all animals.Genomic analysis of Nude mice livers revealed a lack of P21 up-regulation, while a signatureof stimulation of liver regeneration was observed including up-regulation of early responsegenes and up-regulation of circadian genes.When we translated this sub-lethal model to a lethal model (65% mortality) by increasing theJo2 repeated doses to 375 μg/kg, human hepatocyte engraftment was still very low, howeveranimal mortality was corrected by transplantation (only 20% mortality). Genomic findings inlivers from the mice of the lethal Jo2 transplanted group were similar to those of the sublethalJo2 transplanted group, i.e. no selective advantage genomic signature, and signature ofmouse liver regeneration. In conclusion, transplanted human hepatocytes acted as if theymodified Nude mouse liver response to Jo2 by stimulating liver regeneration, leading toincreased survival rate.
Appeared or available online: April 29, 2013