Selective repopulation of normal mouse liver by Fas/CD95-resistant hepatocytes.
Hepatocyte transplantation might represent a potential therapeutic alternative to liver transplantation in the future; however, transplanted cells have a limited capacity to repopulate the liver, as they do not proliferate under normal conditions. Recently, studies in urokinase (uPA) transgenic mice and in fumarylacetoacetate hydrolase (FAH)-deficient mice have shown that the liver can be repopulated by genetically engineered hepatocytes harboring a selective advantage over resident hepatocytes. We have reported that transgenic mice expressing human Bcl-2 in their hepatocytes are protected from Fas/CD95-mediated liver apoptosis. We now show that Bcl-2 transplanted hepatocytes selectively repopulate the liver of mice treated with nonlethal doses of the anti-Fas antibody Jo2. FK 506 immunosuppressed mice were transplanted by splenic injection with Bcl-2 hepatocytes. The livers of female recipients were repopulated by male Bcl-2 transgenic hepatocytes, as much as 16%, after 8 to 12 administrations of Jo2. This only occurred after anti-Fas treatment, confirming that resistance to Fas-induced apoptosis constituted the selective advantage of these transplanted hepatocytes. Thus, we have demonstrated a method for increasing genetic reconstitution of the liver through selective repopulation with modified transgenic hepatocytes, which will allow optimization of cell and gene therapy in the liver.
INSERM U 129 ICGM, Université Paris V René Descartes, Paris, France.
A
A
Mignon
J E
JE
Guidotti
C
C
Mitchell
M
M
Fabre
A
A
Wernet
A
A
De La Coste
O
O
Soubrane
H
H
Gilgenkrantz
A
A
Kahn
D000818:Animals; D017209:Apoptosis; D017690:Cell Transplantation / Q000379:methods*; D002678:Chimera; D005260:Female; D019254:Genes, bcl-2; D006801:Humans; D008099:Liver / Q000166:cytology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D012641:Selection, Genetic; D019014:fas Receptor / Q000378:metabolism*
D019014:fas Receptor