We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Selective repopulation of normal mouse liver by Fas/CD95-resistant hepatocytes.
- Authors
Mignon, Alexandre; Guidotti, Jacques E.; Mitchell, Claudia; Fabre, Monique; Wernet, Anne; De La Coste, Alix; Soubrane, Olivier; Gilgenkrantz, Helene; Kahn, Axel
- Abstract
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.
- Subjects
LIVER cells; LIVER physiology; GENE therapy
- Publication
Nature Medicine, 1998, Vol 4, Issue 10, p1185
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/2681