Fas/CD95 pathway induces mouse liver regeneration and allows for highly efficient retrovirus-mediated gene transfer.
Stable gene transfer into hepatocytes has been proposed to compensate for genetic deficiencies that affect liver function, or to deliver diffusible factors into the circulation. This strategy can be achieved using retroviral vectors; however, cell division must occur. We describe a simple and reproductive method that enables the induction of hepatocyte replication in a controlled fashion, thus allowing an efficient in vivo retroviral liver transduction that is applicable to mouse models of human genetic disorders. The approach is based on liver susceptibility to apoptosis via the Fas/CD95 pathway. We show that, 4 days following a single Fas agonist antibody (JO2) injection, hepatocyte replication occurs, the intensity of which is correlated with the level of the induced hepatic cytolysis. This treatment enables in vivo liver transduction, and its efficiency also correlates with the level of hepatic cytolysis. When recombinant retroviral vectors were infused intravenously during the period of hepatocyte replication, 15.4% +/- 1.7% of the hepatocytes were transduced, reaching up to 32.5%.
Guidotti
J E
JE
U.129 INSERM, ICGM, Paris, France.
Mallet
V O
VO
Parlier
D
D
Mitchell
C
C
Fabre
M
M
Jaffray
P
P
Lambert
M
M
Kahn
A
A
Gilgenkrantz
H
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D022781:Hepatocytes / Q000166:cytology; D007267:Injections; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012190:Retroviridae / Q000235:genetics*; D014161:Transduction, Genetic; D014462:Ultrafiltration; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D019014:fas Receptor; D000410:Alanine Transaminase