Experimental models of acute and chronic liver failure in nude mice to study hepatocyte transplantation.
Although hepatocyte transplantation is a promising therapy for acute liver failure in human, there is still a lack of animal models suffering from hepatic injury in which the benefits of hepatocyte transplantation could be evaluated solely, without the bias caused by immunosuppression. As a consequence, the aim of the study was first to develop reproducible models of partial hepatectomy and of thioacetamide (TA)- or Jo2-induced acute liver failure in nude mice. Chronic liver disease was also investigated by repeated injections of sublethal doses of thioacetamide. Survival rates, routine histologic observations, alanin aminotransferase sera content, Ki67, and caspase 3 immunodetection were investigated both after 40% partial hepatectomy and after toxic-induced damages. Liver injuries were more severe and/or precocious in nude mice than in Balb/c mice for a given treatment with a maximum of acute injury obtained 24 h after single toxic injection, and were found to be transitory and reversible within 10 days. Toxics induced apoptosis followed by necrosis, confirming recent published data. Onset of fibrosis leading to reproducible chronic cirrhosis in nude mice correlated with increasing number of Ki67-positive cells, indicating that high levels of cell proliferation occurred. Chronic cirrhosis progressively reversed to fibrosis when the treatment ceased. Preliminary results demonstrated that engrafted xenogeneic hepatocytes could be detected in the host liver by anti-MHC class I immunohistochemistry. Fractions enriched in 2n or 4n hepatocytes by cell sorting using a flow cytometer were equivalent to the unpurified fraction in terms of engraftment in control nude mice or in nude mice subjected to PH. However, in mice suffering from liver injury 24 h after Jo2 or TA treatment, the engraftment of 2n hepatocytes was about twice that of an unpurified hepatocyte population or of a population enriched in 4n hepatocytes.
Gandillet
Amaud
A
Laboratoire de Chirurgie Expérimentale, Fondation Transplantation, 67200 Strasbourg, France.
Vidal
Isabelle
I
Alexandre
Eliane
E
Audet
Maxime
M
Chenard-Neu
Marie-Pierre
MP
Stutzmann
Jeanne
J
Heyd
Bruno
B
Jaeck
Daniel
D
Richert
Lysiane
L
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury; D002908:Chronic Disease; D004195:Disease Models, Animal; D006085:Graft Survival / Q000502:physiology; D006498:Hepatectomy; D022781:Hepatocytes / Q000637:transplantation*; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology; D008107:Liver Diseases / Q000628:therapy*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000628:therapy*; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide
D013853:Thioacetamide