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Experimental Models of Acute and Chronic Liver Failure in Nude Mice to Study Hepatocyte Transplantation

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Abstract:

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.

Keywords: Apoptosis; Hepatocyte transplantation; Necrosis; Nude mice; Partial hepatectomy; Regeneration; Toxics

Document Type: Review Article

DOI: http://dx.doi.org/10.3727/000000005783983061

Affiliations: 1: Laboratoire de Chirurgie Expérimentale, Fondation Transplantation, 67200 Strasbourg, France 2: Laboratoire de Chirurgie Expérimentale, Fondation Transplantation, 67200 Strasbourg, France, Laboratoire de Biologie Cellulaire, Faculté de Médecine et de Pharmacie, 25030 Besançon, France 3: Laboratoire de Chirurgie Expérimentale, Fondation Transplantation, 67200 Strasbourg, France, Centre de Chirurgie Viscérale et de Transplantation, Hôpital de Hautepierre, 67098 Strasbourg, France 4: Service d'Anatomo-Pathologie, Hôpital de Hautepierre, 67098 Strasbourg, France 5: INSERM U381, 67200 Strasbourg, France 6: Service de Chirurgie Digestive et Vasculaire, Hôpital Jean Minjoz, 25000, Besançon, France

Publication date: May 1, 2005

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

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