Therapeutic efficacy of human hepatocyte transplantation in a SCID/uPA mouse model with inducible liver disease

Autor: David Bond, D. Lorne Tyrrell, Jamie T. Lewis, Banu Sis, Norman M. Kneteman, Toshiyasu Kawahara, Donna N. Douglas, Karl P. Fischer
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Male
Pathology
Cell Transplantation
medicine.medical_treatment
viruses
lcsh:Medicine
Apoptosis
Herpesvirus 1
Human
Mice
SCID
Liver transplantation
medicine.disease_cause
Mice
Liver disease
0302 clinical medicine
lcsh:Science
0303 health sciences
Multidisciplinary
Reverse Transcriptase Polymerase Chain Reaction
Liver Diseases
3. Good health
Pharmacology/Drug Interactions
Liver
030220 oncology & carcinogenesis
Female
Research Article
medicine.drug
Ganciclovir
medicine.medical_specialty
Surgery/Transplantation
Cell Survival
Hepatitis C virus
Immunoblotting
Transplantation
Heterologous
Mice
Transgenic
Gastroenterology and Hepatology
Biology
Transfection
Thymidine Kinase
Cell Line
Gastroenterology and Hepatology/Hepatology
03 medical and health sciences
Immune system
Cell Line
Tumor
Parenchyma
medicine
Animals
Humans
030304 developmental biology
Pharmacology
Genetics and Genomics/Gene Therapy
lcsh:R
medicine.disease
Urokinase-Type Plasminogen Activator
Transplantation
Disease Models
Animal
Microscopy
Electron
Thymidine kinase
Hepatocytes
lcsh:Q
Pharmacology/Drug Development
Zdroj: PLoS ONE, Vol 5, Iss 2, p e9209 (2010)
PLoS ONE
ISSN: 1932-6203
Popis: Background Severe Combined Immune Deficient (SCID)/Urokinase-type Plasminogen Activator (uPA) mice undergo liver failure and are useful hosts for the propagation of transplanted human hepatocytes (HH) which must compete with recipient-derived hepatocytes for replacement of the diseased liver parenchyma. While partial replacement by HH has proven useful for studies with Hepatitis C virus, complete replacement of SCID/uPA mouse liver by HH has never been achieved and limits the broader application of these mice for other areas of biomedical research. The herpes simplex virus type-1 thymidine kinase (HSVtk)/ganciclovir (GCV) system is a powerful tool for cell-specific ablation in transgenic animals. The aim of this study was to selectively eliminate murine-derived parenchymal liver cells from humanized SCID/uPA mouse liver in order to achieve mice with completely humanized liver parenchyma. Thus, we reproduced the HSVtk (vTK)/GCV system of hepatic failure in SCID/uPA mice. Methodology/Principal Findings In vitro experiments demonstrated efficient killing of vTK expressing hepatoma cells after GCV treatment. For in vivo experiments, expression of vTK was targeted to the livers of FVB/N and SCID/uPA mice. Hepatic sensitivity to GCV was first established in FVB/N mice since these mice do not undergo liver failure inherent to SCID/uPA mice. Hepatic vTK expression was found to be an integral component of GCV-induced pathologic and biochemical alterations and caused death due to liver dysfunction in vTK transgenic FVB/N and non-transplanted SCID/uPA mice. In SCID/uPA mice with humanized liver, vTK/GCV caused death despite extensive replacement of the mouse liver parenchyma with HH (ranging from 32–87%). Surprisingly, vTK/GCV-dependent apoptosis and mitochondrial aberrations were also localized to bystander vTK-negative HH. Conclusions/Significance Extensive replacement of mouse liver parenchyma by HH does not provide a secure therapeutic advantage against vTK/GCV-induced cytotoxicity targeted to residual mouse hepatocytes. Functional support by engrafted HH may be secured by strategies aimed at limiting this bystander effect.
Databáze: OpenAIRE
Externí odkaz: