Abstract
Mice harbouring a humanized liver represent a powerful tool for translating preclinical studies of drug metabolism and pharmacokinetics into humans, as well as the exploitation of basic studies on liver pathophysiology including hepatitis C virus (HCV) infection. Human adult stem cells injected into immunocompetent mice at preimmune stages of development, generate chimeric animals harbouring a liver with relatively discrete foci of human hepatocyte-like cells. In this study, we have evaluated whether similar protocol of xenotransplantation in the presence of selective pressure might lead to a higher human-intomouse liver repopulation, leading to a relevant improvement of liver function. Human CD34+/CD133+ cells were microinjected into blastocysts from genetically-modified mice committed to develop a lethal hepatopathy, due to the absence of the enzyme fumarylacetoacetate hydrolase (FAH). Following xenotransplantation, mouse survival was followed over time and histochemical evidence of liverchimerism was assessed. The survival expectancy of seven out of 21 intrablastocyst xenotransplanted FAH knockout (Fah-/-) mice was significantly higher as compared with non-xenotransplanted mice. Several nodules of human hepatocyte-like cells were revealed by immunohistochemistry in the liver of rescued mice. Our data positively support the hypothesis that preimmune xenotransplantation of human stem cells into immunocompetent mice harbouring a lethal hepatic disease might lead to a functionally relevant human-mouse liver chimerism and marks a significant advancement towards theestablishment of a novel translational preclinical model for liver diseases.
Original language | English |
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Pages (from-to) | 280-286 |
Number of pages | 7 |
Journal | Laboratory Animals |
Volume | 46 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2012 |
Keywords
- Fah-/- mice
- Human stem cells
- Humanized mice
- NTBC
- Xenotransplantation
ASJC Scopus subject areas
- Animal Science and Zoology
- veterinary(all)