ARTÍCULO

Usage of adenovirus expressing thymidine kinase mediated hepatocellular damage for enabling mouse liver repopulation with allogenic or xenogenic hepatocytes

Autores: Moreno Luqui, Daniel; Balasiddaiah, A.; Lamas Longarela, Óscar; Duret, C.; Neri Valencia, Leyre; Guembe Echarri, Laura; Galarraga, M.; Larrea Leoz, María Esther; Daujat-Chavanieu, M.; Muntane, J.; Maurel, P.; Riezu Boj, José Ignacio; Prieto Valtueña, Jesús María; Aldabe Arregui, Rafael
Título de la revista: PLOS ONE
ISSN: 1932-6203
Volumen: 8
Número: 9
Páginas: e74948
Fecha de publicación: 2013
Resumen:
It has been shown that the liver of immunodeficient mice can be efficiently repopulated with human hepatocytes when subjected to chronic hepatocellular damage. Mice with such chimeric livers represent useful reagents for medical and clinical studies. However all previously reported models of humanized livers are difficult to implement as they involve cross-breeding of immunodeficient mice with mice exhibiting genetic alterations causing sustained hepatic injury. In this paper we attempted to create chimeric livers by inducing persistent hepatocellular damage in immunodeficient Rag2(-/-) gamma c(-/-) mice using an adenovirus encoding herpes virus thymidine kinase (AdTk) and two consecutive doses of ganciclovir (GCV). We found that this treatment resulted in hepatocellular damage persisting for at least 10 weeks and enabled efficient engraftment and proliferation within the liver of either human or allogenic hepatocytes. Interestingly, while the nodules generated from the transplanted mouse hepatocytes were well vascularized, the human hepatocytes experienced progressive depolarization and exhibited reduced numbers of murine endothelial cells inside the nodules. In conclusion, AdTk/GCV-induced liver damage licenses the liver of immunodeficient mice for allogenic and xenogenic hepatocyte repopulation. This approach represents a simple alternative strategy for chimeric liver generation using immunodeficient mice without additional genetic manipulation of the germ line.