Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model.

Humanized liver rodent models, in which the host liver parenchyma is repopulated by human hepatocytes, have been increasingly used for drug development and disease research. Unlike the leading humanized liver mouse model in which Fumarylacetoacetate Hydrolase (Fah), Recombination Activating Gene (Rag)-2 and Interleukin-2 Receptor Gamma (Il2rg) genes were inactivated simultaneously, generation of similar recipient rats has been challenging. Here, using Velocigene and 1-cell-embryo-targeting technologies, we generated a rat model deficient in Fah, Rag1/2 and Il2rg genes, similar to humanized liver mice. These rats were efficiently engrafted with Fah-expressing hepatocytes from rat, mouse and human. Humanized liver rats expressed human albumin and complement proteins in serum and showed a normal liver zonation pattern. Further, approaches were developed for gene delivery through viral transduction of human hepatocytes either in vivo, or in vitro prior to engraftment, providing a novel platform to study liver disease and hepatocyte-targeted therapies. © 2022. The Author(s).

Citation

Marisa Carbonaro, Jeffrey Lee, Evangelos Pefanis, Mathieu Desclaux, Kehui Wang, Alexander Pennington, Hui Huang, Alejo Mujica, Jose Rojas, Roxanne Ally, Daniel Kennedy, Michael Brown, Vitaliy Rogulin, Sven Moller-Tank, Leah Sabin, Brian Zambrowicz, Gavin Thurston, Zhe Li. Efficient engraftment and viral transduction of human hepatocytes in an FRG rat liver humanization model. Scientific reports. 2022 Aug 18;12(1):14079

Mesh Tags

PMID: 35982097

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