Robust Expansion of Human Hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- Mice

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2007 Aug 1

PMID 17664939

Citations 400

Authors

Hisaya Azuma

Nicole Paulk

Aarati Ranade

Craig Dorrell

Muhsen Al-Dhalimy

Ewa Ellis

Stephen Strom

Mark A Kay

Milton Finegold

Markus Grompe

Affiliations

Soon will be listed here.

Abstract

Mice that could be highly repopulated with human hepatocytes would have many potential uses in drug development and research applications. The best available model of liver humanization, the uroplasminogen-activator transgenic model, has major practical limitations. To provide a broadly useful hepatic xenorepopulation system, we generated severely immunodeficient, fumarylacetoacetate hydrolase (Fah)-deficient mice. After pretreatment with a urokinase-expressing adenovirus, these animals could be highly engrafted (up to 90%) with human hepatocytes from multiple sources, including liver biopsies. Furthermore, human cells could be serially transplanted from primary donors and repopulate the liver for at least four sequential rounds. The expanded cells displayed typical human drug metabolism. This system provides a robust platform to produce high-quality human hepatocytes for tissue culture. It may also be useful for testing the toxicity of drug metabolites and for evaluating pathogens dependent on human liver cells for replication.

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