Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice
Open accessAbstract
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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HTI is caused by loss-of-function of fumarylacetoacetate hydrolase (FAH).
“HTI is caused by loss-of-function of fumarylacetoacetate hydrolase (FAH), a key enzyme of the tyrosine catabolic pathway 13, 14.”
From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [13]
The Fahmut/mut mouse model is particularly suitable for testing ABE.
“Thus, this mouse model is particularly suitable for testing ABE13, 15.”
From Adenine base editing in an adult mouse model of tyrosinaemia (2019) · cites this paper as [13]
HTI is a particularly suitable model for gene repair-based therapy because repaired hepatocytes will expand and repopulate the liver.
“The liver disease hereditary tyrosinemia type I (HTI) is a particularly suitable model for gene repair-based therapy because the repaired hepatocytes will expand and repopulate the liver6,7.”
From Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo (2016) · cites this paper as [7]
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- Authors
- Azuma, H., Paulk, N., Ranade, A., Dorrell, C., Al-Dhalimy, M., Ellis, E., Strom, S., Kay, M. A., Finegold, M., & Grompe, M.
- Affiliations
- Oregon Health & Science University (US)
- University of Pittsburgh Medical Center (US)
- Stanford University (US)
- Baylor College of Medicine (US)
- Corresponding author
- Grompe, Markus
- Venue
- Nature Biotechnology
- Published
- 2007-07-29
- Volume
- 25
- Issue
- 8
- Pages
- 903-910
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC3404624
- OpenAlex
- W2162807448
- Cited by
- 835
- References
- 42
- Citations by year
- 2026: 33 · 2025: 28 · 2024: 43 · 2023: 37 · 2022: 55 · 2021: 55 · 2020: 60 · 2019: 47 · 2018: 59 · 2017: 60 · 2016: 41 · 2015: 56 · 2014: 58 · 2013: 52 · 2012: 44
- FWCI
- 26.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (n01dk092310-000)
- National Cancer Institute (F31CA130116)
- National Institute of General Medical Sciences (GM06346)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048252, R01-DK48252, DK-92310)
- U.S. National Library of Medicine (N01 DK092310)
- Topics
- Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- human hepatocytes, liver xenotransplantation, fumarylacetoacetate hydrolase, immunodeficient mice, serial transplantation, drug metabolism
- MeSH terms
- Animals, DNA-Binding Proteins, Humans, Hydrolases, Mice, Knockout, Cell Culture Techniques, Hepatocytes, Tissue Engineering, Mice, Interleukin Receptor Common gamma Subunit
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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