Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis
Open accessAbstract
Background & aims Patients with progressive familial intrahepatic cholestasis (PFIC) type 3 have a mutation in the MDR3 gene, encoding the hepatocanalicular phospholipid translocator. In general, liver failure develops within the first decade of life in these patients. Previous studies have shown that in the mdr2-knockout mouse, the animal model for this disease, the absence of phospholipids in bile causes chronic bile salt-induced damage to hepatocytes. We aimed to test the efficacy of hepatocyte transplantation and liver repopulation in this disease model.Methods Transgenic MDR3-expressing hepatocytes as well as normal mdr2(+/+) hepatocytes were transplanted in mdr2(-/-) mice, and liver repopulation was assessed by immunohistochemistry and measurement of biliary lipid secretion.Results Transplanted hepatocytes partially repopulated the liver, restored phospholipid secretion, and diminished liver pathology. Repopulation was stronger when hepatocellular damage was enhanced by a bile salt-supplemented diet. After 1 year, however, these animals developed multiple hepatic tumors, and biliary phospholipid secretion decreased. In transplanted animals receiving a control diet, repopulation was slower but eventually remained stable at 21%, while liver pathology was completely abrogated and tumor formation was prevented.Conclusions These results suggest that moderate liver pathology is a safe condition for the induction of effective hepatocyte repopulation and that this therapy is potentially applicable to patients with PFIC type 3.
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Several disorders in which selection has been shown include Fanconi's anemia, Wilson's disease, many bile-acid transporter defects, and junctional epidermolysis bullosa.
“While this situation is an exception, there are several disorders in which selection has been shown, including Fanconi’s anemia,41 the copper storage disorder Wilson’s disease,42 many bile-acid transporter defects,43 and junctional epidermolysis bullosa44 to name a few.”
From Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡ (2010) · cites this paper as [43]
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- Authors
- De Vree, J. M. L., Ottenhoff, R., Bosma, P. J., Smith, A. J., Aten, J., & Oude Elferink, R. P. J.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2000-12
- Volume
- 119
- Issue
- 6
- Pages
- 1720-1730
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2115772492
- Cited by
- 186
- References
- 26
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 11 · 2013: 4 · 2012: 11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- progressive familial intrahepatic cholestasis type 3, hepatocyte transplantation, liver repopulation, biliary phospholipid secretion, liver tumors, liver failure, cholestatic liver disease
- MeSH terms
- Animals, Cholestasis, Diet, Liver, Liver Neoplasms, Male, Mice, Transgenic, Phospholipids, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Transporters, Cholates, Hepatocytes, Mice
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