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Improved Hepatocyte Engraftment after Portal Vein Occlusion in LDL Receptor-Deficient WHHL Rabbits and Lentiviral-Mediated Phenotypic Correction in Vitro
- Source :
- Cell Medicine. 4:85-98
- Publication Year :
- 2012
- Publisher :
- SAGE Publications, 2012.
-
Abstract
- Innovative cell-based therapies are considered as alternatives to liver transplantation. Recent progress in lentivirus-mediated hepatocyte transduction has renewed interest in cell therapy for the treatment of inherited liver diseases. However, hepatocyte transplantation is still hampered by inefficient hepatocyte engraftment. We previously showed that partial portal vein embolization (PVE) improved hepatocyte engraftment in a nonhuman primate model. We developed here an ex vivo approach based on PVE and lentiviral-mediated transduction of hepatocytes from normal (New Zealand White, NZW) and Watanabe heritable hyperlipidemic (WHHL) rabbits: the large animal model of familial hypercholesterolemia type IIa (FH). FH is a life-threatening human inherited autosomal disease caused by a mutation in the low-density lipoprotein receptor (LDLR) gene, which leads to severe hyperc-holesterolemia and premature coronary heart disease. Rabbit hepatocytes were isolated from the resected left liver lobe, and the portal branches of the median lobes were embolized with Histoacryl® glue under radiologic guidance. NZW and WHHL hepatocytes were each labeled with Hoechst dye or transduced with lentivirus expressing GFP under the control of a liver-specific promoter (mTTR, a modified murine transthyretin promoter) and were then immediately transplanted back into donor animals. In our conditions, 65–70% of the NZW and WHHL hepatocytes were transduced. Liver repopulation after transplantation with the Hoechst-labeled hepatocytes was 3.5 ± 2%. It was 1.4 ± 0.6% after transplantation with either the transduced NZW hepatocytes or the transduced WHHL hepatocytes, which was close to that obtained with Hoechst-labeled cells, given the mean transduction efficacy. Transgene expression persisted for at least 8 weeks posttransplantation. Transduction of WHHL hepatocytes with an LDLR-encoding vector resulted in phenotypic correction in vitro as assessed by internalization of fluorescent LDL ligands. In conclusion, our results have applications for the treatment of inherited metabolic liver diseases, such as FH, by transplantation of lentivirally transduced hepatocytes.
- Subjects :
- medicine.medical_specialty
medicine.medical_treatment
Familial hypercholesterolemia
Liver transplantation
Biology
medicine.disease
Article
Viral vector
Transplantation
medicine.anatomical_structure
Endocrinology
Internal medicine
Hepatocyte
LDL receptor
medicine
Cancer research
General Earth and Planetary Sciences
Ex vivo
General Environmental Science
Lipoprotein
Subjects
Details
- ISSN :
- 21551790
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- Cell Medicine
- Accession number :
- edsair.doi.dedup.....19b459e0d7b4812d0eb093df4ad2960f