Liver cell transplantation leads to repopulation and functional correction in a mouse model of Wilson's disease

Allen, Katrina J.; Cheah, Daphne M. Y.; Wright, Paul; Gazeas, Sophie; Pettigrew-Buck, Nicole E; Deal, Yolanda; Mercer, Julian F. B.; Williamson, Robert

doi:10.1111/j.1440-1746.2004.03451.x

Cited by 37 publications

(25 citation statements)

References 21 publications

(51 reference statements)

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“…The data supports and extends previous data from the tx mouse and patients with Wilson disease (Rauch 1983;Howell & Mercer 1994;Gow et al 2000;Michalczyk et al 2000;Allen et al 2004). Our data provides further evidence of the remarkable ability of mice to control excess copper intake without resulting ill health, even when a major biliary excretion mechanism has been ablated by mutation.…”

Section: Discussionsupporting

confidence: 89%

Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading

et al. 2006

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The toxic milk (tx) mouse is a rodent model for Wilson disease, an inherited disorder of copper overload. Here we assessed the effect of copper accumulation in the tx mouse on zinc and iron metabolism. Copper, zinc and iron concentrations were determined in the liver, kidney, spleen and brain of control and copper-loaded animals by atomic absorption spectroscopy. Copper concentration increased dramatically in the liver, and was also significantly higher in the spleen, kidney and brain of control tx mice in the first few months of life compared with normal DL mice. Hepatic zinc was increased with age in the tx mouse, but zinc concentrations in the other organs were normal. Liver and kidney iron concentrations were significantly lower at birth in tx mice, but increased quickly to be comparable with control mice by 2 months of age. Iron concentration in the spleen was significantly higher in tx mice, but was lower in 5 day old tx pups. Copper-loading studies showed that normal DL mice ingesting 300 mg/l copper in their diet for 3 months maintained normal liver, kidney and brain copper, zinc and iron levels. Copper-loading of tx mice did not increase the already high liver copper concentrations, but spleen and brain copper concentrations were increased. Despite a significant elevation of copper in the brain of the copper-loaded tx mice no behavioural changes were observed. The livers of copper-loaded tx mice had a lower zinc concentration than control tx mice, whilst the kidney had double the concentration of iron suggesting that there was increased erythrocyte hemolysis in the copper-loaded mutants.

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Section: Discussionsupporting

confidence: 89%

Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading

et al. 2006

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“…One possible explanation was that the lack of ATP7B activity in the cerebellum was compensated by ATP7A [53,54]. Liver cell transplantation was proved to restore hepatic copper homeostasis in a WD mouse model by reducing copper levels in the hepatic and extrahepatic tissues [55].…”

Section: Discussionmentioning

confidence: 99%

Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson’s Disease

Xiao

Deng

et al. 2018

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Background: Wilson’s disease (WD) is an autosomal recessive disease, which is characterized by an excessive copper accumulation in the liver and brain, leading to subsequent hepatic and/or neurological disorders. The causative gene for WD has been identified as the ATPase Cu²⁺ transporting beta polypeptide gene (ATP7B), which encodes a protein called copper-transporting ATPase 2. ATP7B mutations may lead to reduced biliary excretion of excess copper and disrupted copper homeostasis, resulting in various clinical symptoms of WD. Methods: Direct sequencing of the ATP7B gene was performed in 7 Han Chinese families with WD, and haplotype analysis was conducted in families having the same mutation. Results: Nine ATP7B gene mutations were identified, including 7 missense mutations (p.Asp765Gly, p.Arg778Leu, p.Thr888Pro, p.Pro992Leu, p.Asp1047Val, p.Ile1148Thr and p.Ala1295Val), 1 duplication mutation (c.525dupA), and 1 nonsense mutation (p.Gly837*). Combined with our previous data, haplotype analysis revealed that the founder effect accounted for 48% of alleles in Han Chinese, constituted by high allele frequency mutations p.Arg778Leu, p.Pro992Leu and p.Ala1295Val. Conclusion: This study revealed genetic defects of 7 Han Chinese families with WD, and has implications for their genetic counseling and clinical management.

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“…Both MRI and optical imaging allowed the assessment of the intrahepatic distribution of the labeled cells. This is of crucial importance, as it is believed that functional transplanted cells usually migrate within the liver parenchyma and remain distant from main portal branches [30]. As a result, assessing the success of LCT with imaging techniques would require the detection of both perivascular and peripheral cells.…”

Section: Discussionmentioning

confidence: 99%

“…Huh7 hepatoma cells were incubated at 37°C with AMNP in RPMI culture medium supplemented with 5 mM citrate at various iron concentrations (0.5 mM, 1 mM, 2 mM, 5 mM and 10 mM) and for various times (15,30, 60 and 120 min). The cells were then washed three times and incubated in nanoparticles-free RPMI for one additional hour at 37°C to permit internalization of the nanoparticles (chase period).…”

Section: Magnetic Cell Labeling and Iron Load Quantificationmentioning

confidence: 99%

Magnetic targeting of iron-oxide-labeled fluorescent hepatoma cells to the liver

et al. 2009

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The purpose of this study was to determine whether an external magnet field can induce preferential trafficking of magnetically labeled Huh7 hepatoma cells to the liver following liver cell transplantation. Huh7 hepatoma cells were labeled with anionic magnetic nanoparticles (AMNP) and tagged with a fluorescent membrane marker (PKH67). Iron-uptake was measured by magnetophoresis. Twenty C57Bl6 mice received an intrasplenic injection of 2 x 10(6) labeled cells. An external magnet (0.29 T; 25 T/m) was placed over the liver of 13 randomly selected animals (magnet group), while the remaining 7 animals served as controls. MRI (1.5 T) and confocal fluorescence microscopy (CFM) were performed 10 days post-transplantation. The presence and location of labeled cells within the livers were compared in the magnet group and controls, and confronted with histological analysis representing the standard of reference. Mean iron content per cell was 6 pg. Based on histology, labeled cells were more frequently present within recipient livers in the magnet group (p < 0.01) where their distribution was preferentially peri-vascular (p < 0.05). MRI and CFM gave similar results for the overall detection of transplanted cells (kappa = 0.828) and for the identification of peri-vascular cells (kappa = 0.78). Application of an external magnet can modify the trafficking of transplanted cells, especially by promoting the formation of perivascular aggregates.

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Liver cell transplantation leads to repopulation and functional correction in a mouse model of Wilson's disease

Abstract: Transplanted liver cells can proliferate and correct a non-fatal metabolic liver disease, with some restoration of hepatic copper homeostasis after 4 months leading to reduced copper levels in the liver and extrahepatic tissues, but not in the brain.

Cited by 37 publications

References 21 publications

Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading

Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading

Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson’s Disease

Magnetic targeting of iron-oxide-labeled fluorescent hepatoma cells to the liver

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