Diminution of toxic copper accumulation in toxic milk mice modeling Wilson disease by embryonic hepatocyte intrasplenic transplantation

Zhu, Shengmei; Liang, Xiaoyan; Lu, Bing-xun; Pan, Suyue; Chen, Xi; Tang, Qihe; Wang, Ying; Huang, Fan

doi:10.3748/wjg.v11.i24.3691

Cited by 10 publications

(3 citation statements)

References 21 publications

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“…Several of these mouse models have been evaluated by transplantation of primary hepatocytes or precursors. For instance intrasplenic transplantation of embryonic hepatocytes isolated from 14-day fetal mouse livers into a mouse model of Wilson's disease reduced toxic copper accumulation [65]. However, to our knowledge an improvement of liver function in these mouse models (Table 3) by cell therapy with human extrahepatic stem cells has not yet been reported.…”

Section: No Functional Improvement Reportedmentioning

confidence: 98%

Present status and perspectives of cell-based therapies for liver diseases

Nüssler

König

Ott

et al. 2006

Journal of Hepatology

177

129

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Section: No Functional Improvement Reportedmentioning

confidence: 98%

Present status and perspectives of cell-based therapies for liver diseases

Nüssler

König

Ott

et al. 2006

Journal of Hepatology

177

129

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“…In fact, the latter concentration is the one observed in the serum of ATP7B-deficient mice at the age of 28 weeks and older (30). Interestingly, transplantation of only hepatocytes of ATP7Bdeficient mice into spleens of their control littermates increases serum copper levels by 60% (59). Overall, the above studies indicate that the production of neutrophils is not diminished by high copper concentrations (serum and liver), and during systemic inflammation, these cells infiltrate liver even stronger than in genetically wild type mice.…”

Section: Discussionmentioning

confidence: 92%

Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release

et al. 2020

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Neutrophil extracellular traps (NETs) contribute to pathological disorders, and their release was directly linked to numerous diseases. With intravital microscopy (IVM), we showed previously that NETs also contribute to the pathology of systemic inflammation and are strongly deposited in liver sinusoids. Over a decade since NET discovery, still not much is known about the metabolic or microenvironmental aspects of their formation. Copper is a vital trace element essential for many biological processes, albeit its excess is potentially cytotoxic; thus, copper levels are tightly controlled by factors such as copper transporting ATPases, ATP7A, and ATP7B. By employing IVM, we studied the impact of copper on NET formation during endotoxemia in liver vasculature on two mice models of copper excess or deficiency, Wilson (ATP7B mutants) and Menkes (ATP7A mutants) diseases, respectively. Here, we show that respective ATP7 mutations lead to diminished NET release during systemic inflammation despite unaltered intrinsic capacity of neutrophils to cast NETs as tested ex vivo. In Menkes disease mice, the in vivo effect is mostly due to diminished neutrophil infiltration of the liver as unmutated mice with a subchronic copper deficiency release even more NETs than their controls during endotoxemia, whereas in Wilson disease mice, excess copper directly diminishes the capacity to release NETs, and this was further confirmed by ex vivo studies on isolated neutrophils co-cultured with exogenous copper and a copper-chelating agent. Taken together, the study extends our understanding on how microenvironmental factors affect NET release by showing that copper is not a prerequisite for NET release but its excess affects the trap casting by neutrophils.

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“…Consistently, our previous study has demonstrated that embryonic hepatocytes are capable of differentiating into mature hepatocytes in vivo and partially correct abnormalities of copper metabolism after intraspleenic transplantation of homogeneous embryonic hepatocytes in toxic milk (tx) mice [9]. However, hepatocytes that are used for transplantation have to be obtained from the limited supply of donors.…”

Section: Introductionmentioning

confidence: 94%

Early stage transplantation of bone marrow cells markedly ameliorates copper metabolism and restores liver function in a mouse model of Wilson disease

et al. 2011

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BackgroundRecent studies have demonstrated that normal bone marrow (BM) cells transplantation can correct liver injury in a mouse model of Wilson disease (WD). However, it still remains unknown when BM cells transplantation should be administered. The aim of this study was to investigate the potential impact of normal BM cells transplantation at different stages of WD to correct liver injury in toxic milk (tx) mice.MethodsRecipient tx mice were sublethally irradiated (5 Gy) prior to transplantation. The congenic wild-type (DL) BM cells labeled with CM-DiI were transplanted via caudal vein injection into tx mice at the early (2 months of age) or late stage (5 months of age) of WD. The same volume of saline or tx BM cells were injected as controls. The DL donor cell population, copper concentration, serum ceruloplasmin oxidase activity and aspartate aminotransferase (AST) levels in the various groups were evaluated at 1, 4, 8 and 12 weeks post-transplant, respectively.ResultsThe DL BM cells population was observed from 1 to 12 weeks and peaked by the 4th week in the recipient liver after transplantation. DL BM cells transplantation during the early stage significantly corrected copper accumulation, AST across the observed time points and serum ceruloplasmin oxidase activity through 8 to 12 weeks in tx mice compared with those treated with saline or tx BM cells (all P < 0.05). In contrast, BM cells transplantation during the late stage only corrected AST levels from 4 to 12 weeks post-transplant and copper accumulation at 12 weeks post-transplant (all P < 0.05). No significant difference was found between the saline and tx BM cells transplantation groups across the observed time points (P > 0.05).ConclusionsEarly stage transplantation of normal BM cells is better than late stage transplantation in correcting liver function and copper metabolism in a mouse model of WD.

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Diminution of toxic copper accumulation in toxic milk mice modeling Wilson disease by embryonic hepatocyte intrasplenic transplantation

Abstract: Embryonic hepatocytes are capable of differentiating into mature hepatocytes in vivo. After transplantation, the hereditary abnormalities of copper metabolism in TX mice could be corrected partially by intrasplenic transplantation of homogeneous embryonic hepatocytes.

Cited by 10 publications

References 21 publications

Present status and perspectives of cell-based therapies for liver diseases

Present status and perspectives of cell-based therapies for liver diseases

Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release

Early stage transplantation of bone marrow cells markedly ameliorates copper metabolism and restores liver function in a mouse model of Wilson disease

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