Bioimaging of copper deposition in Wilson's diseases mouse liver by laser ablation inductively coupled plasma mass spectrometry imaging (LA-ICP-MSI)

M-M, Pornwilard; Merle, Uta; Weiskirchen, Ralf; Becker, J. Sabine

doi:10.1016/j.ijms.2013.07.006

Cited by 17 publications

(10 citation statements)

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“…Recently, we have shown that metal bio-imaging via LA-ICP-MS is a novel, highly sensitive innovative diagnostic tool that allows simultaneous measurement of over fifty different metal concentrations in liver tissue with a high sensitivity, spatial resolution, specificity, and quantification ability [ 23 , 24 ]. We here used this methodology to get more insight into the cerebral distribution of various metals during progression of WD.…”

Section: Resultsmentioning

confidence: 99%

Simultaneous monitoring of cerebral metal accumulation in an experimental model of Wilson’s disease by laser ablation inductively coupled plasma mass spectrometry

et al. 2014

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BackgroundNeuropsychiatric affection involving extrapyramidal symptoms is a frequent component of Wilson’s disease (WD). WD is caused by a genetic defect of the copper (Cu) efflux pump ATPase7B. Mouse strains with natural or engineered transgenic defects of the Atp7b gene have served as model of WD. These show a gradual accumulation and concentration of Cu in liver, kidneys, and brain. However, still little is known about the regional distribution of Cu inside the brain, its influence on other metals and subsequent pathophysiological mechanisms. We have applied laser ablation inductively coupled plasma mass spectrometry and performed comparative metal bio-imaging in brain sections of wild type and Atp7b null mice in the age range of 11–24 months. Messenger RNA and protein expression of a panel of inflammatory markers were assessed using RT-PCR and Western blots of brain homogenates.ResultsWe could confirm Cu accumulation in brain parenchyma by a factor of two in WD (5.5 μg g−1 in the cortex) vs. controls (2.7 μg g−1) that was already fully established at 11 months. In the periventricular regions (PVR) known as structures of prominent Cu content, Cu was reduced in turn by a factor of 3. This corroborates the view of the PVR as efflux compartments with active transport of Cu into the cerebrospinal fluid. Furthermore, the gradient of Cu increasing downstream the PVR was relieved. Otherwise the architecture of Cu distribution was essentially maintained. Zinc (Zn) was increased by up to 40% especially in regions of high Cu but not in typical Zn accumulator regions, a side effect due to the fact that Zn is to some degree a substrate of Cu-ATPases. The concentrations of iron (Fe) and manganese (Mn) were constant throughout all regions assessed. Inflammatory markers TNF-α, TIMP-1 and the capillary proliferation marker α-SMA were increased by a factor of 2–3 in WD.ConclusionsThis study confirmed stable cerebral Cu accumulation in parenchyma and discovered reduced Cu in cerebrospinal fluid in Atp7b null mice underlining the diagnostic value of micro-local analytical techniques.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2202-15-98) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Simultaneous monitoring of cerebral metal accumulation in an experimental model of Wilson’s disease by laser ablation inductively coupled plasma mass spectrometry

et al. 2014

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“…We have recently established a quantitative biometal imaging technique of mouse and human liver tissue allowing simultaneous measurement and quantification of various metals in thin cryo-sections 14,15. This methodology is based on LA-ICP-MS which is capable to detect metals and several non-metals at very low concentrations with minimal requirements in sample preparation and processing expenditures 29.…”

Section: Discussionmentioning

confidence: 99%

“…To demonstrate the hepatic distribution of various metals and metalloids in normal control mice, we generated cryosections of respective livers and performed LA-ICP-MS imaging following our protocols that we have published before 14,15. This analysis revealed that Na, Mg, P, K, Ca, Ti, Cr, Ni, Cu, Zn and Pb showed a homogenous distribution with the tissue.…”

Section: Discussionmentioning

confidence: 99%

“…All trace metal concentrations were calculated from ion intensities averaged throughout freely drawn regions of interest and representative images were generated from the continuous list of raw pixel values using modified in-house LA-ICP-MS Image Generation software that is based on the IMAGENA software originally created at the Research Centre Jülich 22. For quantification purposes, matrix-matched laboratory standards were prepared by dosing each analysed element to the pieces of homogenized tissue that were essentially prepared as described 15. As a surrogate of slice thickness, the metal intensities were normalized to the average 13 C ion intensity of respective samples in each measurement as suggested elsewhere 23.…”

Section: Methodsmentioning

confidence: 99%

“…This method allows to image, measure and quantify trace metal distribution in cryo-sections of mouse and human liver tissue samples 14,15. We now extended these studies and performed comparative metal bio-imaging in wild-type and Atp7b deficient mice representing a well-accepted animal model resembling WD in humans 16–18.…”

Section: Introductionmentioning

confidence: 96%

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Laser ablation inductively coupled plasma mass spectrometry imaging of metals in experimental and clinical Wilson's disease

Boaru

Merle

Uerlings

et al. 2015

J Cellular Molecular Medi

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Wilson's disease is an autosomal recessive disorder in which the liver does not properly release copper into bile, resulting in prominent copper accumulation in various tissues. Affected patients suffer from hepatic disorders and severe neurological defects. Experimental studies in mutant mice in which the copper-transporting ATPase gene (Atp7b) is disrupted revealed a drastic, time-dependent accumulation of hepatic copper that is accompanied by formation of regenerative nodes resembling cirrhosis. Therefore, these mice represent an excellent exploratory model for Wilson's disease. However, the precise time course in hepatic copper accumulation and its impact on other trace metals within the liver is yet poorly understood. We have recently established novel laser ablation inductively coupled plasma mass spectrometry protocols allowing quantitative metal imaging in human and murine liver tissue with high sensitivity, spatial resolution, specificity and quantification ability. By use of these techniques, we here aimed to comparatively analyse hepatic metal content in wild-type and Atp7b deficient mice during ageing. We demonstrate that the age-dependent accumulation of hepatic copper is strictly associated with a simultaneous increase in iron and zinc, while the intrahepatic concentration and distribution of other metals or metalloids is not affected. The same findings were obtained in well-defined human liver samples that were obtained from patients suffering from Wilson's disease. We conclude that in Wilson's disease the imbalances of hepatic copper during ageing are closely correlated with alterations in intrahepatic iron and zinc content.

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Trace metal imaging in diagnostic of hepatic metal disease

Susnea

Weiskirchen

2015

Mass Spectrometry Reviews

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The liver is the most central organ and the largest gland of the body that influences and controls a variety of metabolic and catabolic processes. It produces inconceivable many essential proteins, is responsible for the recovery of various food components, degrades toxins, mediates the bile production, and is involved in the excretion of unwanted metabolites. Several of these anabolic or catabolic functions of the liver depend on trace elements. These are either integral part of enzymes, cofactors, or act as chemical catalysts. Therefore, a lack of trace elements can lead to organ failure or systemic illness. Conversely, excessive hepatic trace element deposition resulting from genetic disorders, intoxication, extensive dietary supply, or long-term parenteral nutrition may cause hepatic inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma. Although specific serum parameters currently allow rough assessment of metal deficit and excess, the precise quantification of hepatic metal content in liver is presently only possible by different titration or staining techniques of biopsy specimens. Recently, novel innovative metal imaging techniques were developed that are on the way to replace these traditional methods. In the present review, we summarize the function of different trace elements in liver health and disease and discuss the present knowledge on how quantitative biometal imaging techniques such as synchrotron X-ray fluorescence microscopy, secondary ion mass spectrometry, and laser ablation inductively coupled plasma mass spectrometry enrich diagnostics in the detection and quantification of hepatic metal disorders. We will further discuss sample preparation, sensitivity, spatial resolution, specificity, quantification strategies, and potential future applications of metal bioimaging in experimental research and clinical daily routine. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 35:666-686, 2016.

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Bioimaging of copper deposition in Wilson's diseases mouse liver by laser ablation inductively coupled plasma mass spectrometry imaging (LA-ICP-MSI)

Cited by 17 publications

References 45 publications

Simultaneous monitoring of cerebral metal accumulation in an experimental model of Wilson’s disease by laser ablation inductively coupled plasma mass spectrometry

Simultaneous monitoring of cerebral metal accumulation in an experimental model of Wilson’s disease by laser ablation inductively coupled plasma mass spectrometry

Laser ablation inductively coupled plasma mass spectrometry imaging of metals in experimental and clinical Wilson's disease

Trace metal imaging in diagnostic of hepatic metal disease

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