Human Ex-Vivo Liver Model for Acetaminophen-induced Liver Damage

Schreiter, Thomas; Sowa, Jan-Peter; Schlattjan, Martin; Treckmann, Jürgen; Paul, Andreas; Strucksberg, Karl-Heinz; Baba, Hideo A.; Odenthal, Margarete; Gieseler, Robert K.; Gerken, Guido; Arteel, Gavin E.; Canbay, Ali

doi:10.1038/srep31916

Cited by 20 publications

(20 citation statements)

References 21 publications

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“…The use of APAP toxicity in this platform gives information on cell disruption and necrosis in the hydrogel similar to what ex vivo human models have shown. 39 Additionally, the HUVEC layer is also shown to be disrupted, making this a suitable system for drug testing and assessment of cell death within the hydrogel.…”

Section: Resultsmentioning

confidence: 99%

Bioprinted 3D vascularized tissue model for drug toxicity analysis

et al. 2017

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To develop biomimetic three-dimensional (3D) tissue constructs for drug screening and biological studies, engineered blood vessels should be integrated into the constructs to mimic the drug administration process . The development of perfusable vascularized 3D tissue constructs for studying the drug administration process through an engineered endothelial layer remains an area of intensive research. Here, we report the development of a simple 3D vascularized liver tissue model to study drug toxicity through the incorporation of an engineered endothelial layer. Using a sacrificial bioprinting technique, a hollow microchannel was successfully fabricated in the 3D liver tissue construct created with HepG2/C3A cells encapsulated in a gelatin methacryloyl hydrogel. After seeding human umbilical vein endothelial cells (HUVECs) into the microchannel, we obtained a vascularized tissue construct containing a uniformly coated HUVEC layer within the hollow microchannel. The inclusion of the HUVEC layer into the scaffold resulted in delayed permeability of biomolecules into the 3D liver construct. In addition, the vascularized construct containing the HUVEC layer showed an increased viability of the HepG2/C3A cells within the 3D scaffold compared to that of the 3D liver constructs without the HUVEC layer, demonstrating a protective role of the introduced endothelial cell layer. The 3D vascularized liver model presented in this study is anticipated to provide a better and more accurate liver model system for future drug toxicity testing.

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Section: Resultsmentioning

confidence: 99%

Bioprinted 3D vascularized tissue model for drug toxicity analysis

et al. 2017

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“…Since the main objective of this study was to provide a deep understanding of the mechanical response of the fresh human capsule under the axial and transversal tensile and compressive loadings, only the simple mechanical approach was employed. In addition to that, other indirect injuries, as a result of the Acetaminophen, have also been investigated upon among the human liver samples [31]. Their results revealed a strong damage on low-dose acetaminophen usage.…”

Section: Discussionmentioning

confidence: 99%

An Experimental Study to Measure the Mechanical Properties of the Human Liver

Karimi

Shojaei

2017

Dig Dis

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Background: Since the liver is one of the most important organs of the body that can be injured during trauma, that is, during accidents like car crashes, understanding its mechanical properties is of great interest. Experimental data is needed to address the mechanical properties of the liver to be used for a variety of applications, such as the numerical simulations for medical purposes, including the virtual reality simulators, trauma research, diagnosis objectives, as well as injury biomechanics. However, the data on the mechanical properties of the liver capsule is limited to the animal models or confined to the tensile/compressive loading under single direction. Therefore, this study was aimed at experimentally measuring the axial and transversal mechanical properties of the human liver capsule under both the tensile and compressive loadings. Methods: To do that, 20 human cadavers were autopsied and their liver capsules were excised and histologically analyzed to extract the mean angle of a large fibers population (bundle of the fine collagen fibers). Thereafter, the samples were cut and subjected to a series of axial and transversal tensile/compressive loadings. Results: The results revealed the tensile elastic modulus of 12.16 ± 1.20 (mean ± SD) and 7.17 ± 0.85 kPa under the axial and transversal loadings respectively. Correspondingly, the compressive elastic modulus of 196.54 ± 13.15 and 112.41 ± 8.98 kPa were observed under the axial and transversal loadings respectively. The compressive axial and transversal maximum/failure stress of the capsule were 32.54 and 37.30 times higher than that of the tensile ones respectively. The capsule showed a stiffer behavior under the compressive load compared to the tensile one. In addition, the axial elastic modulus of the capsule was found to be higher than that of the transversal one. Conclusions: The findings of the current study have implications not only for understanding the mechanical properties of the human capsule tissue under tensile/compressive loading, but also for providing unprocessed data for both the doctors and engineers to be used for diagnosis and simulation purposes.

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“…52,53 In addition, previous reports in vitro and ex vivo demonstrated that APAP elicits toxicity at 5-20 mM dependent on the system. [54][55][56] Therefore, we investigated the concentration range of 0.5-8 mM and chose 4 and 8 mM for further analysis based on cell viability results in our system. Exposure of HepaRG to 4 and 8 mM APAP elicited the expected hepatocellular damage in 3D culture conditions.…”

Section: Characterization Of the In Vitro Model And Determination Of mentioning

confidence: 99%

Exosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver InjuryIn Vitro

Messner

Premand

Gaiser

et al. 2020

Applied In Vitro Toxicology

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Introduction: In vitro models for liver disease suffer from the lack of well-established and sensitive biomarkers of cellular damage. MicroRNAs (miRNAs; small noncoding RNAs) represent potential biomarkers for the detection of drug-induced liver injury in vivo and in vitro. Altered physiological state caused by disease or tissue damage results in altered release of exosomal-or protein-bound miRNAs, detectable in body fluids and cell culture media. Materials and Methods: Here, we exposed 3D-HepaRG cultures to methotrexate (MTX) and acetaminophen (APAP) and used q-RT-PCR to investigate miRNAs as potentially sensitive markers of hepatotoxicity in vitro, with a specific focus on the exosomal release. We investigated three miRNAs, miR-122-5p and miR-192-5p, both associated with hepatic damage, and miR-34a-5p, involved with apoptosis. Metabolic activity, urea and albumin release were assessed to confirm key hepatocellular characteristics of 3D-HepaRG. Results: The 3D-HepaRG model was able to metabolise testosterone, produced urea and albumin. APAP treatment increased exosomal release of all three tested miRNAs, while MTX increased miR-122-5p release only. Absolute quantification of miR-122-5p corroborated the release of this miRNA by both treatments. Discussion: Exosomes could be efficiently isolated from 3D-HepaRG, characterized, and used for miRNA extraction and quantification. We identified that total extracellular and exosomal-miR-122-5p release occurred at concentrations lower than those leading to MTX-induced apoptosis/necrosis, which corroborate previous findings using other hepatotoxic compounds. Conclusion: Our results demonstrate the suitability of 3D-HepaRG combined with exosomal miRNA measurement for the detection of hepatotoxicity in vitro. Specifically, exosomal-miR-122-5p is a sensitive marker of APAP-and MTX-induced in vitro damage.

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Human Ex-Vivo Liver Model for Acetaminophen-induced Liver Damage

Cited by 20 publications

References 21 publications

Bioprinted 3D vascularized tissue model for drug toxicity analysis

Bioprinted 3D vascularized tissue model for drug toxicity analysis

An Experimental Study to Measure the Mechanical Properties of the Human Liver

Exosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver InjuryIn Vitro

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