Journal articles: 'In Vitro Liver Models'

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ERKEKOĞLU, Pınar, and Belma KOÇER GÜMÜŞEL. "In Vitro Liver Models in Toxicology." Journal of Literature Pharmacy Sciences 8, no. 1 (2019): 1–17. http://dx.doi.org/10.5336/pharmsci.2018-61664.

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Guillouzo, Andre. "Liver Cell Models in in Vitro Toxicology." Environmental Health Perspectives 106 (April 1998): 511. http://dx.doi.org/10.2307/3433803.

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Guillouzo, A. "Liver cell models in in vitro toxicology." Environmental Health Perspectives 106, suppl 2 (April 1998): 511–32. http://dx.doi.org/10.1289/ehp.98106511.

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Witek, Rafal P., and Jessica A. Bonzo. "Perspective on In Vitro Liver Toxicity Models." Applied In Vitro Toxicology 4, no. 3 (September 2018): 229–31. http://dx.doi.org/10.1089/aivt.2018.29017.wit.

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Soldatow, Valerie Y., Edward L. LeCluyse, Linda G. Griffith, and Ivan Rusyn. "In vitro models for liver toxicity testing." Toxicol. Res. 2, no. 1 (2013): 23–39. http://dx.doi.org/10.1039/c2tx20051a.

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van Grunsven, Leo A. "3D in vitro models of liver fibrosis." Advanced Drug Delivery Reviews 121 (November 2017): 133–46. http://dx.doi.org/10.1016/j.addr.2017.07.004.

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Ye, Shicheng, Jochem W. B. Boeter, Louis C. Penning, Bart Spee, and Kerstin Schneeberger. "Hydrogels for Liver Tissue Engineering." Bioengineering 6, no. 3 (July 5, 2019): 59. http://dx.doi.org/10.3390/bioengineering6030059.

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Bioengineered livers are promising in vitro models for drug testing, toxicological studies, and as disease models, and might in the future be an alternative for donor organs to treat end-stage liver diseases. Liver tissue engineering (LTE) aims to construct liver models that are physiologically relevant. To make bioengineered livers, the two most important ingredients are hepatic cells and supportive materials such as hydrogels. In the past decades, dozens of hydrogels have been developed to act as supportive materials, and some have been used for in vitro models and formed functional liver constructs. However, currently none of the used hydrogels are suitable for in vivo transplantation. Here, the histology of the human liver and its relationship with LTE is introduced. After that, significant characteristics of hydrogels are described focusing on LTE. Then, both natural and synthetic materials utilized in hydrogels for LTE are reviewed individually. Finally, a conclusion is drawn on a comparison of the different hydrogels and their characteristics and ideal hydrogels are proposed to promote LTE.

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Vinken, M. "Liver-based in vitro models for toxicity testing." Toxicology Letters 295 (October 2018): S7. http://dx.doi.org/10.1016/j.toxlet.2018.06.029.

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Garcia, Martha C., Margaret Amankwa-Sakyi, and Thomas J. Flynn. "Cellular glutathione in fatty liver in vitro models." Toxicology in Vitro 25, no. 7 (October 2011): 1501–6. http://dx.doi.org/10.1016/j.tiv.2011.05.011.

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Van de Bovenkamp, M., G. M. M. Groothuis, D. K. F. Meijer, and P. Olinga. "Liver fibrosis in vitro: Cell culture models and precision-cut liver slices." Toxicology in Vitro 21, no. 4 (June 2007): 545–57. http://dx.doi.org/10.1016/j.tiv.2006.12.009.

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Orbach, Sophia M., Rebekah R. Less, Anjaney Kothari, and Padmavathy Rajagopalan. "In Vitro Intestinal and Liver Models for Toxicity Testing." ACS Biomaterials Science & Engineering 3, no. 9 (January 23, 2017): 1898–910. http://dx.doi.org/10.1021/acsbiomaterials.6b00699.

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Müller, Fabrice A., and Shana J. Sturla. "Human in vitro models of nonalcoholic fatty liver disease." Current Opinion in Toxicology 16 (August 2019): 9–16. http://dx.doi.org/10.1016/j.cotox.2019.03.001.

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Mun, Seon Ju, Jaeseo Lee, Yongbo Shin, and Myung Jin Son. "Advanced human liver models for the assessment of drug-induced liver injury." Organoid 2 (July 25, 2022): e17. http://dx.doi.org/10.51335/organoid.2022.2.e17.

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Drug safety issues continue to occur even with drugs that are approved after the completion of clinical studies. Drug-induced liver injury (DILI) is a major obstacle to drug development, because the liver is the primary site of drug metabolism, and injuries caused during this process are severe. Conventional in vitro human liver models, such as 2-dimensional hepatic cell lines, lack in vivo physiological relevance, and animal studies have limitations in the form of species differences and regulatory restrictions. To resolve this issue, an increasing number of 3-dimensional human liver systems, including organoids, are being developed. In this review, we provide an overview of recent assessments of DILI prediction, approaches for in vitro hepatotoxicity evaluation, and a variety of advanced human liver models. We discuss the advantages, limitations, and future perspectives of current human liver models for accurate drug safety evaluations.

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Benesic, Andreas, and Alexander L. Gerbes. "Drug-Induced Liver Injury and Individual Cell Models." Digestive Diseases 33, no. 4 (2015): 486–91. http://dx.doi.org/10.1159/000374094.

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Drug-induced liver injury (DILI) is the most common cause of acute liver failure and accounts for the majority of regulatory actions on drugs. Furthermore, DILI is a relevant cause for project terminations in pharmaceutical development. The idiosyncratic form of DILI is especially a threat in late clinical development phases and postmarketing, respectively. Even the occurrence of only a few idiosyncratic DILI cases in late clinical development or postmarketing may suffice to terminate or withdraw an otherwise promising therapy. Despite advances in preclinical assessment of dose-dependent toxicity, idiosyncratic DILI is still a big challenge for in vitro research: it not only requires individualized models but also a huge number of tests. We have developed and investigated MetaHeps®, a technology involving hepatocyte-like cells generated from peripheral monocytes without genetic modifications. These cells exhibit several hepatocyte-like characteristics and show donor-specific activities of drug-metabolizing enzymes. With MetaHeps we have performed in vitro investigations in patients with DILI suspicion. By investigating MetaHeps derived from DILI patients we could show increased in vitro susceptibility to the drugs involved in the individual patients. MetaHeps testing could also rule out DILI and help to identify other causes of acute liver injury. Moreover, MetaHeps identified the causative agent in polymedicated patients. In conclusion, in vitro research of idiosyncratic DILI requires individual cell models which produce results comparable to the clinical situation. We suggest the MetaHeps technology as a novel tool to cope with these challenges of DILI.

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Sari, Gulce, Gertine W. van Oord, Martijn D. B. van de Garde, Jolanda J. C. Voermans, Andre Boonstra, and Thomas Vanwolleghem. "Sexual Dimorphism in Hepatocyte Xenograft Models." Cell Transplantation 30 (January 1, 2021): 096368972110061. http://dx.doi.org/10.1177/09636897211006132.

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Humanized liver mouse models are crucial tools in liver research, specifically in the fields of liver cell biology, viral hepatitis and drug metabolism. The livers of these humanized mouse models are repopulated by 3-dimensional islands of fully functional primary human hepatocytes (PHH), which are notoriously difficult to maintain in vitro. As low efficiency and high cost hamper widespread use, optimization is of great importance. In the present study, we analyzed experimental factors associated with Hepatitis E virus (HEV) infection and PHH engraftment in 2 xenograft systems on a Nod-SCID-IL2Ry-/- background: the alb-urokinase plasminogen activator mouse model (uPA-NOG, n=399); and the alb-HSV thymidine kinase model (TK-NOG, n = 198). In a first analysis, HEV fecal shedding in liver humanized uPA-NOG and TK-NOG mice with comparable human albumin levels was found to be similar irrespective of the mouse genetic background. In a second analysis, sex, mouse age at transplantation and hepatocyte donor were the most determinant factors for xenograft success in both models. The sexual imbalance for xenograft success was related to higher baseline ALT levels and lower thresholds for ganciclovir induced liver morbidity and mortality in males. These data call for sexual standardization of human hepatocyte xenograft models, but also provide a platform for further studies on mechanisms behind sexual dimorphism in liver diseases.

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Miyamoto, Yoshitaka, Yumie Koshidaka, Katsutoshi Murase, Shoichiro Kanno, Hirofumi Noguchi, Kenji Miyado, Takeshi Ikeya, et al. "Functional Evaluation of 3D Liver Models Labeled with Polysaccharide Functionalized Magnetic Nanoparticles." Materials 15, no. 21 (November 5, 2022): 7823. http://dx.doi.org/10.3390/ma15217823.

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Establishing a rapid in vitro evaluation system for drug screening is essential for the development of new drugs. To reproduce tissues/organs with functions closer to living organisms, in vitro three-dimensional (3D) culture evaluation using microfabrication technology has been reported in recent years. Culture on patterned substrates with controlled hydrophilic and hydrophobic regions (Cell-ableTM) can create 3D liver models (miniature livers) with liver-specific Disse luminal structures and functions. MRI contrast agents are widely used as safe and minimally invasive diagnostic methods. We focused on anionic polysaccharide magnetic iron oxide nanoparticles (Resovist®) and synthesized the four types of nanoparticle derivatives with different properties. Cationic nanoparticles (TMADM) can be used to label target cells in a short time and have been successfully visualized in vivo. In this study, we examined the morphology of various nanoparticles. The morphology of various nanoparticles showed relatively smooth-edged spherical shapes. As 3D liver models, we prepared primary hepatocyte–endothelial cell heterospheroids. The toxicity, CYP3A, and albumin secretory capacity were evaluated in the heterospheroids labeled with various nanoparticles. As the culture period progressed, the heterospheroids labeled with anionic and cationic nanoparticles showed lower liver function than non-labeled heterospheroids. In the future, there is a need to improve the method of creation of artificial 3D liver or to design a low-invasive MRI contrast agent to label the artificial 3D liver.

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Sun, Lulu, and Lijian Hui. "Progress in human liver organoids." Journal of Molecular Cell Biology 12, no. 8 (April 1, 2020): 607–17. http://dx.doi.org/10.1093/jmcb/mjaa013.

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Abstract Understanding the development, regeneration, and disorders of the liver is the major goal in liver biology. Current mechanistic knowledge of human livers has been largely derived from mouse models and cell lines, which fall short in recapitulating the features of human liver cells or the structures and functions of human livers. Organoids as an in vitro system hold the promise to generate organ-like tissues in a dish. Recent advances in human liver organoids also facilitate the understanding of the biology and diseases in this complex organ. Here we review the progress in human liver organoids, mainly focusing on the methods to generate liver organoids, their applications, and possible future directions.

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Donato, M. Teresa, Gloria Gallego-Ferrer, and Laia Tolosa. "In Vitro Models for Studying Chronic Drug-Induced Liver Injury." International Journal of Molecular Sciences 23, no. 19 (September 28, 2022): 11428. http://dx.doi.org/10.3390/ijms231911428.

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Drug-induced liver injury (DILI) is a major clinical problem in terms of patient morbidity and mortality, cost to healthcare systems and failure of the development of new drugs. The need for consistent safety strategies capable of identifying a potential toxicity risk early in the drug discovery pipeline is key. Human DILI is poorly predicted in animals, probably due to the well-known interspecies differences in drug metabolism, pharmacokinetics, and toxicity targets. For this reason, distinct cellular models from primary human hepatocytes or hepatoma cell lines cultured as 2D monolayers to emerging 3D culture systems or the use of multi-cellular systems have been proposed for hepatotoxicity studies. In order to mimic long-term hepatotoxicity in vitro, cell models, which maintain hepatic phenotype for a suitably long period, should be used. On the other hand, repeated-dose administration is a more relevant scenario for therapeutics, providing information not only about toxicity, but also about cumulative effects and/or delayed responses. In this review, we evaluate the existing cell models for DILI prediction focusing on chronic hepatotoxicity, highlighting how better characterization and mechanistic studies could lead to advance DILI prediction.

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Venkatachalam, Ananda Baskaran, Scott Michael Livingstone, Qianni Hu, Ayush Ray, Caroline Wood, Sanem Cimen, and Ian Patrick Joseph Alwayn. "Delivery of Soluble Heme Oxygenase 1 Cell-Penetrating Peptide into Liver Cells in in vitro and ex vivo Models of Cold Ischemia." European Surgical Research 58, no. 1-2 (November 12, 2016): 51–68. http://dx.doi.org/10.1159/000451079.

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Background/Purpose: Liver transplantation is the treatment of choice in patients with end-stage liver disease. During liver transplantation, ischemia-reperfusion injury (IRI) occurs, which is an inevitable consequence of the transplantation process. To reduce the extent of cellular injury, one of the proteins that have been extensively investigated is heme oxygenase 1 (HO-1), which plays an important role in protecting the organs against IRI. The aim of this study was to introduce an active and functional HO-1 protein conjugated to a cell-penetrating peptide (CPP) in vitro and ex vivo into liver cells in hypothermic and anoxic conditions and to assert its cytoprotective effects. Methods: We generated an enzymatically active soluble (s)HO-1-CPP recombinant protein. The ability of the sHO-1-CPP protein to penetrate McA-RH7777, Clone 9, and Hep G2 cells, primary hepatocytes, and Kupffer and human umbilical vein endothelial cells in vitro, as well as its ability to penetrate a whole liver ex vivo under hypothermic and anoxic conditions, was assessed. An in vitro hypoxia-reoxygenation (HR) model was used to determine the cytoprotective effect of the sHO-1-CPP protein. Results: We showed that our recombinant protein sHO-1-CPP can cross cell membranes into rodent and human liver cells in vitro, and the results were further validated ex vivo, where rodent livers were perfused with an organ preservation solution supplemented with sHO-1-CPP under anoxic and hypothermic conditions. Immunohistochemistry revealed an intracellular localization of sHO-1-CPP in zones 1-3 of the perfused livers. The CPP did not exert any significant toxicity on the cells. Treating cells with sHO-1-CPP showed significant cytoprotection in the in vitro HR model. Conclusions: Our findings show that the recombinant protein sHO-1-CPP can be successfully delivered to cells of a whole organ in an ex vivo hypothermic and anoxic perfusion model and that it provides cytoprotection to hepatocytes in an in vitro HR model. These results hold great potential for future repair and protection of donor organs. Future experiments are planned to confirm these data in in vivo models of IRI.

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van Tienderen, Groot Koerkamp, IJzermans, van der Laan, and Verstegen. "Recreating Tumour Complexity in a Dish: Organoid Models to Study Liver Cancer Cells and their Extracellular Environment." Cancers 11, no. 11 (November 1, 2019): 1706. http://dx.doi.org/10.3390/cancers11111706.

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Primary liver cancer, consisting predominantly of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), remains one of the most lethal malignancies worldwide. This high malignancy is related to the complex and dynamic interactions between tumour cells, stromal cells and the extracellular environment. Novel in vitro models that can recapitulate the tumour are essential in increasing our understanding of liver cancer. Herein, primary liver cancer-derived organoids have opened up new avenues due to their patient-specificity, self-organizing ability and potential recapitulation of many of the tumour properties. Organoids are solely of epithelial origin, but incorporation into co-culture models can enable the investigation of the cellular component of the tumour microenvironment. However, the extracellular component also plays a vital role in cancer progression and representation is lacking within current in vitro models. In this review, organoid technology is discussed in the context of liver cancer models through comparisons to other cell culture systems. In addition, the role of the tumour extracellular environment in primary liver cancer will be highlighted with an emphasis on its importance in in vitro modelling. Converging novel organoid-based models with models incorporating the native tumour microenvironment could lead to experimental models that can better recapitulate liver tumours in vivo.

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Dong, Gang, Xiaoquan Huang, Rongxin Chen, Ling Wu, Siyu Jiang, and Shiyao Chen. "Increased PD-L1 Restricts Liver Injury in Nonalcoholic Fatty Liver Disease." Oxidative Medicine and Cellular Longevity 2022 (May 16, 2022): 1–18. http://dx.doi.org/10.1155/2022/5954437.

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PD-L1 is a critical checkpoint that protects tissues from autoimmune injury. Nevertheless, the role of PD-L1 in nonalcoholic fatty liver disease- (NAFLD-) induced liver damage is still unclear. In this study, we examined the role and mechanism of PD-L1 expression on NAFLD-induced liver damage in vitro and in vivo. PD-L1 expression in the livers from patients with NAFLD, and LO2 cells treated by FFA, was significantly increased. FFA triggers a large amount of ROS (generated from NOX4 and damaged mitochondria), promoting the ZNF24 expression and suppressing ZN24 sumoylation, both of which enhance the PD-L1 transcription and expression. The knockdown of PD-L1 increases CD8 + T cells’ damage to FFA-treated LO2 cells, while its upregulation limits the liver injury in NAFLD models. Collectively, we demonstrate that FFA promotes PD-L1 expression through the ROS/ZNF24 pathway and suppresses UBE2I-mediated ZNF24 sumoylation to enhance its transcriptional activity of PD-L1. PD-L1 upregulation limits FFA-induced injury of hepatocytes in vitro and in vivo.

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Lee, Sang Woo, Da Jung Jung, and Gi Seok Jeong. "Gaining New Biological and Therapeutic Applications into the Liver with 3D In Vitro Liver Models." Tissue Engineering and Regenerative Medicine 17, no. 6 (March 23, 2020): 731–45. http://dx.doi.org/10.1007/s13770-020-00245-9.

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Llewellyn, Samantha V., Marije Niemeijer, Penny Nymark, Martijn J. Moné, Bob Water, Gillian E. Conway, Gareth J. S. Jenkins, and Shareen H. Doak. "In Vitro Three‐Dimensional Liver Models for Nanomaterial DNA Damage Assessment." Small 17, no. 15 (January 15, 2021): 2006055. http://dx.doi.org/10.1002/smll.202006055.

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Haugabook, Sharie J., Marc Ferrer, and Elizabeth A. Ottinger. "In vitro and in vivo translational models for rare liver diseases." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1865, no. 5 (May 2019): 1003–18. http://dx.doi.org/10.1016/j.bbadis.2018.07.029.

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Simeonova, Rumyana, Magdalena Kondeva-Burdina, Vessela Vitcheva, and Mitka Mitcheva. "SomeIn Vitro/In VivoChemically-Induced Experimental Models of Liver Oxidative Stress in Rats." BioMed Research International 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/706302.

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Oxidative stress is critically involved in a variety of diseases. Reactive oxygen species (ROS) are highly toxic molecules that are generated during the body's metabolic reactions and can react with and damage some cellular molecules such as lipids, proteins, or DNA. Liver is an important target of the oxidative stress because of its exposure to various prooxidant toxic compounds as well as of its metabolic function and ability to transform some xenobiotics to reactive toxic metabolites (as ROS). To investigate the processes of liver injuries and especially liver oxidative damages there are many experimental models, some of which we discuss further.

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Yun, Chawon, Sou Hyun Kim, and Young-Suk Jung. "Current Research Trends in the Application of In Vitro Three-Dimensional Models of Liver Cells." Pharmaceutics 15, no. 1 (December 24, 2022): 54. http://dx.doi.org/10.3390/pharmaceutics15010054.

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The liver produces and stores various nutrients that are necessary for the body and serves as a chemical plant, metabolizing carbohydrates, fats, hormones, vitamins, and minerals. It is also a vital organ for detoxifying drugs and exogenous harmful substances. Culturing liver cells in vitro under three-dimensional (3D) conditions is considered a primary mechanism for liver tissue engineering. The 3D cell culture system is designed to allow cells to interact in an artificially created environment and has the advantage of mimicking the physiological characteristics of cells in vivo. This system facilitates contact between the cells and the extracellular matrix. Several technically different approaches have been proposed, including bioreactors, chips, and plate-based systems in fluid or static media composed of chemically diverse materials. Compared to conventional two-dimensional monolayer culture in vitro models, the ability to predict the function of the tissues, including the drug metabolism and chemical toxicity, has been enhanced by developing three-dimensional liver culture models. This review discussed the methodology of 3D cell cultures and summarized the advantages of an in vitro liver platform using 3D culture technology.

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Soret, Pierre-Antoine, Julie Magusto, Chantal Housset, and Jérémie Gautheron. "In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal." Journal of Clinical Medicine 10, no. 1 (December 24, 2020): 36. http://dx.doi.org/10.3390/jcm10010036.

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Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), represents the hepatic manifestation of obesity and metabolic syndrome. Due to the spread of the obesity epidemic, NAFLD is becoming the most common chronic liver disease and one of the principal indications for liver transplantation. However, no pharmacological treatment is currently approved to prevent the outbreak of NASH, which leads to fibrosis and cirrhosis. Preclinical research is required to improve our knowledge of NAFLD physiopathology and to identify new therapeutic targets. In the present review, we summarize advances in NAFLD preclinical models from cellular models, including new bioengineered platforms, to in vivo models, with a particular focus on genetic and dietary mouse models. We aim to discuss the advantages and limits of these different models.

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Arez, Francisca, Ana F. Rodrigues, Catarina Brito, and Paula M. Alves. "Bioengineered Liver Cell Models of Hepatotropic Infections." Viruses 13, no. 5 (April 27, 2021): 773. http://dx.doi.org/10.3390/v13050773.

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Hepatitis viruses and liver-stage malaria are within the liver infections causing higher morbidity and mortality rates worldwide. The highly restricted tropism of the major human hepatotropic pathogens—namely, the human hepatitis B and C viruses and the Plasmodium falciparum and Plasmodium vivax parasites—has hampered the development of disease models. These models are crucial for uncovering the molecular mechanisms underlying the biology of infection and governing host–pathogen interaction, as well as for fostering drug development. Bioengineered cell models better recapitulate the human liver microenvironment and extend hepatocyte viability and phenotype in vitro, when compared with conventional two-dimensional cell models. In this article, we review the bioengineering tools employed in the development of hepatic cell models for studying infection, with an emphasis on 3D cell culture strategies, and discuss how those tools contributed to the level of recapitulation attained in the different model layouts. Examples of host–pathogen interactions uncovered by engineered liver models and their usefulness in drug development are also presented. Finally, we address the current bottlenecks, trends, and prospect toward cell models’ reliability, robustness, and reproducibility.

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Pelechá, María, Estela Villanueva-Bádenas, Enrique Timor-López, María Teresa Donato, and Laia Tolosa. "Cell Models and Omics Techniques for the Study of Nonalcoholic Fatty Liver Disease: Focusing on Stem Cell-Derived Cell Models." Antioxidants 11, no. 1 (December 30, 2021): 86. http://dx.doi.org/10.3390/antiox11010086.

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Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in western countries. The molecular mechanisms leading to NAFLD are only partially understood, and effective therapeutic interventions are clearly needed. Therefore, preclinical research is required to improve knowledge about NAFLD physiopathology and to identify new therapeutic targets. Primary human hepatocytes, human hepatic cell lines, and human stem cell-derived hepatocyte-like cells exhibit different hepatic phenotypes and have been widely used for studying NAFLD pathogenesis. In this paper, apart from employing the different in vitro cell models for the in vitro assessment of NAFLD, we also reviewed other approaches (metabolomics, transcriptomics, and high-content screening). We aimed to summarize the characteristics of different cell types and methods and to discuss their major advantages and disadvantages for NAFLD modeling.

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Herrero, Alba, Elisabeth Knetemann, and Inge Mannaerts. "Review: Challenges of In Vitro CAF Modelling in Liver Cancers." Cancers 13, no. 23 (November 24, 2021): 5914. http://dx.doi.org/10.3390/cancers13235914.

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Primary and secondary liver cancer are the third cause of death in the world, and as the incidence is increasing, liver cancer represents a global health burden. Current treatment strategies are insufficient to permanently cure patients from this devastating disease, and therefore other approaches are under investigation. The importance of cancer-associated fibroblasts (CAFs) in the tumour microenvironment is evident, and many pre-clinical studies have shown increased tumour aggressiveness in the presence of CAFs. However, it remains unclear how hepatic stellate cells are triggered by the tumour to become CAFs and how the recently described CAF subtypes originate and orchestrate pro-tumoural effects. Specialized in vitro systems will be needed to address these questions. In this review, we present the currently used in vitro models to study CAFs in primary and secondary liver cancer and highlight the trend from using oversimplified 2D culture systems to more complex 3D models. Relatively few studies report on the impact of cancer (sub)types on CAFs and the tumour microenvironment, and most studies investigated the impact of secreted factors due to the nature of the models.

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Kukla, David A., and Salman R. Khetani. "Bioengineered Liver Models for Investigating Disease Pathogenesis and Regenerative Medicine." Seminars in Liver Disease 41, no. 03 (June 17, 2021): 368–92. http://dx.doi.org/10.1055/s-0041-1731016.

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AbstractOwing to species-specific differences in liver pathways, in vitro human liver models are utilized for elucidating mechanisms underlying disease pathogenesis, drug development, and regenerative medicine. To mitigate limitations with de-differentiated cultures, bioengineers have developed advanced techniques/platforms, including micropatterned cocultures, spheroids/organoids, bioprinting, and microfluidic devices, for perfusing cell cultures and liver slices. Such techniques improve mature functions and culture lifetime of primary and stem-cell human liver cells. Furthermore, bioengineered liver models display several features of liver diseases including infections with pathogens (e.g., malaria, hepatitis C/B viruses, Zika, dengue, yellow fever), alcoholic/nonalcoholic fatty liver disease, and cancer. Here, we discuss features of bioengineered human liver models, their uses for modeling aforementioned diseases, and how such models are being augmented/adapted for fabricating implantable human liver tissues for clinical therapy. Ultimately, continued advances in bioengineered human liver models have the potential to aid the development of novel, safe, and efficacious therapies for liver disease.

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Kulkeaw, Kasem. "Next-Generation Human Liver Models for Antimalarial Drug Assays." Antibiotics 10, no. 6 (May 27, 2021): 642. http://dx.doi.org/10.3390/antibiotics10060642.

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Advances in malaria prevention and treatment have significantly reduced the related morbidity and mortality worldwide, however, malaria continues to be a major threat to global public health. Because Plasmodium parasites reside in the liver prior to the appearance of clinical manifestations caused by intraerythrocytic development, the Plasmodium liver stage represents a vulnerable therapeutic target to prevent progression. Currently, a small number of drugs targeting liver-stage parasites are available, but all cause lethal side effects in glucose-6-phosphate dehydrogenase-deficient individuals, emphasizing the necessity for new drug development. Nevertheless, a longstanding hurdle to developing new drugs is the availability of appropriate in vitro cultures, the crucial conventional platform for evaluating the efficacy and toxicity of drugs in the preclinical phase. Most current cell culture systems rely primarily on growing immortalized or cancerous cells in the form of a two-dimensional monolayer, which is not very physiologically relevant to the complex cellular architecture of the human body. Although primary human cells are more relevant to human physiology, they are mainly hindered by batch-to-batch variation, limited supplies, and ethical issues. Advances in stem cell technologies and multidimensional culture have allowed the modelling of human infectious diseases. Here, current in vitro hepatic models and toolboxes for assaying the antimalarial drug activity are summarized. Given the physiological potential of pluripotent and adult stem cells to model liver-stage malaria, the opportunities and challenges in drug development against liver-stage malaria is highlighted, paving the way to assess the efficacy of hepatic plasmodicidal activity.

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Vergani, Laura. "Fatty Acids and Effects on In Vitro and In Vivo Models of Liver Steatosis." Current Medicinal Chemistry 26, no. 19 (September 12, 2019): 3439–56. http://dx.doi.org/10.2174/0929867324666170518101334.

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Background: Fatty liver, or steatosis, is a condition of excess accumulation of lipids, mainly under form of triglycerides (TG), in the liver, and it is the hallmark of non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common liver disorder world-wide and it has frequently been associated with obesity, hyperlipidemia and insulin resistance. Free fatty acids (FA) are the major mediators of hepatic steatosis; patients with NAFLD have elevated levels of circulating FA that correlate with disease severity. Methods: Steatosis is a reversible condition that can be resolved with changed behaviors, or that can progress towards more severe liver damages such as steatohepatitis (NASH), fibrosis and cirrhosis. In NAFLD, FA of exogenous or endogenous origin accumulate in the hepatocytes and trigger liver damages. Excess TG are stored in cytosolic lipid droplets (LDs) that are dynamic organelles acting as hubs for lipid metabolism. Results: In the first part of this review, we briefly reassumed the main classes of FA and their chemical classification as a function of the presence and number of double bonds, their metabolic pathways and effects on human health. Then, we summarized the main genetic and diet-induced animal models of NAFLD, as well as the cellular models of NAFLD. Conclusions: In recent years, both the diet-induced animal models of NAFLD as well as the cellular models of NAFLD have found ever more application to investigate the mechanisms involved in NAFLD, and we referred to their advantages and disadvantages.

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Zhang, Xuequn, Yiming Lin, Sisi Lin, Chunxiao Li, Jianguo Gao, Zemin Feng, Jinghua Wang, et al. "Silencing of functional p53 attenuates NAFLD by promoting HMGB1-related autophagy induction." Hepatology International 14, no. 5 (June 30, 2020): 828–41. http://dx.doi.org/10.1007/s12072-020-10068-4.

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Abstract Background and aim Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, but its pathogenesis remains imprecisely understood and requires further clarification. Recently, the tumor suppressor p53 has received growing attention for its role in metabolic diseases. In this study, we performed in vivo and in vitro experiments to identify the contribution of p53–autophagy regulation to NAFLD. Methods Livers from wild-type and p53 knockout mice as well as p53-functional HepG2 cells and p53-dysfunctional Huh7 cells were examined for autophagy status and HMGB1 translocation. In vivo and in vitro NAFLD models were established, and steatosis was detected. In the cell models, autophagy status and steatosis were examined by p53 and/or HMGB1 silencing. Results First, the silencing of p53 could induce autophagy both in vivo and in vitro. In addition, p53 knockout attenuated high-fat diet-induced NAFLD in mice. Similarly, knockdown of p53 could alleviate palmitate-induced lipid accumulation in cell models. Furthermore, high mobility group box 1 (HMGB1) was proven to contribute to the effect of silencing p53 on alleviating NAFLD in vitro as an autophagy regulator. Conclusion The anti-NAFLD effect of functional p53 silencing is associated with the HMGB1-mediated induction of autophagy. Graphic abstract

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Sassi, Lisa, Omolola Ajayi, Sara Campinoti, Dipa Natarajan, Claire McQuitty, Riccardo Rayan Siena, Sara Mantero, et al. "A Perfusion Bioreactor for Longitudinal Monitoring of Bioengineered Liver Constructs." Nanomaterials 11, no. 2 (January 21, 2021): 275. http://dx.doi.org/10.3390/nano11020275.

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In the field of in vitro liver disease models, decellularised organ scaffolds maintain the original biomechanical and biological properties of the extracellular matrix and are established supports for in vitro cell culture. However, tissue engineering approaches based on whole organ decellularized scaffolds are hampered by the scarcity of appropriate bioreactors that provide controlled 3D culture conditions. Novel specific bioreactors are needed to support long-term culture of bioengineered constructs allowing non-invasive longitudinal monitoring. Here, we designed and validated a specific bioreactor for long-term 3D culture of whole liver constructs. Whole liver scaffolds were generated by perfusion decellularisation of rat livers. Scaffolds were seeded with Luc+HepG2 and primary human hepatocytes and cultured in static or dynamic conditions using the custom-made bioreactor. The bioreactor included a syringe pump, for continuous unidirectional flow, and a circuit built to allow non-invasive monitoring of culture parameters and media sampling. The bioreactor allowed non-invasive analysis of cell viability, distribution, and function of Luc+HepG2-bioengineered livers cultured for up to 11 days. Constructs cultured in dynamic conditions in the bioreactor showed significantly higher cell viability, measured with bioluminescence, distribution, and functionality (determined by albumin production and expression of CYP enzymes) in comparison to static culture conditions. Finally, our bioreactor supports primary human hepatocyte viability and function for up to 30 days, when seeded in the whole liver scaffolds. Overall, our novel bioreactor is capable of supporting cell survival and metabolism and is suitable for liver tissue engineering for the development of 3D liver disease models.

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Crizer, David M., Sreenivasa C. Ramaiahgari, Stephen S. Ferguson, Julie R. Rice, Paul E. Dunlap, Nisha S. Sipes, Scott S. Auerbach, Bruce Alex Merrick, and Michael J. DeVito. "Benchmark Concentrations for Untargeted Metabolomics Versus Transcriptomics for Liver Injury Compounds in In Vitro Liver Models." Toxicological Sciences 181, no. 2 (March 22, 2021): 175–86. http://dx.doi.org/10.1093/toxsci/kfab036.

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Abstract Interpretation of untargeted metabolomics data from both in vivo and physiologically relevant in vitro model systems continues to be a significant challenge for toxicology research. Potency-based modeling of toxicological responses has served as a pillar of interpretive context and translation of testing data. In this study, we leverage the resolving power of concentration-response modeling through benchmark concentration (BMC) analysis to interpret untargeted metabolomics data from differentiated cultures of HepaRG cells exposed to a panel of reference compounds and integrate data in a potency-aligned framework with matched transcriptomic data. For this work, we characterized biological responses to classical human liver injury compounds and comparator compounds, known to not cause liver injury in humans, at 10 exposure concentrations in spent culture media by untargeted liquid chromatography-mass spectrometry analysis. The analyte features observed (with limited metabolites identified) were analyzed using BMC modeling to derive compound-induced points of departure. The results revealed liver injury compounds produced concentration-related increases in metabolomic response compared to those rarely associated with liver injury (ie, sucrose, potassium chloride). Moreover, the distributions of altered metabolomic features were largely comparable with those observed using high throughput transcriptomics, which were further extended to investigate the potential for in vitro observed biological responses to be observed in humans with exposures at therapeutic doses. These results demonstrate the utility of BMC modeling of untargeted metabolomics data as a sensitive and quantitative indicator of human liver injury potential.

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Tricot, Tine, Catherine M. Verfaillie, and Manoj Kumar. "Current Status and Challenges of Human Induced Pluripotent Stem Cell-Derived Liver Models in Drug Discovery." Cells 11, no. 3 (January 27, 2022): 442. http://dx.doi.org/10.3390/cells11030442.

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The pharmaceutical industry is in high need of efficient and relevant in vitro liver models, which can be incorporated in their drug discovery pipelines to identify potential drugs and their toxicity profiles. Current liver models often rely on cancer cell lines or primary cells, which both have major limitations. However, the development of human induced pluripotent stem cells (hiPSCs) has created a new opportunity for liver disease modeling, drug discovery and liver toxicity research. hiPSCs can be differentiated to any cell of interest, which makes them good candidates for disease modeling and drug discovery. Moreover, hiPSCs, unlike primary cells, can be easily genome-edited, allowing the creation of reporter lines or isogenic controls for patient-derived hiPSCs. Unfortunately, even though liver progeny from hiPSCs has characteristics similar to their in vivo counterparts, the differentiation of iPSCs to fully mature progeny remains highly challenging and is a major obstacle for the full exploitation of these models by pharmaceutical industries. In this review, we discuss current liver-cell differentiation protocols and in vitro iPSC-based liver models that could be used for disease modeling and drug discovery. Furthermore, we will discuss the challenges that still need to be overcome to allow for the successful implementation of these models into pharmaceutical drug discovery platforms.

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Yudhani, Ratih D., Yulia Sari, Dwi A. A. Nugrahaningsih, Eti N. Sholikhah, Maftuchah Rochmanti, Abdul K. R. Purba, Husnul Khotimah, Dian Nugrahenny, and Mustofa Mustofa. "In Vitro Insulin Resistance Model: A Recent Update." Journal of Obesity 2023 (January 18, 2023): 1–13. http://dx.doi.org/10.1155/2023/1964732.

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Insulin resistance, which affects insulin-sensitive tissues, including adipose tissues, skeletal muscle, and the liver, is the central pathophysiological mechanism underlying type 2 diabetes progression. Decreased glucose uptake in insulin-sensitive tissues disrupts insulin signaling pathways, particularly the PI3K/Akt pathway. An in vitro model is appropriate for studying the cellular and molecular mechanisms underlying insulin resistance because it is easy to maintain and the results can be easily reproduced. The application of cell-based models for exploring the pathogenesis of diabetes and insulin resistance as well as for developing drugs for these conditions is well known. However, a comprehensive review of in vitro insulin resistance models is lacking. Therefore, this review was conducted to provide a comprehensive overview and summary of the latest in vitro insulin resistance models, particularly 3T3-L1 (preadipocyte), C2C12 (skeletal muscle), and HepG2 (liver) cell lines induced with palmitic acid, high glucose, or chronic exposure to insulin.

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Howell, Lawrence, Rosalind E. Jenkins, Stephen Lynch, Carrie Duckworth, B. Kevin Park, and Christopher Goldring. "Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification." Archives of Toxicology 95, no. 7 (May 29, 2021): 2413–30. http://dx.doi.org/10.1007/s00204-021-03075-3.

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AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

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Lee, Seung Yeon, Donghyun Kim, Seung Hwan Lee, and Jong Hwan Sung. "Microtechnology-based in vitro models: Mimicking liver function and pathophysiology." APL Bioengineering 5, no. 4 (December 1, 2021): 041505. http://dx.doi.org/10.1063/5.0061896.

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Xing, Jia-Li, Yu-Xin Wang, and Shun-Da Du. "Application and research progress of in vitro liver cancer cell culture models." World Chinese Journal of Digestology 29, no. 11 (June 8, 2021): 563–70. http://dx.doi.org/10.11569/wcjd.v29.i11.563.

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C. Chavez-Tapia, N., N. Rosso, and C. Tiribelli. "In Vitro Models for the Study of Non-Alcoholic Fatty Liver Disease." Current Medicinal Chemistry 18, no. 7 (March 1, 2011): 1079–84. http://dx.doi.org/10.2174/092986711794940842.

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Agarkova, Irina, Simon Messner, Christian Zuppinger, Patrina Gunness, Wolfgang Moritz, Jan G. Hengstler, Magnus Ingelman-Sundberg, and Jens M. Kelm. "Organotypic 3D in vitro microtissue models for cardiac and liver safety assessment." Journal of Pharmacological and Toxicological Methods 70, no. 3 (November 2014): 328. http://dx.doi.org/10.1016/j.vascn.2014.03.068.

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Panday, Regeant, Chase P. Monckton, and Salman R. Khetani. "The Role of Liver Zonation in Physiology, Regeneration, and Disease." Seminars in Liver Disease 42, no. 01 (February 2022): 001–16. http://dx.doi.org/10.1055/s-0041-1742279.

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As blood flows from the portal triad to the central vein, cell-mediated depletion establishes gradients of soluble factors such as oxygen, nutrients, and hormones, which act through molecular pathways (e.g., Wnt/β-catenin, hedgehog) to spatially regulate hepatocyte functions along the sinusoid. Such “zonation” can lead to the compartmentalized initiation of several liver diseases, including alcoholic/non-alcoholic fatty liver diseases, chemical/drug-induced toxicity, and hepatocellular carcinoma, and can also modulate liver regeneration. Transgenic rodent models provide valuable information on the key molecular regulators of zonation, while in vitro models allow for subjecting cells to precisely controlled factor gradients and elucidating species–specific differences in zonation. Here, we discuss the latest advances in both in vivo and in vitro models of liver zonation and pending questions to be addressed moving forward. Ultimately, obtaining a deeper understanding of zonation can lead to the development of more effective therapeutics for liver diseases, microphysiological systems, and scalable cell-based therapies.

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Cui, J., H. P. Wang, Q. Shi, and T. Sun. "Pulsed Microfluid Force-Based On-Chip Modular Fabrication for Liver Lobule-Like 3D Cellular Models." Cyborg and Bionic Systems 2021 (April 8, 2021): 1–12. http://dx.doi.org/10.34133/2021/9871396.

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In vitro three-dimensional (3D) cellular models with native tissue-like architectures and functions have potential as alternatives to human tissues in regenerative medicine and drug discovery. However, it is difficult to replicate liver constructs that mimic in vivo microenvironments using current approaches in tissue engineering because of the vessel-embedded 3D structure and complex cell distribution of the liver. This paper reports a pulsed microflow-based on-chip 3D assembly method to construct 3D liver lobule-like models that replicate the spatial structure and functions of the liver lobule. The heterogeneous cell-laden assembly units with hierarchical cell distribution are fabricated through multistep photopatterning of different cell-laden hydrogels. Through fluid force interaction by pulsed microflow, the hierarchical assembly units are driven to a stack, layer by layer, and thus spatially assemble into 3D cellular models in the closed liquid chamber of the assembly chip. The 3D models with liver lobule-like hexagonal morphology and radial cell distribution allow the dynamic perfusion culture to maintain high cell viability and functional expression during long-term culture in vitro. These results demonstrate that the fabricated 3D liver lobule-like models are promising for drug testing and the study of individual diagnoses and treatments.

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KEISER, J. "In vitro and in vivo trematode models for chemotherapeutic studies." Parasitology 137, no. 3 (December 7, 2009): 589–603. http://dx.doi.org/10.1017/s0031182009991739.

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SUMMARYSchistosomiasis and food-borne trematodiases are chronic parasitic diseases affecting millions of people mostly in the developing world. Additional drugs should be developed as only few drugs are available for treatment and drug resistance might emerge. In vitro and in vivo whole parasite screens represent essential components of the trematodicidal drug discovery cascade. This review describes the current state-of-the-art of in vitro and in vivo screening systems of the blood fluke Schistosoma mansoni, the liver fluke Fasciola hepatica and the intestinal fluke Echinostoma caproni. Examples of in vitro and in vivo evaluation of compounds for activity are presented. To boost the discovery pipeline for these diseases there is a need to develop validated, robust high-throughput in vitro systems with simple readouts.

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Schueller, Florian, Sanchari Roy, Sven Heiko Loosen, Jan Alder, Christiane Koppe, Anne Theres Schneider, Franziska Wandrer, et al. "miR-223 represents a biomarker in acute and chronic liver injury." Clinical Science 131, no. 15 (July 13, 2017): 1971–87. http://dx.doi.org/10.1042/cs20170218.

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Background: Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. Methods: We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl4 injection) and chronic (repetitive CCl4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223−/− mice in these models. Results: miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223−/− mice behaved identical with wild-type (wt) mice in all tested models. Conclusion: miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis.

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Wilson, Garrick K., and Zania Stamataki. "In Vitro Systems for the Study of Hepatitis C Virus Infection." International Journal of Hepatology 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/292591.

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The study of a virus is made possible by the availability of culture systems in which the viral lifecycle can be realized. Such systems support robust virus entry, replication, assembly, and secretion of nascent virions. Furthermore, culture models provide a platform in which therapeutic interventions can be devised or monitored. Hepatitis C virus (HCV) has a restricted tropism to human and chimpanzees; thus investigations of HCV biology have been hindered for many years due to a lack of small animal models. Nevertheless, significant efforts have been directed at developing cell culture models to elucidate the viral lifecycle in vitro. HCV primarily infects liver parenchymal cells commonly known as hepatocytes. The liver is a highly specialized and complex organ and the development of in vitro systems that reflects this complexity has proven difficult. Consequently, host cell receptor molecules that potentiate HCV infection were identified over a decade after the virus was discovered. A summary of the various HCV in vitro culture models, their advantages, and disadvantages are described.

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Brown, Grace E., and Salman R. Khetani. "Microfabrication of liver and heart tissues for drug development." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1750 (May 21, 2018): 20170225. http://dx.doi.org/10.1098/rstb.2017.0225.

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Drug-induced liver- and cardiotoxicity remain among the leading causes of preclinical and clinical drug attrition, marketplace drug withdrawals and black-box warnings on marketed drugs. Unfortunately, animal testing has proven to be insufficient for accurately predicting drug-induced liver- and cardiotoxicity across many drug classes, likely due to significant differences in tissue functions across species. Thus, the field of in vitro human tissue engineering has gained increasing importance over the last 10 years. Technologies such as protein micropatterning, microfluidics, three-dimensional scaffolds and bioprinting have revolutionized in vitro platforms as well as increased the long-term phenotypic stability of both primary cells and stem cell-derived differentiated cells. Here, we discuss advances in engineering approaches for constructing in vitro human liver and heart models with utility for drug development. Design features and validation data of representative models are presented to highlight major trends followed by the discussion of pending issues. Overall, bioengineered liver and heart models have significantly advanced our understanding of organ function and injury, which will prove useful for mitigating the risk of drug-induced organ toxicity to human patients, reducing animal usage for preclinical drug testing, aiding in the discovery of novel therapeutics against human diseases, and ultimately for applications in regenerative medicine. This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.

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Romualdo, Guilherme Ribeiro, Kaat Leroy, Cícero Júlio Silva Costa, Gabriel Bacil Prata, Bart Vanderborght, Tereza Cristina da Silva, Luís Fernando Barbisan, et al. "In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling." Cancers 13, no. 21 (November 8, 2021): 5583. http://dx.doi.org/10.3390/cancers13215583.

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Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.

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Journal articles on the topic 'In Vitro Liver Models'

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