Journal articles: 'Liver cell models'

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Zeilinger, Katrin, Nora Freyer, Georg Damm, Daniel Seehofer, and Fanny Knöspel. "Cell sources forin vitrohuman liver cell culture models." Experimental Biology and Medicine 241, no. 15 (July 24, 2016): 1684–98. http://dx.doi.org/10.1177/1535370216657448.

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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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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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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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Amato, G., T. Saleh, G. Carpino, E. Gaudio, D. Alvaro, and V. Cardinale. "Cell Therapy and Bioengineering in Experimental Liver Regenerative Medicine: In Vivo Injury Models and Grafting Strategies." Current Transplantation Reports 8, no. 2 (May 22, 2021): 76–89. http://dx.doi.org/10.1007/s40472-021-00325-2.

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Abstract Purpose of Review To describe experimental liver injury models used in regenerative medicine, cell therapy strategies to repopulate damaged livers and the efficacy of liver bioengineering. Recent Findings Several animal models have been developed to study different liver conditions. Multiple strategies and modified protocols of cell delivery have been also reported. Furthermore, using bioengineered liver scaffolds has shown promising results that could help in generating a highly functional cell delivery system and/or a whole transplantable liver. Summary To optimize the most effective strategies for liver cell therapy, further studies are required to compare among the performed strategies in the literature and/or innovate a novel modifying technique to overcome the potential limitations. Coating of cells with polymers, decellularized scaffolds, or microbeads could be the most appropriate solution to improve cellular efficacy. Besides, overcoming the problems of liver bioengineering may offer a radical treatment for end-stage liver diseases.

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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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Peters, Marion G. "Animal models of autoimmune liver disease." Immunology and Cell Biology 80, no. 1 (February 2002): 113–16. http://dx.doi.org/10.1046/j.0818-9641.2001.01059.x.

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Alison, Malcolm R. "Adult stem cell-derived liver stem cells as models for hepatotoxicity." Toxicology 226, no. 1 (September 2006): 32. http://dx.doi.org/10.1016/j.tox.2006.05.049.

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So, Juhoon, Angie Kim, Seung-Hoon Lee, and Donghun Shin. "Liver progenitor cell-driven liver regeneration." Experimental & Molecular Medicine 52, no. 8 (August 2020): 1230–38. http://dx.doi.org/10.1038/s12276-020-0483-0.

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Abstract The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver diseases. Hepatocyte-driven liver regeneration that involves the proliferation of preexisting hepatocytes is a primary regeneration mode. On the other hand, liver progenitor cell (LPC)-driven liver regeneration that involves dedifferentiation of biliary epithelial cells or hepatocytes into LPCs, LPC proliferation, and subsequent differentiation of LPCs into hepatocytes is a secondary mode. This secondary mode plays a significant role in liver regeneration when the primary mode does not effectively work, as observed in severe liver injury settings. Thus, promoting LPC-driven liver regeneration may be clinically beneficial to patients with severe liver diseases. In this review, we describe the current understanding of LPC-driven liver regeneration by exploring current knowledge on the activation, origin, and roles of LPCs during regeneration. We also describe animal models used to study LPC-driven liver regeneration, given their potential to further deepen our understanding of the regeneration process. This understanding will eventually contribute to developing strategies to promote LPC-driven liver regeneration in patients with severe liver diseases.

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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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Fernández, Odin Ramírez, Rafael Godínez, Esmeralda Zuñiga Aguilar, Luis E. Gómez Quiroz, María C. Gutiérrez Ruiz, Juan Morales, and Roberto Olayo. "Cell cocultures on coated scaffolds applied to liver models." International Journal of Medical Engineering and Informatics 9, no. 4 (2017): 332. http://dx.doi.org/10.1504/ijmei.2017.086895.

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Morales, Juan, María C. Gutiérrez Ruiz, Rafael Godínez, Esmeralda Zuñiga Aguilar, Luis E. Gómez Quiroz, Roberto Olayo, and Odin Ramírez Fernández. "Cell cocultures on coated scaffolds applied to liver models." International Journal of Medical Engineering and Informatics 9, no. 4 (2017): 332. http://dx.doi.org/10.1504/ijmei.2017.10005937.

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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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Eckert, Christoph, Yong Ook Kim, Henrike Julich, Eva-Carina Heier, Niklas Klein, Elmar Krause, Thomas Tschernig, et al. "Podoplanin discriminates distinct stromal cell populations and a novel progenitor subset in the liver." American Journal of Physiology-Gastrointestinal and Liver Physiology 310, no. 1 (January 1, 2016): G1—G12. http://dx.doi.org/10.1152/ajpgi.00344.2015.

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Podoplanin/gp38+ stromal cells present in lymphoid organs play a central role in the formation and reorganization of the extracellular matrix and in the functional regulation of immune responses. Gp38+ cells are present during embryogenesis and in human livers of primary biliary cirrhosis. Since little is known about their function, we studied gp38+ cells during chronic liver inflammation in models of biliary and parenchymal liver fibrosis and steatohepatitis. Gp38+ cells were analyzed using flow cytometry and confocal microscopy, and the expression of their steady state and inflammation-associated genes was evaluated from healthy and inflamed livers. Gp38+ cells significantly expanded in all three models of liver injury and returned to baseline levels during regression of inflammation. Based on CD133 and gp38 expression in the CD45−CD31−Asgpr1− liver cell fraction, numerous subsets could be identified that were negative for CD133 (gp38hiCD133−, gp38lowCD133−, and gp38−CD133−). Moreover, among the CD133+ cells, previously identified as progenitor population in injured liver, two subpopulations could be distinguished based on their gp38 expression (gp38−CD133+ and CD133+gp38+). Importantly, the distribution of the identified subsets in inflammation illustrated injury-specific changes. Moreover, the gp38+CD133+ cells exhibited liver progenitor cell characteristics similar to the gp38−CD133+ population, thus representing a novel subset within the classical progenitor cell niche. Additionally, these cells expressed distinct sets of inflammatory genes during liver injury. Our study illuminates a novel classification of the stromal/progenitor cell compartment in the liver and pinpoints a hitherto unrecognized injury-related alteration in progenitor subset composition in chronic liver inflammation and fibrosis.

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Lin, Christine, and Salman R. Khetani. "Advances in Engineered Liver Models for Investigating Drug-Induced Liver Injury." BioMed Research International 2016 (2016): 1–20. http://dx.doi.org/10.1155/2016/1829148.

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Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions. The latest platforms coculture PHHs with stromal cells to achieve hepatic stability and enable crosstalk between the various liver cell types towards capturing complex cellular mechanisms in DILI. The recent introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of interindividual differences in idiosyncratic DILI. Liver models are also being coupled to other tissue models via microfluidic perfusion to study the intertissue crosstalk upon drug exposure as in a live organism. Here, we review the major advances being made in the engineering of liver models and readouts as they pertain to DILI investigations. We anticipate that engineered human liver models will reduce drug attrition, animal usage, and cases of DILI in humans.

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Underhill, Gregory H., and Salman R. Khetani. "Bioengineered Liver Models for Drug Testing and Cell Differentiation Studies." Cellular and Molecular Gastroenterology and Hepatology 5, no. 3 (2018): 426–39. http://dx.doi.org/10.1016/j.jcmgh.2017.11.012.

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Pinheiro, Daphne, Isabelle Dias, Karina Ribeiro Silva, Ana Carolina Stumbo, Alessandra Thole, Erika Cortez, Lais de Carvalho, Ralf Weiskirchen, and Simone Carvalho. "Mechanisms Underlying Cell Therapy in Liver Fibrosis: An Overview." Cells 8, no. 11 (October 29, 2019): 1339. http://dx.doi.org/10.3390/cells8111339.

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Fibrosis is a common feature in most pathogenetic processes in the liver, and usually results from a chronic insult that depletes the regenerative capacity of hepatocytes and activates multiple inflammatory pathways, recruiting resident and circulating immune cells, endothelial cells, non-parenchymal hepatic stellate cells, and fibroblasts, which become activated and lead to excessive extracellular matrix accumulation. The ongoing development of liver fibrosis results in a clinically silent and progressive loss of hepatocyte function, demanding the constant need for liver transplantation in clinical practice, and motivating the search for other treatments as the chances of obtaining compatible viable livers become scarcer. Although initially cell therapy has emerged as a plausible alternative to organ transplantation, many factors still challenge the establishment of this technique as a main or even additional therapeutic tool. Herein, the authors discuss the most recent advances and point out the corners and some controversies over several protocols and models that have shown promising results as potential candidates for cell therapy for liver fibrosis, presenting the respective mechanisms proposed for liver regeneration in each case.

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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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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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Albrecht, J. H., J. S. Hoffman, B. T. Kren, and C. J. Steer. "Cyclin and cyclin-dependent kinase 1 mRNA expression in models of regenerating liver and human liver diseases." American Journal of Physiology-Gastrointestinal and Liver Physiology 265, no. 5 (November 1, 1993): G857—G864. http://dx.doi.org/10.1152/ajpgi.1993.265.5.g857.

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There is compelling evidence that the eukaryotic cell cycle is controlled by a family of proteins called cyclins, which complex with cyclin-dependent kinases (CDK) to modulate key events during cell division. We have examined the regulation of these genes in models of experimental liver regeneration and their expression in human liver diseases. Seventy percent partial hepatectomy (PH) was performed on rats and normal BALB/c and athymic nude mice to determine patterns of cyclin and CDK1 mRNA expression. It has been previously shown by [3H]thymidine incorporation that athymic nude mice manifest impaired regeneration after PH. Our results demonstrate a sequential pattern of cyclin and CDK1 transcript expression in each of the models. Cyclin D1 was the most abundant mRNA steady-state transcript in the regenerating livers. CDK1 and cyclins associated with later stages of the cell cycle showed delayed and diminished expression in nude mice compared with normals. Nuclear run-off assays performed at key time points post-PH revealed little change in transcription rates, suggesting that steady-state mRNA expression of the cyclin genes is regulated primarily by posttranscriptional events. Human liver tissue from various acute and chronic hepatic diseases showed increased expression of cyclins A and D1. We conclude that the regenerating liver post-PH offers an excellent in vivo model for studying cyclin and CDK gene expression. Impaired regeneration in the nude mouse is associated with altered cyclin and CDK1 mRNA transcript expression. Furthermore, cyclins may eventually provide clinically relevant molecular markers of regenerative activity in human liver diseases.

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Lurje, Isabella, Linda Hammerich, and Frank Tacke. "Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer." International Journal of Molecular Sciences 21, no. 19 (October 6, 2020): 7378. http://dx.doi.org/10.3390/ijms21197378.

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Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.

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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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Singhal, Mahak, Xiaoting Liu, Donato Inverso, Kai Jiang, Jianing Dai, Hao He, Susanne Bartels, et al. "Endothelial cell fitness dictates the source of regenerating liver vasculature." Journal of Experimental Medicine 215, no. 10 (September 7, 2018): 2497–508. http://dx.doi.org/10.1084/jem.20180008.

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Neoangiogenesis plays a key role in diverse pathophysiological conditions, including liver regeneration. Yet, the source of new endothelial cells (ECs) remains elusive. By analyzing the regeneration of the liver vasculature in irradiation-based myeloablative and nonmyeloablative bone marrow transplantation mouse models, we discovered that neoangiogenesis in livers with intact endothelium was solely mediated by proliferation of resident ECs. However, following irradiation-induced EC damage, bone marrow–derived mononuclear cells were recruited and incorporated into the vasculature. Further experiments with direct bone marrow infusion or granulocyte colony–stimulating factor (G-CSF)–mediated progenitor cell mobilization, which resembles clinically relevant stem cell therapy, demonstrated that bone marrow–derived cells did not contribute to the regeneration of liver vasculature after two-thirds partial hepatectomy (PHx). Taken together, the data reconcile many of the discrepancies in the literature and highlight that the cellular source of regenerating endothelium depends on the fitness of the residual vasculature.

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Bilodeau, Marc. "Liver Cell Death: Update on Apoptosis." Canadian Journal of Gastroenterology 17, no. 8 (2003): 501–6. http://dx.doi.org/10.1155/2003/205751.

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Hepatocyte cell death is a cardinal feature of almost every liver disease. Apoptosis is a mode of cell death characterized by specific morphological and biochemical features. Over the past decade, the importance of apoptosis has been appreciated, and it is now thought to be the main mode of cell death in liver diseases. The recognition that apoptosis can be modulated by the cell itself or by the extracellular environment has given hope that treatments can be designed to modify the evolution of disease. This article presents an overview of this important phenomenon, as well as models of hepatocyte apoptosis and goals of current research. The significance of apoptosis to the pathophysiology of liver disease is discussed.

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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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Tricot, Tine, Jolan De Boeck, and Catherine Verfaillie. "Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand?" Cells 9, no. 3 (February 28, 2020): 566. http://dx.doi.org/10.3390/cells9030566.

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Acute and chronic liver failure is a highly prevalent medical condition with high morbidity and mortality. Currently, the therapy is orthotopic liver transplantation. However, in some instances, chiefly in the setting of metabolic diseases, transplantation of individual cells, specifically functional hepatocytes, can be an acceptable alternative. The gold standard for this therapy is the use of primary human hepatocytes, isolated from livers that are not suitable for whole organ transplantations. Unfortunately, primary human hepatocytes are scarcely available, which has led to the evaluation of alternative sources of functional hepatocytes. In this review, we will compare the ability of most of these candidate alternative cell sources to engraft and repopulate the liver of preclinical animal models with the repopulation ability found with primary human hepatocytes. We will discuss the current shortcomings of the different cell types, and some of the next steps that we believe need to be taken to create alternative hepatocyte progeny capable of regenerating the failing liver.

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Raper, Steven E., and James M. Wilson. "Cell Transplantation in Liver-Directed Gene Therapy." Cell Transplantation 2, no. 5 (September 1993): 381–400. http://dx.doi.org/10.1177/096368979300200504.

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Somatic cell gene therapy is a new field of biomedical research that encompasses a variety of traditional basic research and clinical disciplines. This new approach to therapeutics has the potential to prevent, treat, or cure a variety of inherited and acquired diseases. Two divergent strategies of hepatocyte transplantation are being employed in animal models and clinical trials in an attempt to correct genetic deficiencies. Allogeneic hepatocyte transplantation has two main advantages over autologous cell transplantation. First, invasive surgical procedures are not required in the recipient. Second, allogeneic cells can be administered repetitively, so that multiple harvests are not necessary. The major drawbacks to allogeneic hepatocyte transplants are rejection and the risks of immunosuppression. Although there is no clinical experience with the treatment of genetic disease by allogeneic hepatocyte transplantation, a variety of animal models have been characterized, including the Gunn rat (UDP-glucuronosyl transferase deficient), the Nagase analbuminemic rat, and the Watanabe heritable hyperlipidemic rabbit (LDL receptor deficient). The use of genetically corrected autologous cells represents a different and more elegant approach to the correction of inherited disease. A segment of liver is harvested from the affected individual. Recombinant retroviruses are used to transduce normal genes— with a variety of promoter/enhancer constructs —into the patients own hepatocytes. The genetically corrected hepatocytes are then transplanted back into the patient. This approach, known as ex vivo gene therapy, eliminates the risk of rejection and the need for immunosuppression. The safety and efficacy of this approach has been proven in a variety of preclinical animals models, including Watanabe rabbits, dogs, and Papio spp. A clinical trial for the treatment of familial hypercholesterolemia is currently in progress. A number of approaches for the reintroduction of hepatocytes into the recipient have been proposed, including cathetermediated delivery into the inferior mesenteric vein, the umbilical vein, or into the spleen. Candidate diseases, which are likely to result in the first clinical trials include familial hypercholesterolemia, ornithine transcarbamylase deficiency, Crigler-Najjar syndrome, alpha]-antitrypsin deficiency, and phenylketonuria.

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Guo, Xiaoqing, Ji-Eun Seo, Xilin Li, and Nan Mei. "Genetic toxicity assessment using liver cell models: past, present, and future." Journal of Toxicology and Environmental Health, Part B 23, no. 1 (November 20, 2019): 27–50. http://dx.doi.org/10.1080/10937404.2019.1692744.

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Lemaigre, Frederic, and Kenneth S. Zaret. "Liver development update: new embryo models, cell lineage control, and morphogenesis." Current Opinion in Genetics & Development 14, no. 5 (October 2004): 582–90. http://dx.doi.org/10.1016/j.gde.2004.08.004.

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Ramli, Muhammad Nadzim Bin, Yee Siang Lim, Chwee Tat Koe, Deniz Demircioglu, Weiquan Tng, Kevin Andrew Uy Gonzales, Cheng Peow Tan, et al. "Human Pluripotent Stem Cell-Derived Organoids as Models of Liver Disease." Gastroenterology 159, no. 4 (October 2020): 1471–86. http://dx.doi.org/10.1053/j.gastro.2020.06.010.

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Aravalli, Rajagopal N., and Clifford J. Steer. "Utility of Common Marmoset (Callithrix jacchus) Embryonic Stem Cells in Liver Disease Modeling, Tissue Engineering and Drug Metabolism." Genes 11, no. 7 (June 30, 2020): 729. http://dx.doi.org/10.3390/genes11070729.

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The incidence of liver disease is increasing significantly worldwide and, as a result, there is a pressing need to develop new technologies and applications for end-stage liver diseases. For many of them, orthotopic liver transplantation is the only viable therapeutic option. Stem cells that are capable of differentiating into all liver cell types and could closely mimic human liver disease are extremely valuable for disease modeling, tissue regeneration and repair, and for drug metabolism studies to develop novel therapeutic treatments. Despite the extensive research efforts, positive results from rodent models have not translated meaningfully into realistic preclinical models and therapies. The common marmoset Callithrix jacchus has emerged as a viable non-human primate model to study various human diseases because of its distinct features and close physiologic, genetic and metabolic similarities to humans. C. jacchus embryonic stem cells (cjESC) and recently generated cjESC-derived hepatocyte-like cells (cjESC-HLCs) could fill the gaps in disease modeling, liver regeneration and metabolic studies. They are extremely useful for cell therapy to regenerate and repair damaged liver tissues in vivo as they could efficiently engraft into the liver parenchyma. For in vitro studies, they would be advantageous for drug design and metabolism in developing novel drugs and cell-based therapies. Specifically, they express both phase I and II metabolic enzymes that share similar substrate specificities, inhibition and induction characteristics, and drug metabolism as their human counterparts. In addition, cjESCs and cjESC-HLCs are advantageous for investigations on emerging research areas, including blastocyst complementation to generate entire livers, and bioengineering of discarded livers to regenerate whole livers for transplantation.

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Takemura, Shigekazu, Hideki Azuma, Mayuko Osada-Oka, Shoji Kubo, Toshihiko Shibata, and Yukiko Minamiyama. "S-allyl-glutathione improves experimental liver fibrosis by regulating Kupffer cell activation in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 314, no. 2 (February 1, 2018): G150—G163. http://dx.doi.org/10.1152/ajpgi.00023.2017.

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S-allyl-glutathione (SAG) is one of the metabolites of diallyl sulfide (DAS), a component of garlic. DAS has shown preventative effects on carcinogenesis in animal models. However, whether synthetic SAG can improve liver fibrosis has not been investigated. We examined the potential preventive effects of SAG on acute and chronic models of liver fibrosis by chronic carbon tetrachloride (CCl4) administration. SAG inhibited liver fibrogenesis induced by CCl4 in a dose-dependent manner and reduced heat shock protein-47 (HSP47), a collagen-specific chaperone, and other fibrosis markers. In fibrosis regression models, after administration of either CCl4 for 9 wk or dimethyl nitrosamine (DMN) for 6 wk, SAG markedly accelerated fibrolysis in both models. In the regression stage of DMN-treated liver, SAG normalized the ratio of M2 phenotype (expression of mannose receptor) in Kupffer cells (KCs). Consistent with these results, the culture supernatants of SAG-treated M2-phenotype KCs inhibited collagen-α1(I) chain (COL1A1) mRNA expression in primary culture-activated rat hepatic stellate cells (HSCs). However, SAG did not directly inhibit HSC activation. In an acute model of CCl4 single injection, SAG inhibited hepatic injury dose dependently consistent with the inhibited the elevation of the bilirubin and ALT levels. These findings suggest that SAG could improve the fibrogenic and fibrolysis cascade via the regulation of excess activated and polarized KCs. SAG may also serve as a preventive and therapeutic agent in fibrosis of other organs for which current clinical therapy is unavailable. NEW & NOTEWORTHY S-allyl-glutathione (SAG) is a metabolite of diallyl sulfide, a component of garlic. SAG increased hepatic glutathione levels and GSH-to-GSSG ratio in normal rats. SAG treatment before or after liver fibrosis from chronic CCl4 administration improved liver fibrosis and regression. SAG decreased heat shock protein-47 (HSP47), a collagen-specific chaperone, and other fibrosis markers in CCl4-treated livers. SAG-treated Kupffer cell conditioned medium also inhibited collagen-α1(I) chain (COL1A1) mRNA expression and other markers in primary culture hepatic stellate cells.

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Marin, Jose J. G., Elisa Herraez, Elisa Lozano, Rocio I. R. Macias, and Oscar Briz. "Models for Understanding Resistance to Chemotherapy in Liver Cancer." Cancers 11, no. 11 (October 29, 2019): 1677. http://dx.doi.org/10.3390/cancers11111677.

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The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance.

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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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Vidal, Isabelle, and Lysiane Richert. "The Nude Mouse as Model for Liver Deficiency Study and Treatment and Xenotransplantation." International Journal of Hepatology 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/140147.

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We aimed at reviewing the various uses of Nude mouse for the development of liver deficiency models and evaluation of efficacy of hepatic cell xenotransplantation. The first part records the large range of liver deficiency models that can be developed in Nude mice: surgical partial hepatectomy, acute toxic liver deficiency, chronic cirrhosis, and transgenic liver injury. The second part tackles the outcome of rat hepatocyte as well as human cell transplantation, both mature hepatocyte and hepatic progenitor, into Nude mouse submitted to liver injury. Results are discussed and compared to other available immunodeficient mouse models. The issue of humanized liver creation is also addressed. Altogether, these results show that Nude mouse appears to be a suitable small animal model to expand our insight into liver cell engraftment and regeneration.

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Shojaie, Layla, Andrea Iorga, and Lily Dara. "Cell Death in Liver Diseases: A Review." International Journal of Molecular Sciences 21, no. 24 (December 18, 2020): 9682. http://dx.doi.org/10.3390/ijms21249682.

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Regulated cell death (RCD) is pivotal in directing the severity and outcome of liver injury. Hepatocyte cell death is a critical event in the progression of liver disease due to resultant inflammation leading to fibrosis. Apoptosis, necrosis, necroptosis, autophagy, and recently, pyroptosis and ferroptosis, have all been investigated in the pathogenesis of various liver diseases. These cell death subroutines display distinct features, while sharing many similar characteristics with considerable overlap and crosstalk. Multiple types of cell death modes can likely coexist, and the death of different liver cell populations may contribute to liver injury in each type of disease. This review addresses the known signaling cascades in each cell death pathway and its implications in liver disease. In this review, we describe the common findings in each disease model, as well as the controversies and the limitations of current data with a particular focus on cell death-related research in humans and in rodent models of alcoholic liver disease, non-alcoholic fatty liver disease and steatohepatitis (NASH/NAFLD), acetaminophen (APAP)-induced hepatotoxicity, autoimmune hepatitis, cholestatic liver disease, and viral hepatitis.

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Yokoi, Tsuyoshi, and Shingo Oda. "Models of Idiosyncratic Drug-Induced Liver Injury." Annual Review of Pharmacology and Toxicology 61, no. 1 (January 6, 2021): 247–68. http://dx.doi.org/10.1146/annurev-pharmtox-030220-015007.

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Drug-induced liver injury (DILI) is a leading cause of attrition during the early and late stages of drug development and after a drug is marketed. DILI is generally classified as either intrinsic or idiosyncratic. Intrinsic DILI is dose dependent and predictable (e.g., acetaminophen toxicity). However, predicting the occurrence of idiosyncratic DILI, which has a very low incidence and is associated with severe liver damage, is difficult because of its complex nature and the poor understanding of its mechanism. Considering drug metabolism and pharmacokinetics, we established experimental animal models of DILI for 14 clinical drugs that cause idiosyncratic DILI in humans, which is characterized by the formation of reactive metabolites and the involvement of both innate and adaptive immunity. On the basis of the biomarker data obtained from the animal models, we developed a cell-based assay system that predicts the potential risks of drugs for inducing DILI. These findings increase our understanding of the mechanisms of DILI and may help predict and prevent idiosyncratic DILI due to certain drugs.

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Haga, Junko, Shin Enosawa, and Eiji Kobayashi. "Cell Therapy for Liver Disease Using Bioimaging Rats." Cell Medicine 9, no. 1-2 (January 2017): 3–7. http://dx.doi.org/10.3727/215517916x693104.

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Advances in stem cell research suggest that cell therapy is a potential alternative to liver transplantation. The use of individualized and minimally invasive cell therapy is desirable to avoid rejection and reduce patient burden. While allo-hepatocyte transplantation has been performed for metabolic hepatic disease, auto-bone marrow transplantation (BMT) has shifted toward mesenchymal stem cells (MSCs) transplantation for liver cirrhosis. In this article, an overview of cell transplantation research for liver disease is provided through our recent rat studies. We have developed various kinds of rat imaging models and have evaluated the effect of cell therapy for liver disease. Bone marrow cells (BMCs) of the Alb-DsRed2 rat were transplanted via the portal vein (PV) in acute and chronic liver damage models. The number of Alb-DsRed2+ albumin-producing cells increased, and the size of the cells increased in the chronic liver damage model as well as in the acute liver damage model. Luciferase transgenic (luc-Tg) rat hepatocytes were transplanted into the hepatectomized LEW rat via the PV. Luminescence intensity lasted for 2 months in the hepatectomized rat. BMCs obtained from green fluorescent protein (GFP) Tg rats were transplanted repeatedly via the PV using an implanted catheter with a port. Repeated BMT via the PV reduced the liver fibrosis. Adipocyte-derived MSCs from the luc-Tg rat were transplanted into the hepatectomized rat model via the PV after ischemic reperfusion. MSCs inhibited hepatocyte apoptosis and promoted liver regeneration. Transplanting the optimal number of cells by an effective and safe way is important for clinical application. Bioimaging rats are a powerful tool for cell transplantation research because it makes observation of the in vivo kinetics of transplanted cells possible. Cell transplantation research using bioimaging rats contributes greatly to evaluating effective methods of cell therapy.

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Thuy, Le Thi Thanh, Hoang Hai, and Norifumi Kawada. "Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis." Clinical and Molecular Hepatology 26, no. 3 (July 1, 2020): 280–93. http://dx.doi.org/10.3350/cmh.2020.0037.

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Cytoglobin (Cygb), a stellate cell-specific globin, has recently drawn attention due to its association with liver fibrosis. In the livers of both humans and rodents, Cygb is expressed only in stellate cells and can be utilized as a marker to distinguish stellate cells from hepatic fibroblast-derived myofibroblasts. Loss of Cygb accelerates liver fibrosis and cancer development in mouse models of chronic liver injury including diethylnitrosamine-induced hepatocellular carcinoma, bile duct ligation-induced cholestasis, thioacetamide-induced hepatic fibrosis, and choline-deficient L-amino acid-defined diet-induced non-alcoholic steatohepatitis. This review focuses on the history of research into the role of reactive oxygen species and nitrogen species in liver fibrosis and discusses the current perception of Cygb as a novel radical scavenger with an emphasis on its role in hepatic stellate cell activation and fibrosis.

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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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Hall, Katherine C., Sylvie G. Bernier, Sarah Jacobson, Guang Liu, Ping Y. Zhang, Renee Sarno, Victoria Catanzano, Mark G. Currie, and Jaime L. Masferrer. "sGC stimulator praliciguat suppresses stellate cell fibrotic transformation and inhibits fibrosis and inflammation in models of NASH." Proceedings of the National Academy of Sciences 116, no. 22 (May 13, 2019): 11057–62. http://dx.doi.org/10.1073/pnas.1821045116.

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Endothelial dysfunction and reduced nitric oxide (NO) signaling are a key element of the pathophysiology of nonalcoholic steatohepatitis (NASH). Stimulators of soluble guanylate cyclase (sGC) enhance NO signaling; have been shown preclinically to reduce inflammation, fibrosis, and steatosis; and thus have been proposed as potential therapies for NASH and fibrotic liver diseases. Praliciguat, an oral sGC stimulator with extensive distribution to the liver, was used to explore the role of this signaling pathway in NASH. We found that sGC is expressed in hepatic stellate cells and stellate-derived myofibroblasts, but not in hepatocytes. Praliciguat acted directly on isolated hepatic stellate cells to inhibit fibrotic and inflammatory signaling potentially through regulation of AMPK and SMAD7. Using in vivo microdialysis, we demonstrated stimulation of the NO–sGC pathway by praliciguat in both healthy and fibrotic livers. In preclinical models of NASH, praliciguat treatment was associated with lower levels of liver fibrosis and lower expression of fibrotic and inflammatory biomarkers. Praliciguat treatment lowered hepatic steatosis and plasma cholesterol levels. The antiinflammatory and antifibrotic effects of praliciguat were recapitulated in human microtissues in vitro. These data provide a plausible cellular basis for the mechanism of action of sGC stimulators and suggest the potential therapeutic utility of praliciguat in the treatment of NASH.

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Harmon, Daniel B., Chao Wu, Nikolaos Dedousis, Ian J. Sipula, Maja Stefanovic-Racic, Gabriele Schoiswohl, Christopher P. O’Donnell, et al. "Adipose tissue-derived free fatty acids initiate myeloid cell accumulation in mouse liver in states of lipid oversupply." American Journal of Physiology-Endocrinology and Metabolism 315, no. 5 (November 1, 2018): E758—E770. http://dx.doi.org/10.1152/ajpendo.00172.2018.

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Accumulation of myeloid cells in the liver, notably dendritic cells (DCs) and monocytes/macrophages (MCs), is a major component of the metainflammation of obesity. However, the mechanism(s) stimulating hepatic DC/MC infiltration remain ill defined. Herein, we addressed the hypothesis that adipose tissue (AT) free fatty acids (FFAs) play a central role in the initiation of hepatic DC/MC accumulation, using a number of mouse models of altered FFA supply to the liver. In two models of acute FFA elevation (lipid infusion and fasting) hepatic DC/MC and triglycerides (TGs) but not AT DC/MC were increased without altering plasma cytokines (PCs; TNFα and monocyte chemoattractant protein 1) and with variable effects on oxidative stress (OxS) markers. However, fasting in mice with profoundly reduced AT lipolysis (AT-specific deletion of adipose TG lipase; AAKO) failed to elevate liver DC/MC, TG, or PC, but liver OxS increased. Livers of obese AAKO mice that are known to be resistant to steatosis were similarly protected from inflammation. In high-fat feeding studies of 1, 3, 6, or 20-wk duration, liver DC/MC accumulation dissociated from PC and OxS but tracked with liver TGs. Furthermore, decreasing OxS by ~80% in obese mice failed to decrease liver DC/MC. Therefore, FFA and more specifically AT-derived FFA stimulate hepatic DC/MC accumulation, thus recapitulating the pathology of the obese liver. In a number of cases the effects of FFA can be dissociated from OxS and PC but match well with liver TG, a marker of FFA oversupply.

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Verfaillie, C., M. Kumar, B. Topkrakhisar, T. Tricot, J. De Smedt, and S. Gosh. "Creation of functional pluripotent stem cell-derived hepatocyte-like cell and more complex liver models." Toxicology Letters 350 (September 2021): S23. http://dx.doi.org/10.1016/s0378-4274(21)00290-3.

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Vondráček, Jan, and Miroslav Machala. "Environmental Ligands of the Aryl Hydrocarbon Receptor and Their Effects in Models of Adult Liver Progenitor Cells." Stem Cells International 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/4326194.

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The toxicity of environmental and dietary ligands of the aryl hydrocarbon receptor (AhR) in mature liver parenchymal cells is well appreciated, while considerably less attention has been paid to their impact on cell populations exhibiting phenotypic features of liver progenitor cells. Here, we discuss the results suggesting that the consequences of the AhR activation in the cellular models derived from bipotent liver progenitors could markedly differ from those in hepatocytes. In contact-inhibited liver progenitor cells, the AhR agonists induce a range of effects potentially linked with tumor promotion. They can stimulate cell cycle progression/proliferation and deregulate cell-to-cell communication, which is associated with downregulation of proteins forming gap junctions, adherens junctions, and desmosomes (such as connexin 43, E-cadherin,β-catenin, and plakoglobin), as well as with reduced cell adhesion and inhibition of intercellular communication. At the same time, toxic AhR ligands may affect the activity of the signaling pathways contributing to regulation of liver progenitor cell activation and/or differentiation, such as downregulation of Wnt/β-catenin and TGF-βsignaling, or upregulation of transcriptional targets of YAP/TAZ, the effectors of Hippo signaling pathway. These data illustrate the need to better understand the potential role of liver progenitors in the AhR-mediated liver carcinogenesis and tumor promotion.

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Albrecht, J. H., M. Y. Hu, and F. B. Cerra. "Distinct Patterns of Cyclin D1 Regulation in Models of Liver Regeneration and Human Liver." Biochemical and Biophysical Research Communications 209, no. 2 (April 1995): 648–55. http://dx.doi.org/10.1006/bbrc.1995.1548.

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Andrewartha, Neil, and George Yeoh. "Human Amnion Epithelial Cell Therapy for Chronic Liver Disease." Stem Cells International 2019 (August 7, 2019): 1–10. http://dx.doi.org/10.1155/2019/8106482.

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Liver fibrosis is a common consequence of chronic liver disease. Over time, liver fibrosis can develop into liver cirrhosis. Current therapies for liver fibrosis are limited, and liver transplant is the only curative therapy for patients who progress to end-stage disease. A potential approach to treat chronic liver disease with increasing interest is cell-based therapy. Among the multiple cell types which have been proposed for therapeutic uses, human amnion epithelial cells and amniotic fluid-derived mesenchymal cells are promising. These cells are highly abundant, and their use poses no ethical concern. Furthermore, they exert potent anti-inflammatory and antifibrotic effects in animal models of liver injury. This review highlights the therapeutic characteristics and discusses how human amnion epithelial cells can be utilised as a therapeutic tool for chronic liver disease.

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Cotovio, João P., and Tiago G. Fernandes. "Production of Human Pluripotent Stem Cell-Derived Hepatic Cell Lineages and Liver Organoids: Current Status and Potential Applications." Bioengineering 7, no. 2 (April 9, 2020): 36. http://dx.doi.org/10.3390/bioengineering7020036.

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Liver disease is one of the leading causes of death worldwide, leading to the death of approximately 2 million people per year. Current therapies include orthotopic liver transplantation, however, donor organ shortage remains a great challenge. In addition, the development of novel therapeutics has been limited due to the lack of in vitro models that mimic in vivo liver physiology. Accordingly, hepatic cell lineages derived from human pluripotent stem cells (hPSCs) represent a promising cell source for liver cell therapy, disease modelling, and drug discovery. Moreover, the development of new culture systems bringing together the multiple liver-specific hepatic cell types triggered the development of hPSC-derived liver organoids. Therefore, these human liver-based platforms hold great potential for clinical applications. In this review, the production of the different hepatic cell lineages from hPSCs, including hepatocytes, as well as the emerging strategies to generate hPSC-derived liver organoids will be assessed, while current biomedical applications will be highlighted.

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Khan, Hilal Ahmad, Muhammad Zishan Ahmad, Junaid Ali Khan, and Muhammad Imran Arshad. "Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance." Hepatobiliary & Pancreatic Diseases International 16, no. 3 (June 2017): 245–56. http://dx.doi.org/10.1016/s1499-3872(17)60014-6.

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Luparello, Claudio. "Cadmium-Associated Molecular Signatures in Cancer Cell Models." Cancers 13, no. 11 (June 5, 2021): 2823. http://dx.doi.org/10.3390/cancers13112823.

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The exposure of cancer cells to cadmium and its compounds is often associated with the development of more malignant phenotypes, thereby contributing to the acceleration of tumor progression. It is known that cadmium is a transcriptional regulator that induces molecular reprogramming, and therefore the study of differentially expressed genes has enabled the identification and classification of molecular signatures inherent in human neoplastic cells upon cadmium exposure as useful biomarkers that are potentially transferable to clinical research. This review recapitulates selected studies that report the detection of cadmium-associated signatures in breast, gastric, colon, liver, lung, and nasopharyngeal tumor cell models, as specifically demonstrated by individual gene or whole genome expression profiling. Where available, the molecular, biochemical, and/or physiological aspects associated with the targeted gene activation or silencing in the discussed cell models are also outlined.

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Journal articles on the topic 'Liver cell models'

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