5,958
views
0
recommends
+1 Recommend
0 collections
    8
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

      review-article
      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,   , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
      Archives of Toxicology
      Springer Berlin Heidelberg
      Non-parenchymal cells, Mechanisms of gene regulation, DILI, 3D Models, Cryopreservation, Clearance, Mathematical modeling
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references1,607

          • Record: found
          • Abstract: found
          • Article: not found

          Liver fibrosis.

          Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Development of monocytes, macrophages, and dendritic cells.

            Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Nuclear export of microRNA precursors.

              MicroRNAs (miRNAs), which function as regulators of gene expression in eukaryotes, are processed from larger transcripts by sequential action of nuclear and cytoplasmic ribonuclease III-like endonucleases. We show that Exportin-5 (Exp5) mediates efficient nuclear export of short miRNA precursors (pre-miRNAs) and that its depletion by RNA interference results in reduced miRNA levels. Exp5 binds correctly processed pre-miRNAs directly and specifically, in a Ran guanosine triphosphate-dependent manner, but interacts only weakly with extended pre-miRNAs that yield incorrect miRNAs when processed by Dicer in vitro. Thus, Exp5 is key to miRNA biogenesis and may help coordinate nuclear and cytoplasmic processing steps.
                Bookmark

                Author and article information

                Contributors
                +49-6150-186617 , +49-6150-187351 , nickyhewittltd@yahoo.co.uk
                claus.kordes@med.uni-duesseldorf.de
                Wolfgang.Thasler@med.uni-muenchen.de
                thomas.weiss@ukr.de
                Journal
                Arch Toxicol
                Arch. Toxicol
                Archives of Toxicology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-5761
                1432-0738
                23 August 2013
                23 August 2013
                2013
                : 87
                : 1315-1530
                Affiliations
                [ ]Leibniz Research Centre for Working Environment and Human Factors (IFADO), 44139 Dortmund, Germany
                [ ]SWS, Wingertstrasse 25, 64390 Erzhausen, Germany
                [ ]Liver and Stem Cell Technologies, Madison, WI 53711 USA
                [ ]Department of Molecular and Clinical Pharmacology, Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
                [ ]Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany
                [ ]Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
                [ ]Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 151-921 Korea
                [ ]Department of Chemistry, Durham University, Durham, DH1 3LE UK
                [ ]Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland
                [ ]Department of Medical Sciences, University of Torino, 10126 Turin, Italy
                [ ]Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, Freiburg, Germany
                [ ]Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
                [ ]Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 USA
                [ ]Department of Toxicology, Centre for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
                [ ]BG Trauma Center, Siegfried Weller Institut, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
                [ ]Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo, 202-8585 Japan
                [ ]Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama Biopharmaceutical R&D Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan
                [ ]FORIM GMBH, 68165 Mannheim, Germany
                [ ]Fresenius Medical Care, Bad Homburg, Germany
                [ ]InSphero AG, 8952 Schlieren, Switzerland
                [ ]Institute of Biochemistry, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
                [ ]Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany
                [ ]Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany
                [ ]Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany
                [ ]GRK 1104 From Cells to Organs, Molecular Mechanisms of Organogenesis, Faculty of Biology, University of Freiburg, Freiburg, Germany
                [ ]Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, 04107 Leipzig, Germany
                [ ]INRIA (French National Institute for Research in Computer Science and Control), Domaine de Voluceau-Rocquencourt, B.P. 105, 78153 Le Chesnay Cedex, France
                [ ]Department of Surgery, Liver Regeneration, Core Facility, Human in Vitro Models of the Liver, Ludwig Maximilians University of Munich, Munich, Germany
                [ ]Merck and Co, Rahway, NJ USA
                [ ]Merck KGaA, 64283 Darmstadt, Germany
                [ ]Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
                [ ]Reinnervate Limited, NETPark Incubator, Thomas Wright Way, Sedgefield, TS21 3FD UK
                [ ]Biological and Biomedical Sciences, Durham University, Durham, DH13LE UK
                [ ]Centre for Applied Pharmacokinetic Research (CAPKR), School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT UK
                [ ]The Hamner Institutes for Health Sciences, Research Triangle Park, NC USA
                [ ]Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI USA
                [ ]Experimental Transplantation Surgery, Department of General Visceral, and Vascular Surgery, Friedrich-Schiller-University Jena, 07745 Jena, Germany
                [ ]Institute of Pathology, Friedrich-Schiller-University Jena, 07745 Jena, Germany
                [ ]Unidad de Hepatología Experimental, IIS Hospital La Fe Avda Campanar 21, 46009 Valencia, Spain
                [ ]CIBERehd, Fondo de Investigaciones Sanitarias, Barcelona, Spain
                [ ]Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
                [ ]Institut für Biochemie Abteilung Mathematische Systembiochemie, Universitätsmedizin Berlin (Charité), Charitéplatz 1, 10117 Berlin, Germany
                [ ]Department of Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany
                [ ]Department of Laboratory Medicine (Malmö), Center for Molecular Pathology, Lund University, Jan Waldenströms gata 59, 205 02 Malmö, Sweden
                [ ]Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
                [ ]Department of Pharmacy, Pharmacokinetics Toxicology and Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
                [ ]Department of Surgery, Ludwig-Maximilians-University of Munich Hospital Grosshadern, Munich, Germany
                [ ]Department of Pediatrics and Juvenile Medicine, University of Regensburg Hospital, Regensburg, Germany
                [ ]UPMC University of Paris 06, CNRS UMR 7598, Laboratoire Jacques-Louis Lions, 4, pl. Jussieu, 75252 Paris cedex 05, France
                Article
                1078
                10.1007/s00204-013-1078-5
                3753504
                23974980
                bb1e411d-1043-453e-83f4-bccd9068b07f
                © The Author(s) 2013

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 2 May 2013
                : 6 May 2013
                Categories
                Review Article
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2013

                Toxicology
                non-parenchymal cells,mechanisms of gene regulation,dili,3d models,cryopreservation,clearance,mathematical modeling

                Comments

                Comment on this article