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. - Inria - Institut national de recherche en sciences et technologies du numérique Access content directly
Journal Articles Archives of Toxicology Year : 2013

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.

Patricio Godoy (1) , Nicola J Hewitt (2) , Ute Albrecht (3) , Melvin E Andersen (4) , Nariman Ansari (5) , Sudin Bhattacharya (4) , Johannes Georg Bode (3) , Jennifer Bolleyn (6) , Christoph Borner (7) , Jan Böttger (8) , Albert Braeuning (9) , Robert A Budinsky (10) , Britta Burkhardt (11) , Neil R Cameron (12) , Giovanni Camussi (13) , Chong-Su Cho (14) , Yun-Jaie Choi (14) , J. Craig Rowlands (10) , Uta Dahmen (15) , Georg Damm (16) , Olaf Dirsch (17) , María Teresa Donato (18) , Jian Dong (4) , Steven Dooley (19) , Dirk Drasdo (20) , Rowena Eakins (21) , Karine Sá Ferreira (7) , Valentina Fonsato (13) , Joanna Fraczek (6) , Rolf Gebhardt (8) , Andrew Gibson (21) , Matthias Glanemann (16) , Chris E P Goldring (21) , María José Gómez-Lechón (22) , Geny M M Groothuis (23) , Lena Gustavsson (24) , Christelle Guyot (25) , David Hallifax (26) , Seddik Hammad (27) , Adam Hayward (28) , Dieter Häussinger (3) , Claus Hellerbrand (29) , Philip Hewitt (30) , Stefan Hoehme (8) , Hermann-Georg Holzhütter (16) , J Brian Houston (26) , Jens Hrach (31) , Kiyomi Ito (32) , Hartmut Jaeschke (33) , Verena Keitel (3) , Jens M Kelm (34) , B. Kevin Park (21) , Claus Kordes (3) , Gerd A Kullak-Ublick (25) , Edward L Lecluyse (4) , Peng Lu (4) , Jennifer Luebke-Wheeler (35) , Anna Lutz (7) , Daniel J Maltman (36) , Madlen Matz-Soja (37) , Patrick Mcmullen (4) , Irmgard Merfort (38) , Simon Messner (34) , Christoph Meyer (19) , Jessica Mwinyi (25) , Dean J Naisbitt (21) , Andreas K Nussler (11) , Peter Olinga (23) , Francesco Pampaloni (5) , Jingbo Pi (4) , Linda Pluta (4) , Stefan A Przyborski (36) , Anup Ramachandran (33) , Vera Rogiers (6) , Cliff Rowe (21) , Celine Schelcher (39) , Kathrin Schmich (38) , Michael Schwarz (9) , Bijay Singh (14) , Ernst H K Stelzer (5) , Bruno Stieger (25) , Regina Stöber (1) , Yuichi Sugiyama (40) , Ciro Tetta (41) , Wolfgang E Thasler (42) , Tamara Vanhaecke (6) , Mathieu Vinken (6) , Thomas S Weiss (29) , Agata Widera (1) , Courtney G Woods (4) , Jinghai James Xu (43) , Kathy M Yarborough (4) , Jan G Hengstler (1)
1 IFADO - Leibniz Research Centre for Working Environment and Human Factors [Dortmund]
2 Auteur indépendant
3 Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]
4 The Hamner Institutes For Health Sciences
5 Goethe-University Frankfurt am Main
6 VUB - Vrije Universiteit Brussel
7 University of Freiburg [Freiburg]
8 Leipzig University / Universität Leipzig
9 Department of Experimental and Clinical Pharmacology andToxicology [Tübingen]
10 The Dow Chemical Company
11 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
12 Department of Chemistry [Durham, UK]
13 UNITO - Università degli studi di Torino = University of Turin
14 SNU - Seoul National University [Seoul]
15 Department of General, Visceral and Vascular Surgery [Jena]
16 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
17 Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany]
18 UV - Universitat de València
19 Universität Heidelberg [Heidelberg] = Heidelberg University
20 BANG - Nonlinear Analysis for Biology and Geophysical flows
21 University of Liverpool
22 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
23 University of Groningen [Groningen]
24 Skane University Hospital [Lund]
25 University hospital of Zurich [Zurich]
26 University of Manchester [Manchester]
27 South Valley University [Qena]
28 Durham University
29 University Hospital Regensburg
30 Merck [Darmstadt]
31 FORIM GmbH [Mannheim]
32 Musashino University [Tokyo]
33 University of Kansas Medical Center [Kansas City, KS, USA]
34 InSphero [Schlieren]
35 Stem Cell Technologies [Madison]
36 NETPark Incubator [Sedgefield]
37 Institut für Biochemie [Leipzig]
38 Department of Pharmaceutical Biology and Biotechnology [Freiburg]
39 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
40 YBIRD - Yokohama Biopharmaceutical Research and Development Center [Yokohama]
41 Fresenius Medical Care [Bad Homburg]
42 University-Hospital Munich-Großhadern [München]
43 Merck & Co. Inc
Adam Hayward
  • Function : Author
Philip Hewitt
  • Function : Author
Jens Hrach
  • Function : Author
Jens M Kelm
  • Function : Author
Tamara Vanhaecke
Jinghai James Xu
  • Function : Author

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.

Dates and versions

hal-00939009 , version 1 (29-01-2014)

Identifiers

Cite

Patricio Godoy, Nicola J Hewitt, Ute Albrecht, Melvin E Andersen, Nariman Ansari, et al.. 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.. Archives of Toxicology, 2013, 87 (8), pp.1315-530. ⟨10.1007/s00204-013-1078-5⟩. ⟨hal-00939009⟩
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