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
Creators: name: Godoy, Patricio
name: Hewitt, Nicola J.
name: Albrecht, Ute
name: Andersen, Melvin E.
name: Ansari, Nariman
name: Bhattacharya, Sudin
name: Bode, Johannes Georg
name: Bolleyn, Jennifer
name: Borner, Christoph
name: Böttger, Jan
name: Braeuning, Albert
name: Budinsky, Robert A.
name: Burkhardt, Britta
name: Cameron, Neil R.
name: Camussi, Giovanni
name: Cho, Chong-Su
name: Choi, Yun-Jaie
name: Craig Rowlands, J.
name: Dahmen, Uta
name: Damm, Georg
name: Dirsch, Olaf
name: Donato, María Teresa
name: Dong, Jian
name: Dooley, Steven
name: Drasdo, Dirk
name: Eakins, Rowena
name: Ferreira, Karine Sá
name: Fonsato, Valentina
name: Fraczek, Joanna
name: Gebhardt, Rolf
name: Gibson, Andrew
name: Glanemann, Matthias
name: Goldring, Chris E. P.
name: Gómez-Lechón, María José
name: Groothuis, Geny M. M.
name: Gustavsson, Lena
name: Guyot, Christelle
name: Hallifax, David
name: Hammad, Seddik
name: Hayward, Adam
name: Häussinger, Dieter
name: Hellerbrand, Claus
name: Hewitt, Philip
name: Hoehme, Stefan
name: Holzhütter, Hermann-Georg
name: Houston, J. Brian
name: Hrach, Jens
name: Ito, Kiyomi
name: Jaeschke, Hartmut
name: Keitel, Verena
name: Kelm, Jens M.
name: Kevin Park, B.
name: Kordes, Claus
name: Kullak-Ublick, Gerd A.
name: LeCluyse, Edward L.
name: Lu, Peng
name: Luebke-Wheeler, Jennifer
name: Lutz, Anna
name: Maltman, Daniel J.
name: Matz-Soja, Madlen
name: McMullen, Patrick
name: Merfort, Irmgard
name: Messner, Simon
name: Meyer, Christoph
name: Mwinyi, Jessica
name: Naisbitt, Dean J.
name: Nussler, Andreas K.
name: Olinga, Peter
name: Pampaloni, Francesco
name: Pi, Jingbo
name: Pluta, Linda
name: Przyborski, Stefan A.
name: Ramachandran, Anup
name: Rogiers, Vera
name: Rowe, Cliff
name: Schelcher, Celine
name: Schmich, Kathrin
name: Schwarz, Michael
name: Singh, Bijay
name: Stelzer, Ernst H. K.
name: Stieger, Bruno
name: Stöber, Regina
name: Sugiyama, Yuichi
name: Tetta, Ciro
name: Thasler, Wolfgang E.
name: Vanhaecke, Tamara
name: Vinken, Mathieu
name: Weiss, Thomas S.
name: Widera, Agata
name: Woods, Courtney G.
name: Xu, Jinghai James
name: Yarborough, Kathy M.
name: Hengstler, Jan G.
Publisher: name: Universität Regensburg
Year: 2013
Subjects: subject: Non-parenchymal cells Mechanisms of gene regulation DILI 3D Models Cryopreservation Clearance Mathematical modeling
subject: 610 Medizin

description: 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.