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
(2013) In Archives of Toxicology 87(8). p.1315-1530- 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-4 alpha, 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-4 alpha), resulting in up- and downregulation of hundreds of... (More)
- 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-4 alpha, 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-4 alpha), 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. (Less)
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https://lup.lub.lu.se/record/4063481
- author
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Non-parenchymal cells, Mechanisms of gene regulation, DILI, 3D Models, Cryopreservation, Clearance, Mathematical modeling
- in
- Archives of Toxicology
- volume
- 87
- issue
- 8
- pages
- 1315 - 1530
- publisher
- Springer
- external identifiers
-
- wos:000323652100002
- scopus:84883464564
- pmid:23974980
- ISSN
- 0340-5761
- DOI
- 10.1007/s00204-013-1078-5
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200)
- id
- a42865f2-9437-4cc3-8115-9a8cc4525bb2 (old id 4063481)
- date added to LUP
- 2016-04-01 13:21:40
- date last changed
- 2022-04-21 20:46:28
@article{a42865f2-9437-4cc3-8115-9a8cc4525bb2,
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-4 alpha, 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-4 alpha), 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.}},
author = {{Godoy, Patricio and Hewitt, Nicola J. and Albrecht, Ute and Andersen, Melvin E. and Ansari, Nariman and Bhattacharya, Sudin and Bode, Johannes Georg and Bolleyn, Jennifer and Borner, Christoph and Boettger, Jan and Braeuning, Albert and Budinsky, Robert A. and Burkhardt, Britta and Cameron, Neil R. and Camussi, Giovanni and Cho, Chong-Su and Choi, Yun-Jaie and Rowlands, J. Craig and Dahmen, Uta and Damm, Georg and Dirsch, Olaf and Teresa Donato, Maria and Dong, Jian and Dooley, Steven and Drasdo, Dirk and Eakins, Rowena and Ferreira, Karine Sa and Fonsato, Valentina and Fraczek, Joanna and Gebhardt, Rolf and Gibson, Andrew and Glanemann, Matthias and Goldring, Chris E. P. and Jose Gomez-Lechon, Maria and Groothuis, Geny M. M. and Gustavsson, Lena and Guyot, Christelle and Hallifax, David and Hammad, Seddik and Hayward, Adam and Haeussinger, Dieter and Hellerbrand, Claus and Hewitt, Philip and Hoehme, Stefan and Holzhuetter, Hermann-Georg and Houston, J. Brian and Hrach, Jens and Ito, Kiyomi and Jaeschke, Hartmut and Keitel, Verena and Kelm, Jens M. and Park, B. Kevin and Kordes, Claus and Kullak-Ublick, Gerd A. and LeCluyse, Edward L. and Lu, Peng and Luebke-Wheeler, Jennifer and Lutz, Anna and Maltman, Daniel J. and Matz-Soja, Madlen and McMullen, Patrick and Merfort, Irmgard and Messner, Simon and Meyer, Christoph and Mwinyi, Jessica and Naisbitt, Dean J. and Nussler, Andreas K. and Olinga, Peter and Pampaloni, Francesco and Pi, Jingbo and Pluta, Linda and Przyborski, Stefan A. and Ramachandran, Anup and Rogiers, Vera and Rowe, Cliff and Schelcher, Celine and Schmich, Kathrin and Schwarz, Michael and Singh, Bijay and Stelzer, Ernst H. K. and Stieger, Bruno and Stoeber, Regina and Sugiyama, Yuichi and Tetta, Ciro and Thasler, Wolfgang E. and Vanhaecke, Tamara and Vinken, Mathieu and Weiss, Thomas S. and Widera, Agata and Woods, Courtney G. and Xu, Jinghai James and Yarborough, Kathy M. and Hengstler, Jan G.}},
issn = {{0340-5761}},
keywords = {{Non-parenchymal cells; Mechanisms of gene regulation; DILI; 3D Models; Cryopreservation; Clearance; Mathematical modeling}},
language = {{eng}},
number = {{8}},
pages = {{1315--1530}},
publisher = {{Springer}},
series = {{Archives of Toxicology}},
title = {{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}},
url = {{https://lup.lub.lu.se/search/files/3322378/4589277}},
doi = {{10.1007/s00204-013-1078-5}},
volume = {{87}},
year = {{2013}},
}