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, Nicola J. Hewitt, Ute Albrecht, Melvin E. Andersen, Nariman Ansari, Sudin Bhattacharya, Johannes Georg Bode, Jennifer Bolleyn, Christoph Borner, Jan Böttger, Albert Braeuning, Robert A. Budinsky, Britta Burkhardt, Neil R. Cameron, Giovanni Camussi, Chong Su Cho, Yun Jaie Choi, J. Craig Rowlands, Uta Dahmen, Georg Damm & 73 others Olaf Dirsch, María Teresa Donato, Jian Dong, Steven Dooley, Dirk Drasdo, Rowena Eakins, Karine Sá Ferreira, Valentina Fonsato, Joanna Fraczek, Rolf Gebhardt, Andrew Gibson, Matthias Glanemann, Chris E P Goldring, María José Gómez-Lechón, Geny M M Groothuis, Lena Gustavsson, Christelle Guyot, David Hallifax, Seddik Hammad, Adam Hayward, Dieter Häussinger, Claus Hellerbrand, Philip Hewitt, Stefan Hoehme, Hermann Georg Holzhütter, J. Brian Houston, Jens Hrach, Kiyomi Ito, Hartmut Jaeschke, Verena Keitel, Jens M. Kelm, B. Kevin Park, Claus Kordes, Gerd A. Kullak-Ublick, Edward L. Lecluyse, Peng Lu, Jennifer Luebke-Wheeler, Anna Lutz, Daniel J. Maltman, Madlen Matz-Soja, Patrick McMullen, Irmgard Merfort, Simon Messner, Christoph Meyer, Jessica Mwinyi, Dean J. Naisbitt, Andreas K. Nussler, Peter Olinga, Francesco Pampaloni, Jingbo Pi, Linda Pluta, Stefan A. Przyborski, Anup Ramachandran, Vera Rogiers, Cliff Rowe, Celine Schelcher, Kathrin Schmich, Michael Schwarz, Bijay Singh, Ernst H K Stelzer, Bruno Stieger, Regina Stöber, Yuichi Sugiyama, Ciro Tetta, Wolfgang E. Thasler, Tamara Vanhaecke, Mathieu Vinken, Thomas S. Weiss, Agata Widera, Courtney G. Woods, Jinghai James Xu, Kathy M. Yarborough, Jan G. Hengstler

Research output: Research - peer-reviewArticle

  • 349 Citations

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.

LanguageEnglish (US)
Pages1315-1530
Number of pages216
JournalArchives of Toxicology
Volume87
Issue number8
DOIs
StatePublished - Aug 2013
Externally publishedYes

Profile

Hepatocytes
Liver
In Vitro Techniques
Cell signaling
Metabolism
Pharmaceutical Preparations
Drug interactions
Peroxisome Proliferator-Activated Receptors
Mitogen-Activated Protein Kinase Kinases
Cytoplasmic and Nuclear Receptors
Stem cells
Genes
Industry
Culture Techniques
MAP Kinase Signaling System
Drug Industry
Coculture Techniques
Drug Interactions
Hepatocellular Carcinoma
Up-Regulation

Keywords

  • Clearance
  • Cryopreservation
  • DILI*3D Models
  • Mathematical modeling
  • Mechanisms of gene regulation
  • Non-parenchymal cells

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

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

In: Archives of Toxicology, Vol. 87, No. 8, 08.2013, p. 1315-1530.

Research output: Research - peer-reviewArticle

Godoy, P, Hewitt, NJ, Albrecht, U, Andersen, ME, Ansari, N, Bhattacharya, S, Bode, JG, Bolleyn, J, Borner, C, Böttger, J, Braeuning, A, Budinsky, RA, Burkhardt, B, Cameron, NR, Camussi, G, Cho, CS, Choi, YJ, Craig Rowlands, J, Dahmen, U, Damm, G, Dirsch, O, Donato, MT, Dong, J, Dooley, S, Drasdo, D, Eakins, R, Ferreira, KS, Fonsato, V, Fraczek, J, Gebhardt, R, Gibson, A, Glanemann, M, Goldring, CEP, Gómez-Lechón, MJ, Groothuis, GMM, Gustavsson, L, Guyot, C, Hallifax, D, Hammad, S, Hayward, A, Häussinger, D, Hellerbrand, C, Hewitt, P, Hoehme, S, Holzhütter, HG, Houston, JB, Hrach, J, Ito, K, Jaeschke, H, Keitel, V, Kelm, JM, Kevin Park, B, Kordes, C, Kullak-Ublick, GA, Lecluyse, EL, Lu, P, Luebke-Wheeler, J, Lutz, A, Maltman, DJ, Matz-Soja, M, McMullen, P, Merfort, I, Messner, S, Meyer, C, Mwinyi, J, Naisbitt, DJ, Nussler, AK, Olinga, P, Pampaloni, F, Pi, J, Pluta, L, Przyborski, SA, Ramachandran, A, Rogiers, V, Rowe, C, Schelcher, C, Schmich, K, Schwarz, M, Singh, B, Stelzer, EHK, Stieger, B, Stöber, R, Sugiyama, Y, Tetta, C, Thasler, WE, Vanhaecke, T, Vinken, M, Weiss, TS, Widera, A, Woods, CG, Xu, JJ, Yarborough, KM & Hengstler, JG 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' Archives of Toxicology, vol 87, no. 8, pp. 1315-1530. DOI: 10.1007/s00204-013-1078-5
Godoy, Patricio ; Hewitt, Nicola J. ; Albrecht, Ute ; Andersen, Melvin E. ; Ansari, Nariman ; Bhattacharya, Sudin ; Bode, Johannes Georg ; Bolleyn, Jennifer ; Borner, Christoph ; Böttger, Jan ; Braeuning, Albert ; Budinsky, Robert A. ; Burkhardt, Britta ; Cameron, Neil R. ; Camussi, Giovanni ; Cho, Chong Su ; Choi, Yun Jaie ; Craig Rowlands, J. ; Dahmen, Uta ; Damm, Georg ; Dirsch, Olaf ; Donato, María Teresa ; Dong, Jian ; Dooley, Steven ; Drasdo, Dirk ; Eakins, Rowena ; Ferreira, Karine Sá ; Fonsato, Valentina ; Fraczek, Joanna ; Gebhardt, Rolf ; Gibson, Andrew ; Glanemann, Matthias ; Goldring, Chris E P ; Gómez-Lechón, María José ; Groothuis, Geny M M ; Gustavsson, Lena ; Guyot, Christelle ; Hallifax, David ; Hammad, Seddik ; Hayward, Adam ; Häussinger, Dieter ; Hellerbrand, Claus ; Hewitt, Philip ; Hoehme, Stefan ; Holzhütter, Hermann Georg ; Houston, J. Brian ; Hrach, Jens ; Ito, Kiyomi ; Jaeschke, Hartmut ; Keitel, Verena ; Kelm, Jens M. ; Kevin Park, B. ; Kordes, Claus ; Kullak-Ublick, Gerd A. ; Lecluyse, Edward L. ; Lu, Peng ; Luebke-Wheeler, Jennifer ; Lutz, Anna ; Maltman, Daniel J. ; Matz-Soja, Madlen ; McMullen, Patrick ; Merfort, Irmgard ; Messner, Simon ; Meyer, Christoph ; Mwinyi, Jessica ; Naisbitt, Dean J. ; Nussler, Andreas K. ; Olinga, Peter ; Pampaloni, Francesco ; Pi, Jingbo ; Pluta, Linda ; Przyborski, Stefan A. ; Ramachandran, Anup ; Rogiers, Vera ; Rowe, Cliff ; Schelcher, Celine ; Schmich, Kathrin ; Schwarz, Michael ; Singh, Bijay ; Stelzer, Ernst H K ; Stieger, Bruno ; Stöber, Regina ; Sugiyama, Yuichi ; Tetta, Ciro ; Thasler, Wolfgang E. ; Vanhaecke, Tamara ; Vinken, Mathieu ; Weiss, Thomas S. ; Widera, Agata ; Woods, Courtney G. ; Xu, Jinghai James ; Yarborough, Kathy M. ; Hengstler, Jan G./ 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. In: Archives of Toxicology. 2013 ; Vol. 87, No. 8. pp. 1315-1530
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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.",
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TY - JOUR

T1 - 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

AU - Godoy,Patricio

AU - Hewitt,Nicola J.

AU - Albrecht,Ute

AU - Andersen,Melvin E.

AU - Ansari,Nariman

AU - Bhattacharya,Sudin

AU - Bode,Johannes Georg

AU - Bolleyn,Jennifer

AU - Borner,Christoph

AU - Böttger,Jan

AU - Braeuning,Albert

AU - Budinsky,Robert A.

AU - Burkhardt,Britta

AU - Cameron,Neil R.

AU - Camussi,Giovanni

AU - Cho,Chong Su

AU - Choi,Yun Jaie

AU - Craig Rowlands,J.

AU - Dahmen,Uta

AU - Damm,Georg

AU - Dirsch,Olaf

AU - Donato,María Teresa

AU - Dong,Jian

AU - Dooley,Steven

AU - Drasdo,Dirk

AU - Eakins,Rowena

AU - Ferreira,Karine Sá

AU - Fonsato,Valentina

AU - Fraczek,Joanna

AU - Gebhardt,Rolf

AU - Gibson,Andrew

AU - Glanemann,Matthias

AU - Goldring,Chris E P

AU - Gómez-Lechón,María José

AU - Groothuis,Geny M M

AU - Gustavsson,Lena

AU - Guyot,Christelle

AU - Hallifax,David

AU - Hammad,Seddik

AU - Hayward,Adam

AU - Häussinger,Dieter

AU - Hellerbrand,Claus

AU - Hewitt,Philip

AU - Hoehme,Stefan

AU - Holzhütter,Hermann Georg

AU - Houston,J. Brian

AU - Hrach,Jens

AU - Ito,Kiyomi

AU - Jaeschke,Hartmut

AU - Keitel,Verena

AU - Kelm,Jens M.

AU - Kevin Park,B.

AU - Kordes,Claus

AU - Kullak-Ublick,Gerd A.

AU - Lecluyse,Edward L.

AU - Lu,Peng

AU - Luebke-Wheeler,Jennifer

AU - Lutz,Anna

AU - Maltman,Daniel J.

AU - Matz-Soja,Madlen

AU - McMullen,Patrick

AU - Merfort,Irmgard

AU - Messner,Simon

AU - Meyer,Christoph

AU - Mwinyi,Jessica

AU - Naisbitt,Dean J.

AU - Nussler,Andreas K.

AU - Olinga,Peter

AU - Pampaloni,Francesco

AU - Pi,Jingbo

AU - Pluta,Linda

AU - Przyborski,Stefan A.

AU - Ramachandran,Anup

AU - Rogiers,Vera

AU - Rowe,Cliff

AU - Schelcher,Celine

AU - Schmich,Kathrin

AU - Schwarz,Michael

AU - Singh,Bijay

AU - Stelzer,Ernst H K

AU - Stieger,Bruno

AU - Stöber,Regina

AU - Sugiyama,Yuichi

AU - Tetta,Ciro

AU - Thasler,Wolfgang E.

AU - Vanhaecke,Tamara

AU - Vinken,Mathieu

AU - Weiss,Thomas S.

AU - Widera,Agata

AU - Woods,Courtney G.

AU - Xu,Jinghai James

AU - Yarborough,Kathy M.

AU - Hengstler,Jan G.

PY - 2013/8

Y1 - 2013/8

N2 - 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.

AB - 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.

KW - Clearance

KW - Cryopreservation

KW - DILI3D Models

KW - Mathematical modeling

KW - Mechanisms of gene regulation

KW - Non-parenchymal cells

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JF - Archiv fur Toxikologie

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