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Comparing in vitro human liver models to in vivo human liver using RNA-Seq

The liver plays an important role in xenobiotic metabolism and represents a primary target for toxic substances. Many different in vitro cell models have been developed in the past decades. In this study, we used RNA-sequencing (RNA-Seq) to analyze the following human in vitro liver cell models in c...

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Autores principales: Gupta, Rajinder, Schrooders, Yannick, Hauser, Duncan, van Herwijnen, Marcel, Albrecht, Wiebke, ter Braak, Bas, Brecklinghaus, Tim, Castell, Jose V., Elenschneider, Leroy, Escher, Sylvia, Guye, Patrick, Hengstler, Jan G., Ghallab, Ahmed, Hansen, Tanja, Leist, Marcel, Maclennan, Richard, Moritz, Wolfgang, Tolosa, Laia, Tricot, Tine, Verfaillie, Catherine, Walker, Paul, van de Water, Bob, Kleinjans, Jos, Caiment, Florian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870774/
https://www.ncbi.nlm.nih.gov/pubmed/33106934
http://dx.doi.org/10.1007/s00204-020-02937-6
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author Gupta, Rajinder
Schrooders, Yannick
Hauser, Duncan
van Herwijnen, Marcel
Albrecht, Wiebke
ter Braak, Bas
Brecklinghaus, Tim
Castell, Jose V.
Elenschneider, Leroy
Escher, Sylvia
Guye, Patrick
Hengstler, Jan G.
Ghallab, Ahmed
Hansen, Tanja
Leist, Marcel
Maclennan, Richard
Moritz, Wolfgang
Tolosa, Laia
Tricot, Tine
Verfaillie, Catherine
Walker, Paul
van de Water, Bob
Kleinjans, Jos
Caiment, Florian
author_facet Gupta, Rajinder
Schrooders, Yannick
Hauser, Duncan
van Herwijnen, Marcel
Albrecht, Wiebke
ter Braak, Bas
Brecklinghaus, Tim
Castell, Jose V.
Elenschneider, Leroy
Escher, Sylvia
Guye, Patrick
Hengstler, Jan G.
Ghallab, Ahmed
Hansen, Tanja
Leist, Marcel
Maclennan, Richard
Moritz, Wolfgang
Tolosa, Laia
Tricot, Tine
Verfaillie, Catherine
Walker, Paul
van de Water, Bob
Kleinjans, Jos
Caiment, Florian
author_sort Gupta, Rajinder
collection PubMed
description The liver plays an important role in xenobiotic metabolism and represents a primary target for toxic substances. Many different in vitro cell models have been developed in the past decades. In this study, we used RNA-sequencing (RNA-Seq) to analyze the following human in vitro liver cell models in comparison to human liver tissue: cancer-derived cell lines (HepG2, HepaRG 3D), induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-HLCs), cancerous human liver-derived assays (hPCLiS, human precision cut liver slices), non-cancerous human liver-derived assays (PHH, primary human hepatocytes) and 3D liver microtissues. First, using CellNet, we analyzed whether these liver in vitro cell models were indeed classified as liver, based on their baseline expression profile and gene regulatory networks (GRN). More comprehensive analyses using non-differentially expressed genes (non-DEGs) and differential transcript usage (DTU) were applied to assess the coverage for important liver pathways. Through different analyses, we noticed that 3D liver microtissues exhibited a high similarity with in vivo liver, in terms of CellNet (C/T score: 0.98), non-DEGs (10,363) and pathway coverage (highest for 19 out of 20 liver specific pathways shown) at the beginning of the incubation period (0 h) followed by a decrease during long-term incubation for 168 and 336 h. PHH also showed a high degree of similarity with human liver tissue and allowed stable conditions for a short-term cultivation period of 24 h. Using the same metrics, HepG2 cells illustrated the lowest similarity (C/T: 0.51, non-DEGs: 5623, and pathways coverage: least for 7 out of 20) with human liver tissue. The HepG2 are widely used in hepatotoxicity studies, however, due to their lower similarity, they should be used with caution. HepaRG models, iPSC-HLCs, and hPCLiS ranged clearly behind microtissues and PHH but showed higher similarity to human liver tissue than HepG2 cells. In conclusion, this study offers a resource of RNA-Seq data of several biological replicates of human liver cell models in vitro compared to human liver tissue. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00204-020-02937-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-78707742021-02-16 Comparing in vitro human liver models to in vivo human liver using RNA-Seq Gupta, Rajinder Schrooders, Yannick Hauser, Duncan van Herwijnen, Marcel Albrecht, Wiebke ter Braak, Bas Brecklinghaus, Tim Castell, Jose V. Elenschneider, Leroy Escher, Sylvia Guye, Patrick Hengstler, Jan G. Ghallab, Ahmed Hansen, Tanja Leist, Marcel Maclennan, Richard Moritz, Wolfgang Tolosa, Laia Tricot, Tine Verfaillie, Catherine Walker, Paul van de Water, Bob Kleinjans, Jos Caiment, Florian Arch Toxicol In Vitro Systems The liver plays an important role in xenobiotic metabolism and represents a primary target for toxic substances. Many different in vitro cell models have been developed in the past decades. In this study, we used RNA-sequencing (RNA-Seq) to analyze the following human in vitro liver cell models in comparison to human liver tissue: cancer-derived cell lines (HepG2, HepaRG 3D), induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-HLCs), cancerous human liver-derived assays (hPCLiS, human precision cut liver slices), non-cancerous human liver-derived assays (PHH, primary human hepatocytes) and 3D liver microtissues. First, using CellNet, we analyzed whether these liver in vitro cell models were indeed classified as liver, based on their baseline expression profile and gene regulatory networks (GRN). More comprehensive analyses using non-differentially expressed genes (non-DEGs) and differential transcript usage (DTU) were applied to assess the coverage for important liver pathways. Through different analyses, we noticed that 3D liver microtissues exhibited a high similarity with in vivo liver, in terms of CellNet (C/T score: 0.98), non-DEGs (10,363) and pathway coverage (highest for 19 out of 20 liver specific pathways shown) at the beginning of the incubation period (0 h) followed by a decrease during long-term incubation for 168 and 336 h. PHH also showed a high degree of similarity with human liver tissue and allowed stable conditions for a short-term cultivation period of 24 h. Using the same metrics, HepG2 cells illustrated the lowest similarity (C/T: 0.51, non-DEGs: 5623, and pathways coverage: least for 7 out of 20) with human liver tissue. The HepG2 are widely used in hepatotoxicity studies, however, due to their lower similarity, they should be used with caution. HepaRG models, iPSC-HLCs, and hPCLiS ranged clearly behind microtissues and PHH but showed higher similarity to human liver tissue than HepG2 cells. In conclusion, this study offers a resource of RNA-Seq data of several biological replicates of human liver cell models in vitro compared to human liver tissue. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00204-020-02937-6) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-10-27 2021 /pmc/articles/PMC7870774/ /pubmed/33106934 http://dx.doi.org/10.1007/s00204-020-02937-6 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle In Vitro Systems
Gupta, Rajinder
Schrooders, Yannick
Hauser, Duncan
van Herwijnen, Marcel
Albrecht, Wiebke
ter Braak, Bas
Brecklinghaus, Tim
Castell, Jose V.
Elenschneider, Leroy
Escher, Sylvia
Guye, Patrick
Hengstler, Jan G.
Ghallab, Ahmed
Hansen, Tanja
Leist, Marcel
Maclennan, Richard
Moritz, Wolfgang
Tolosa, Laia
Tricot, Tine
Verfaillie, Catherine
Walker, Paul
van de Water, Bob
Kleinjans, Jos
Caiment, Florian
Comparing in vitro human liver models to in vivo human liver using RNA-Seq
title Comparing in vitro human liver models to in vivo human liver using RNA-Seq
title_full Comparing in vitro human liver models to in vivo human liver using RNA-Seq
title_fullStr Comparing in vitro human liver models to in vivo human liver using RNA-Seq
title_full_unstemmed Comparing in vitro human liver models to in vivo human liver using RNA-Seq
title_short Comparing in vitro human liver models to in vivo human liver using RNA-Seq
title_sort comparing in vitro human liver models to in vivo human liver using rna-seq
topic In Vitro Systems
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870774/
https://www.ncbi.nlm.nih.gov/pubmed/33106934
http://dx.doi.org/10.1007/s00204-020-02937-6
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