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

Fecha de publicación: 27/10/2020 Fecha Ahead of Print: 27/10/2020

Autores de IIS La Fe

José Vicente Castell Ripoll

Autor
Laia Tolosa Pardo

Autor

Participantes ajenos a IIS La Fe

Gupta R
Schrooders Y
Hauser D
van Herwijnen M
Albrecht W
Ter Braak B
Brecklinghaus T
Elenschneider L
Escher S
Guye P
Hengstler JG
Ghallab A
Hansen T
Leist M
Maclennan R
Moritz W
Tricot T
Verfaillie C
Walker P
van de Water B
Kleinjans J
Caiment F

Grupos

Hepatología experimental y Trasplante hepático

Investigador Principal

Laia Tolosa Pardo
Unidad Mixta de Investigación en Hepatología Experimental

Investigador Principal

Ramiro Jover Atienza

Abstract

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.

Datos de la publicación

ISSN/ISSNe:: 0340-5761, 1432-0738
Tipo:: Article
Páginas:: 573-589
DOI:: 10.1007/s00204-020-02937-6
Factor de Impacto:: 1,264 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Albrecht W:: Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Dortmund, Germany
Brecklinghaus T:: Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Dortmund, Germany
Castell JV:: Instituto de Investigación. Instituto de Investigación Sanitaria La Fe, Experimental Hepatology Unit, Valencia, Spain
Elenschneider L:: Fraunhofer Institute for Toxicology and Experimental Medicine Preclinical Pharmacology and In-Vitro Toxicology, Nikolai-Fuchs-Straße 1, 30625, Hannover, Germany
Escher S:: Fraunhofer Institute for Toxicology and Experimental Medicine Preclinical Pharmacology and In-Vitro Toxicology, Nikolai-Fuchs-Straße 1, 30625, Hannover, Germany
Guye P:: InSphero AG, Wagistrasse 27, 8952, Schlieren, Switzerland
Hengstler JG:: Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Dortmund, Germany
Ghallab A:: Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Dortmund, Germany

Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt
Hansen T:: Fraunhofer Institute for Toxicology and Experimental Medicine Preclinical Pharmacology and In-Vitro Toxicology, Nikolai-Fuchs-Straße 1, 30625, Hannover, Germany
Leist M:: In Vitro Toxicology and Biomedicine, Department Inaugurated, Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany
Maclennan R:: Cyprotex Discovery, No 24 Mereside, Alderley Park, Cheshire, SK10 4TG, UK
Moritz W:: InSphero AG, Wagistrasse 27, 8952, Schlieren, Switzerland
Tolosa L:: Instituto de Investigación. Instituto de Investigación Sanitaria La Fe, Unidad Hepatología Experimental, Valencia, Spain
Tricot T:: Stem Cell Institute, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000, Leuven, Belgium
Verfaillie C:: Stem Cell Institute, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000, Leuven, Belgium
Walker P:: Cyprotex Discovery, No 24 Mereside, Alderley Park, Cheshire, SK10 4TG, UK

Keywords

CellNet, In vitro liver, In vivo liver, Non-DEGs, Non-DEGsDTU-, Pathway coverage, RNA-seq

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