Godoy, Patricio, Widera, Agata, Schmidt-Heck, Wolfgang, Campos, Gisela, Meyer, Christoph, Cadenas, Cristina, Reif, Raymond, Stoeber, Regina, Hammad, Seddik, Puetter, Larissa, Gianmoena, Kathrin, Marchan, Rosemarie ORCID: 0000-0003-4414-1633, Ghallab, Ahmed ORCID: 0000-0003-0695-3403, Edlund, Karolina, Nuessler, Andreas, Thasler, Wolfgang E., Damm, Georg, Seehofer, Daniel, Weiss, Thomas S. ORCID: 0000-0003-0336-0581, Dirsch, Olaf, Dahmen, Uta, Gebhardt, Rolf, Chaudhari, Umesh ORCID: 0000-0002-7743-4371, Meganathan, Kesavan, Sachinidis, Agapios, Kelm, Jens, Hofmann, Ute ORCID: 0000-0003-0823-9027, Zahedi, Rene P., Guthke, Reinhard, Bluethgen, Nils, Dooley, Steven and Hengstler, Jan G. (2016). Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue. Arch. Toxicol., 90 (10). S. 2513 - 2530. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

It is well known that isolation and cultivation of primary hepatocytes cause major gene expression alterations. In the present genome-wide, time-resolved study of cultivated human and mouse hepatocytes, we made the observation that expression changes in culture strongly resemble alterations in liver diseases. Hepatocytes of both species were cultivated in collagen sandwich and in monolayer conditions. Genome-wide data were also obtained from human NAFLD, cirrhosis, HCC and hepatitis B virus-infected tissue as well as mouse livers after partial hepatectomy, CCl4 intoxication, obesity, HCC and LPS. A strong similarity between cultivation and disease-induced expression alterations was observed. For example, expression changes in hepatocytes induced by 1-day cultivation and 1-day CCl4 exposure in vivo correlated with R = 0.615 (p < 0.001). Interspecies comparison identified predominantly similar responses in human and mouse hepatocytes but also a set of genes that responded differently. Unsupervised clustering of altered genes identified three main clusters: (1) downregulated genes corresponding to mature liver functions, (2) upregulation of an inflammation/RNA processing cluster and (3) upregulated migration/cell cycle-associated genes. Gene regulatory network analysis highlights overrepresented and deregulated HNF4 and CAR (Cluster 1), Kruppel-like factors MafF and ELK1 (Cluster 2) as well as ETF (Cluster 3) among the interspecies conserved key regulators of expression changes. Interventions ameliorating but not abrogating cultivation-induced responses include removal of non-parenchymal cells, generation of the hepatocytes' own matrix in spheroids, supplementation with bile salts and siRNA-mediated suppression of key transcription factors. In conclusion, this study shows that gene regulatory network alterations of cultivated hepatocytes resemble those of inflammatory liver diseases and should therefore be considered and exploited as disease models.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Godoy, PatricioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Widera, AgataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt-Heck, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campos, GiselaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyer, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cadenas, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reif, RaymondUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoeber, ReginaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammad, SeddikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puetter, LarissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gianmoena, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marchan, RosemarieUNSPECIFIEDorcid.org/0000-0003-4414-1633UNSPECIFIED
Ghallab, AhmedUNSPECIFIEDorcid.org/0000-0003-0695-3403UNSPECIFIED
Edlund, KarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuessler, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thasler, Wolfgang E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Damm, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seehofer, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weiss, Thomas S.UNSPECIFIEDorcid.org/0000-0003-0336-0581UNSPECIFIED
Dirsch, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahmen, UtaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gebhardt, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chaudhari, UmeshUNSPECIFIEDorcid.org/0000-0002-7743-4371UNSPECIFIED
Meganathan, KesavanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sachinidis, AgapiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelm, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofmann, UteUNSPECIFIEDorcid.org/0000-0003-0823-9027UNSPECIFIED
Zahedi, Rene P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guthke, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bluethgen, NilsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dooley, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hengstler, Jan G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-261261
DOI: 10.1007/s00204-016-1761-4
Journal or Publication Title: Arch. Toxicol.
Volume: 90
Number: 10
Page Range: S. 2513 - 2530
Date: 2016
Publisher: SPRINGER HEIDELBERG
Place of Publication: HEIDELBERG
ISSN: 1432-0738
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
IN-VITRO SYSTEMS; EXPRESSION PROFILES; STEM-CELLS; DIFFERENTIATION; HEPATOTOXICITY; CULTURE; MATRIX; DRIVE; ORGAN; VIVOMultiple languages
ToxicologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26126

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