Godoy, Patricio and Widera, Agata and Schmidt-Heck, Wolfgang and Campos, Gisela and Meyer, Christoph and Cadenas, Cristina and Reif, Raymond and Stoeber, Regina and Hammad, Seddik and Puetter, Larissa and Gianmoena, Kathrin and Marchan, Rosemarie and Ghallab, Ahmed and Edlund, Karolina and Nuessler, Andreas and Thasler, Wolfgang E. and Damm, Georg and Seehofer, Daniel and Weiss, Thomas S. and Dirsch, Olaf and Dahmen, Uta and Gebhardt, Rolf and Chaudhari, Umesh and Meganathan, Kesavan and Sachinidis, Agapios and Kelm, Jens and Hofmann, Ute and Zahedi, Rene P. and Guthke, Reinhard and Bluethgen, Nils and Dooley, Steven and Hengstler, Jan G. (2016) Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue. ARCHIVES OF TOXICOLOGY, 90 (10). pp. 2513-2529. ISSN 0340-5761, 1432-0738
Full text not available from this repository. (Request a copy)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: | Article |
|---|---|
| Uncontrolled Keywords: | IN-VITRO SYSTEMS; EXPRESSION PROFILES; STEM-CELLS; DIFFERENTIATION; HEPATOTOXICITY; CULTURE; MATRIX; DRIVE; ORGAN; VIVO; Gene arrays; Bioinformatics; Inflammation; Metabolism; Differentiation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Apr 2019 13:03 |
| Last Modified: | 24 Apr 2019 13:03 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4198 |
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