Dokumentenart: | Artikel | ||||||
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Titel eines Journals oder einer Zeitschrift: | Archives of Toxicology | ||||||
Verlag: | SPRINGER HEIDELBERG | ||||||
Ort der Veröffentlichung: | HEIDELBERG | ||||||
Band: | 90 | ||||||
Nummer des Zeitschriftenheftes oder des Kapitels: | 10 | ||||||
Seitenbereich: | S. 2513-2529 | ||||||
Datum: | 2016 | ||||||
Institutionen: | Medizin > Lehrstuhl für Kinder- und Jugendmedizin | ||||||
Identifikationsnummer: |
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Stichwörter / Keywords: | IN-VITRO SYSTEMS; EXPRESSION PROFILES; STEM-CELLS; DIFFERENTIATION; HEPATOTOXICITY; CULTURE; MATRIX; DRIVE; ORGAN; VIVO; Gene arrays; Bioinformatics; Inflammation; Metabolism; Differentiation | ||||||
Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||||
Status: | Veröffentlicht | ||||||
Begutachtet: | Ja, diese Version wurde begutachtet | ||||||
An der Universität Regensburg entstanden: | Ja | ||||||
Dokumenten-ID: | 42958 |
Zusammenfassung
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 ...
Zusammenfassung
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.
Metadaten zuletzt geändert: 13 Aug 2024 12:04