Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Molecular anatomy of gene expression responses in stressed hepatocytes

ABSTRACT: It is well-known that isolation and cultivation of primary hepatocytes causes 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 one day cultivation and one 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 minority 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, (3) upregulated migration/cell-cycle associated genes. Gene regulatory network analysis highlights overrepresented and deregulated HNF4 and CAR (cluster 1), KrÃ¼ppel-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 by far not abrogating cultivation-induced responses include removal of non-parenchymal cells, generation of the hepatocytesâ own matrix in spheroids, supplementation with bile salts and siRNA mediated suppression of key transcription factors. In conclusion, the 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.

ORGANISM(S): Mus musculus

SUBMITTER: Jan Hengstler

PROVIDER: E-MTAB-4444 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue.

Godoy Patricio P Widera Agata A Schmidt-Heck Wolfgang W Campos Gisela G Meyer Christoph C Cadenas Cristina C Reif Raymond R Stöber Regina R Hammad Seddik S Pütter Larissa L Gianmoena Kathrin K Marchan Rosemarie R Ghallab Ahmed A Edlund Karolina K Nüssler Andreas A Thasler Wolfgang E WE Damm Georg G Seehofer Daniel D Weiss Thomas S TS Dirsch Olaf O Dahmen Uta U Gebhardt Rolf R Chaudhari Umesh U Meganathan Kesavan K Sachinidis Agapios A Kelm Jens J Hofmann Ute U Zahedi René P RP Guthke Reinhard R Blüthgen Nils N Dooley Steven S Hengstler Jan G JG

Archives of toxicology 20160623 10

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-infe ...[more]

PMID: 27339419

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Dataset Information

Molecular anatomy of gene expression responses in stressed hepatocytes

Publications

Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue.

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