Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profile of human embryonic stem cell-derived hepatocyte-like cells in matrigel and recombinant laminins

ABSTRACT: Stem cell derived somatic cells represent an unlimited resource for basic and translational science. While promising, there are significant hurdles that must be overcome. Our focus is on the generation of the major cell type of the human liver, the hepatocyte. Current protocols produce variable populations of hepatocytes, which is the product of using undefined components in the differentiation process. To tackle this issue, we have designed a defined differentiation process using recombinant laminin substrates as extracellular matrix support, and compared the hepatic differentiation potential obtained with this matrix to that of matrigel. Human embryonic stem cells H9 were replated onto matrigel, pure laminin 521 and the laminin 521:111 mix (1:3 ratio, referred to as laminin 111 mix) coated wells.

ORGANISM(S): Homo sapiens

SUBMITTER: Wolfgang Schmidt-Heck

PROVIDER: E-MTAB-3994 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description: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.

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Gene expression profile of human embryonic stem cell-derived hepatocyte-like cells in matrigel and recombinant laminins

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