A Comprehensive Profiling of Genome-Wide Transcriptional Programs of Primary Hepatocytes in Vitro Cultures

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The liver is one of most important organs in our bodies and performs many essential functions including metabolism, synthesis, secretion, detoxification, and storage. Hepatocytes are the principal cell type that accounts for 80% of liver and involved in major liver-specific functions. In vitro hepatic culture systems are important tools in development of pharmaceuticals, toxicity testing, and the design of bio-artificial liver devices. In hepatic tissue engineering two widely used culture systems are collagen sandwich and hepatocyte monolayers. There has been little investigation into gene expression profiling of hepatocytes for each culture system. Genome-wide gene expression profiles of primary hepatocytes were measured for each cell culture system using Affymetrix GeneChips and analyzed via Gene Set Enrichment Analysis (GSEA) which is a powerful method to elicit biologically meaningful information from microarray data at the level of gene sets. A comprehensive gene expression study of hepatocytes in collagen sandwich system shows that gene expression monotonically diverges from that in hepatocyte monolayers over an eight-day culture period. Gene sets related to liver-specific functions such as metabolism of cholesterol, fatty acid and amino acid, urea and albumin production, and alcohol metabolism were shown to be gradually up-regulated in the time-dependent manner. Monooxygenases such as cytochrome-P450 enzymes exhibited significant up-regulation in collagen sandwich cultures after three days in comparison to hepatocyte monolayers. Gene sets associated with de-differentiation of hepatocytes were up-regulated in hepatocytes monolayers over the culture period. These temporal genome-wide gene expression studies provide insights into the up- and down-regulation of various liver-specific phenotypic functions and thus help understand subsequent physiological phenomena. These results provide a baseline for further systems biology of engineered liver tissues. Ongoing investigations include the global gene expression profiles of hepatocytes in in vitro liver mimics and understanding of underlying inter-cellular communications.



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