HGF-, EGF-, and dexamethasone-induced gene expression patterns during formation of tissue in hepatic organoid cultures.
Corticosteroids, hepatocyte growth factor (HGF), and epidermal growth factor (EGF) play important roles in hepatic biology. We have previously shown that these molecules are required for formation of tissue with specific histology in complex organoid cultures. Dexamethasone suppresses growth and induces hepatocyte maturation; HGF and EGF are needed for formation of the nonepithelial elements. All three are needed for formation of the biliary epithelium. The gene expression patterns by which corticosteroids, HGF, and EGF mediate their effects in hepatic tissue formation are distinct. These patterns affect many gene families and are described in detail. In terms of main findings, dexamethasone induces expression of both HNF4 and C/EBPalpha, essential transcription factors for hepatocyte differentiation. It suppresses hepatocyte growth by suppressing many molecules associated with growth in liver and other tissues, including IL-6, CXC-chemokine receptor, amphiregulin, COX-2, HIF, etc. HGF and EGF induce all members of the TGF-beta family. They also induced multiple CNS-related genes, probably associated with stellate cells. Dexamethasone, as well as HGF and EGF, induces expression of HNF6-beta, associated with biliary epithelium formation. Combined addition of all three molecules is associated with mature histology in which hepatocyte and biliary lineages are separate and HNF4 is expressed only in hepatocyte nuclei. In conclusion, the results provide new and surprising information on the gene expression alterations by which corticosteroids, HGF, and EGF exert their effects on formation of hepatic tissue. The results underscore the usefulness of the organoid cultures for generating information on histogenesis, which cannot be obtained by other culture or whole animal models.
Michalopoulos
George K
GK
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. michalopoulosgk@msx.upmc.edu
Bowen
William C
WC
Mulè
Karen
K
Luo
Jianhua
J
D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D003907:Dexamethasone / Q000494:pharmacology*; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D009940:Organoids / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014157:Transcription Factors / Q000235:genetics
D015415:Biomarkers; D004338:Drug Combinations; D005938:Glucocorticoids; D012333:RNA, Messenger; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D003907:Dexamethasone