title: Hepatocyte-ductal transdifferentiation is mediated by reciprocal repression of SOX9 and C/EBPα.
abstract: Primary hepatocytes rapidly dedifferentiate when cultured in vitro. We have studied the mechanism of hepatocyte dedifferentiation by using two culture media: one that maintains hepatocytes in a differentiated state and another that allows dedifferentiation. We show that dedifferentiation involves partial transformation of hepatocytes into cells that resemble biliary epithelial cells. Lineage labeling and time-lapse filming confirm that the dedifferentiated cells are derived from hepatocytes and not from contaminating ductal or fibroblastic cells in the original culture. Furthermore, we establish that the conversion of hepatocytes to biliary-like cells is regulated by mutual antagonism of CCAAT/enhancer binding protein alpha (C/EBPα) and SOX9, which have opposing effects on the expression of hepatocyte and ductal genes. Thus, hepatocyte dedifferentiation induces the biliary gene expression program by alleviating C/EBPα-mediated repression of Sox9. We propose that reciprocal antagonism of C/EBPα and SOX9 also operates in the formation of hepatocytes and biliary ducts from hepatoblasts during normal embryonic development. These data demonstrate that reprogramming of differentiated cells can be used to model the acquisition and maintenance of cell fate in vivo.
authors.affiliation: 1 Centre for Regenerative Medicine, Department of Biology & Biochemistry University of Bath , Claverton Down, Bath, BA2 7AY, United Kingdom .
authors.forename: Kathy E
authors.initials: KE
authors.lastname: O'Neill
authors.forename: Shifaan
authors.initials: S
authors.lastname: Thowfeequ
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Eberhard
authors.forename: James R
authors.initials: JR
authors.lastname: Dutton
authors.forename: David
authors.initials: D
authors.lastname: Tosh
authors.forename: Jonathan M W
authors.initials: JM
authors.lastname: Slack
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D003470:Culture Media; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D003470:Culture Media; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse