Hepatocyte-ductal transdifferentiation is mediated by reciprocal repression of SOX9 and C/EBPα

K.E. O'Neill, S. Thowfeequ, W-C Li, D. Eberhard, J.R. Dutton, D. Tosh, J.M.W. Slack

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)314-323
Number of pages10
JournalCellular Reprogramming
Volume16
Issue number5
Early online date25 Aug 2014
DOIs
Publication statusPublished - 22 Sep 2014

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Hepatocytes
CCAAT-Enhancer-Binding Protein-alpha
Protein C
Embryonic Development
Culture Media
Epithelial Cells
Maintenance
Gene Expression
Genes

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Hepatocyte-ductal transdifferentiation is mediated by reciprocal repression of SOX9 and C/EBPα. / O'Neill, K.E.; Thowfeequ, S.; Li, W-C; Eberhard, D.; Dutton, J.R.; Tosh, D.; Slack, J.M.W.

In: Cellular Reprogramming, Vol. 16, No. 5, 22.09.2014, p. 314-323.

Research output: Contribution to journalArticle

O'Neill, K.E. ; Thowfeequ, S. ; Li, W-C ; Eberhard, D. ; Dutton, J.R. ; Tosh, D. ; Slack, J.M.W. / Hepatocyte-ductal transdifferentiation is mediated by reciprocal repression of SOX9 and C/EBPα. In: Cellular Reprogramming. 2014 ; Vol. 16, No. 5. pp. 314-323.
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