Transforming growth factor-β1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro

Aki Kaimori, James Potter, Jun Ya Kaimori, Connie Wang, Esteban Mezey, Ayman Koteish

Research output: Contribution to journalArticle

Abstract

Liver fibrosis is a progressive pathologic process that involves deposition of excess extracellular matrix leading to distorted architecture and culminating in cirrhosis. The role of transforming growth factor-β(TGF- β) as a key molecule in the development and progression of hepatic fibrosis via the activation of hepatic stellate cells, among other fibroblast populations, is without controversy. We hereby show that TGF-β1 induces an epithelial-to-mesenchymal transition (EMT) state in mature hepatocytes in vitro. EMT state was marked by significant up-regulation of α1(I) collagen mRNA expression and type I collagen deposition. Similar changes were found in a "normal" mouse hepatocyte cell line (AML12), thus confirming that hepatocytes are capable of EMT changes and type I collagen synthesis. We also show that in hepatocytes in the EMT state, TGF-β1 induces the snail-1 transcription factor and activates the Smad2/3 pathway. Evidence for a central role of the TGF-β1/Smad pathway is further supported by the inhibition of EMT by Smad4 silencing using small interference RNA technology. In conclusion, TGF-β1, a known pro-apoptotic cytokine in mature hepatocytes, is capable of mediating phenotypic changes and plasticity in the form of EMT, resulting in collagen deposition. Our findings support a potentially crucial role for EMT in the development and progression of hepatic fibrogenesis.

Original languageEnglish (US)
Pages (from-to)22089-22101
Number of pages13
JournalJournal of Biological Chemistry
Volume282
Issue number30
DOIs
StatePublished - Jul 27 2007

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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