The Epithelial Mesenchymal Transition Confers Resistance to the Apoptotic Effects of Transforming Growth Factor β in Fetal Rat Hepatocytes

Abstract

Fetal rat hepatocytes treated with transforming growth factor β (TGF-β) die by apoptosis. However, a subpopulation of them survives and undergoes an epithelial mesenchymal transition (EMT). This transition also occurs upon incubation with fetal bovine serum. We have isolated the subpopulations that undergo EMT (TGF-β-treated-fetal hepatocytes: TβT-FH; serum-treated-fetal hepatocytes: ST-FH) and show that they present high levels of vimentin and Snail expression and lack cytokeratin 18 and E-cadherin. Both TβT-FH and ST-FH cells require mitogens to grow and maintain the response to TGF-β in terms of growth inhibition. However, they lack differentiation markers such as the liver-enriched transcription factors hepatocyte nuclear factor 4 (HNF-4) or HNF-1α and express the progenitor marker OV-6. Interestingly, the EMT process confers them resistance to the apoptotic effect of TGF-β, with cells showing higher levels of active AKT and Bcl-xL than fetal hepatocytes. In summary, these cells are refractory to the apoptotic effects of TGF-β, showing characteristics of liver progenitors and of some hepatocellular carcinoma cells.