Nuclear factor (erythroid-derived-2)-like 2 (Nrf2) signalling is involved in transdifferentiation of hepatocyte-like cells

The identification of key regulators in hepatic progenitor cells differentiation is determinant for organ regeneration and may improve stem cell transplantation for end-stage liver disease. Mesenchymal, embryonic and pluripotent stem cells have been investigated as potential sources for hepatic differentiation, but their unstable function and atypical morphology limit the usefulness for cell treatment. The human bipotent liver progenitor cell line HepaRG is applied for toxicity screening, viral hepatitis research, hepatocyte differentiation and transplantation testing. Since redox-dependent signaling molecules are involved in the regulation of stem cell self-renewal and differentiation, we studied the role of Nrf2 – the main transcription factor involved in the oxidative stress response – in HepaRG transdifferentiation. Nrf2 was upregulated in undifferentiated HepaRG, which exhibited higher free radical production as compared to transdifferentiated cells. Pharmacological and genetic inhibition of Nrf2 led to morphological, phenotypical and functional patterns characteristic of transdifferentiated elements. To conclude, we show a determinant role of Nrf2 in the process of HepaRG transdifferentiation, suggesting that this redox-dependent transcription factor represents a potential target to regulate the commitment of undifferentiated hepatic progenitor cells into specific lineages.