Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation

Abstract

The stem cell ability to self-renew and lead regeneration relies on the balance of complex signals in their microenvironment. The identification of modulators of hepatic progenitor cell (HPC) activation is determinant for liver regeneration and may improve cell transplantation for end-stage liver disease. This investigation used different models to point out the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a key regulator of the HPC fate. We initially proved that in vivo models of biliary epithelial cells (BECs)/HPC activation show hepatic oxidative stress, which activates primary BECs/HPCs in vitro. NRF2 downregulation and silencing were associated with morphological, phenotypic, and functional modifications distinctive of differentiated cells. Furthermore, NRF2 activation in the biliary tract repressed the ductular reaction in injured liver. To definitely assess the importance of NRF2 in HPC biology, we applied a xenograft model by inhibiting NRF2 in the human derived HepaRG cell line and transplanting into SCID/beige mice administered with anti-Fas antibody to induce hepatocellular apoptosis; this resulted in effective human hepatocyte repopulation with reduced liver injury. To conclude, NRF2 inhibition leads to the activation and differentiation of liver progenitors. This redox-dependent transcription factor represents a potential target to regulate the commitment of undifferentiated hepatic progenitors into specific lineages.

Nrf2 Transcriptional Activity Governs Intestine Development

“…Given this striking increase in the Nrf2 level between E14.5 and E15.5 in the whole embryo, it would be worthy verifying whether this rise accounts for enhanced proliferation only at the intestinal level or at the organismal level. For instance, Nrf2 regulates the proliferation of enterocytes [ 15 ], hepatocytes [ 26 , 27 ], satellite cells [ 28 ], neuronal progenitor cells [ 29 ], and endothelial cells [ 16 ]. Thus, it is plausible that the regulation occurs at the organismal level and is not tissue specific.…”

The advantages of physical exercise as a preventive strategy against NAFLD in postmenopausal women

“…150 In addition, redox signalling pathways, such as the nuclear factor kappa B (NF-ĸF), and Keap1-Nrf2 cascades, display pivotal roles in normal physiological processes by providing adequate metabolic/cytoprotective responses upon adverse conditions, sustaining cellular homeostasis or triggering other protective systems, such as the inflammatory response to re-establish appropriate functional conditions. 151,152 Thus, the mechanisms by which ROS contribute to NAFLD progression may be related to both widespread oxidative damage and dysregulated redox signalling processes and inflammation, although the exact cross-talks between mechanisms are still under investigation. 153…”

Liver Regeneration and Cell Transplantation for End-Stage Liver Disease

“…In a quiescent state, the microenvironment keeps LPCs as the progenitor phenotype and inhibits cell differentiation. Liver injuries trigger specific alterations of the microenvironment, promoting the differentiation of LPCs toward a hepatocyte phenotype or BEC phenotype regulated by a variety of signaling pathways [ 24 ]. VEGF is considered an important cytokine during the activation of LPC-mediated liver regeneration in patients with nonalcoholic steatohepatitis (NASH) [ 25 ].…”

“…NRF2 is constitutively activated in LPCs to maintain their stemness features, whereas it is inhibited in case of LPC activation. NRF2 inhibition favors engraftment and repopulation of damaged cells by transplanted elements, which increases the transplantation efficiency of LPCs [ 24 ]. A recent study in vitro demonstrated that autophagy regulates hepatic differentiation of LPCs through the Wnt signaling pathway [ 31 ].…”