Retinoic acid generates a beneficial microenvironment for liver progenitor cell activation in acute liver failure

Massive hepatic necrosis is the most severe lesion in acute liver failure (ALF). To survive, liver progenitor cell (LPC)-derived regeneration is required, which is initiated by the ductular reaction. In ALF, high levels of retinoic acid (RA) are secreted into the microenvironment by the activated hepatic stellate cells (HSCs), which is the active form of vitamin A that activates the retinoic acid receptor (RAR). In this study, we investigated the function of RA in LPCs through RNA sequencing analysis and functional assays in cells and patients. Our results showed that in the ALF condition with inflammation or during the cell culture in vitro, HSCs, including phHSCs and LX-2 cells, will be activated. Subsequently, activated HSCs secrete high levels of RA, inducing RARα nuclear translocation in LPC. Based on RNA-seq analysis and investigations in HepaRG cells, atRA treatment activates the WNT-β-Catenin pathway, enhances stemness genes expression, promotes energy storage, and elevates the expression of ATP-binding cassette (ABC) transporters partially dependent on RARα in HepaRG cells, which is pivotal for the LPC activation, expansion, and the subsequent differentiation into hepatocytes in the conditions of ALF. Further, these signaling pathways induced by atRA treatment were confirmed by co-culture HepaRG with LX-2 cells. In addition, ALF patients with positive RARα nuclear staining in the LPCs displayed a better MELD score compared to the ALF patients who lost RARα nuclear expression. In conclusion, RA secreted by activated HSCs promotes LPCs activation, which is significant for the subsequent LPC-mediated liver regeneration in ALF.