The balance between Notch/Wnt signaling regulates progenitor cells' commitment during liver repair: Mystery solved?

During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholan- giocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myo- fibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepato- cytes. By these two pathways adult parenchymal regeneration dur- ing chronic liver injury is promoted. 2012 European Association for the Study of the Liver. Published