PAR3-mediated coordination of hepatocyte proliferation, maturation, and architecture in liver development and regeneration

The liver’s ability to coordinate cell proliferation, polarization, and maturation with architectural assembly is fundamental to its metabolic functions and regenerative capacity. However, the mechanisms that integrate these processes remain incompletely understood. Using murine and human models, we show that hepatic polarity and bile canaliculi (BC) formation initiate at sites of cell division during the hepatoblast stage, and that BC elongation is temporally associated with oriented cell division during hepatocyte differentiation. This process involves PAR3- and YAP-dependent modulation of ERK/MAPK signaling. PAR3 forms a protein complex that localizes a subset of IQGAP1 to tight junctions, thereby restricting ERK/MAPK activation at the basolateral membrane. This regulation is required for efficient BC elongation and hepatocyte maturation. Together, these findings reveal a stage-dependent mechanism linking liver architecture to functional maturation and provide insights into liver development, regeneration, and potential therapeutic strategies for metabolic liver disease and liver failure. Here they show that PAR3 promotes bile canaliculus elongation and hepatocyte maturation by restricting ERK/MAPK signaling, linking liver architecture formation with functional maturation during development and regeneration.