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

The coordination of cell proliferation, polarization, and maturation with architectural assembly is crucial for liver development and regeneration, yet the mechanisms underlying this coordination remain unclear. Using both murine and human models, we demonstrate that hepatic cell polarity and bile canaliculi (BC) formation initiate at sites of cell division during the hepatoblast stage, while BC elongation occurs following hepatocyte differentiation. This elongation requires suppression of ERK/MAPK activity mediated by PAR3 and YAP. PAR3 interacts with a complex network of proteins, including IQGAP1, at tight junctions, thereby sequestering IQGAP1 from basolateral membranes where it typically promotes growth factor-induced ERK/MAPK activation. This PAR3-ERK/MAPK pathway further regulates actin organization and oriented cell division, both essential for BC elongation and hepatocyte maturation throughout liver development and regeneration. These findings provide new insights into a fundamental mechanism integrating cell proliferation, maturation, and architectural assembly, with implications for regenerative medicine and liver disease therapies.