Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration

The mechanisms of organ size control remain poorly understood. Akey question is how cells collectively sense the overall status of atissue. We addressed this problem focusing on mouse liver regeneration. Using digital tissue reconstruction and quantitative imageanalysis, we found that the apical surface of hepatocytes formingthe bile canalicular network expands concomitant with an increasein F-actin and phospho-myosin, to compensate an overload of bileacids. These changes are sensed by the Hippo transcriptional coactivator YAP, which localizes to apical F-actin-rich regions andtranslocates to the nucleus in dependence of the integrity of theactin cytoskeleton. This mechanism tolerates moderate bile acidfluctuations under tissue homeostasis, but activates YAP in responseto sustained bile acid overload. Using an integrated biophysical–biochemical model of bile pressure and Hippo signaling, weexplained this behavior by the existence of a mechano-sensorymechanism that activates YAP in a switch-like manner. We proposethat the apical surface of hepatocytes acts as a self-regulatorymechano-sensory system that responds to critical levels of bile acidsas readout of tissue status.