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

Abstract

The mechanisms of organ size control remain poorly understood. A key question is how cells collectively sense the overall status of a tissue. We addressed this problem focusing on mouse liver regeneration. Using digital tissue reconstruction and quantitative image analysis, we found that the apical surface of hepatocytes forming the bile canalicular network expands concomitant with an increase in F‐actin and phospho‐myosin, to compensate an overload of bile acids. These changes are sensed by the Hippo transcriptional co‐activator YAP, which localizes to apical F‐actin‐rich regions and translocates to the nucleus in dependence of the integrity of the actin cytoskeleton. This mechanism tolerates moderate bile acid fluctuations under tissue homeostasis, but activates YAP in response to sustained bile acid overload. Using an integrated biophysical–biochemical model of bile pressure and Hippo signaling, we explained this behavior by the existence of a mechano‐sensory mechanism that activates YAP in a switch‐like manner. We propose that the apical surface of hepatocytes acts as a self‐regulatory mechano‐sensory system that responds to critical levels of bile acids as readout of tissue status.

Determination by Relaxation Tests of the Mechanical Properties of Soft Polyacrylamide Gels Made for Mechanobiology Studies

“…Cell density was measured by counting the number of nuclei (DAPI) covering an area of 547.95 µm × 365.3 µm. Finally, localization of nuclear YAP protein was calculated by measuring fluorescence intensity, using the corrected total cell fluorescence [CTCF = Integrated Density − (Area of selected cell × Mean fluorescence of background readings] [ 40 ] in the area merged by DAPI.…”

Anisotropic expansion of hepatocyte lumina enforced by apical bulkheads

“…The position of the bulkheads could be determined by mechano-sensing mechanisms coupled to the tension and local curvature through the actin cortical mesh (Meyer et al, 2020). The bulkheads were detected in the embryonic liver, suggesting that they are not a cell culture artefact but have physiological relevance.…”

The Molecular Network of YAP/Yorkie at the Cell Cortex and their Role in Ocular Morphogenesis

“…Recently, work from Skouloudaki et al, Xu et al, and Meyer et al showed that Yki in the Drosophila trachea/wing disc and YAP in murine hepatocytes are enriched in the apical F-actin area, where they interact with actin cytoskeleton molecules to regulate tissue morphogenesis [ 14 , 18 , 19 ]. More specifically, these groups found that Yki and YAP interact with actin cytoskeletal components, such as Twinstar (Tsr), Trio, Dia, and Cingulin.…”

“…On the other hand, Meyer et al found that during liver resection, the apical membrane of hepatocytes expanded and actomyosin contractility increased. These changes are “sensed” by YAP, which is recruited to the apical cortex of hepatocytes and translocates in the nucleus [ 14 ]. YAP nuclear translocation can be modified by perturbations of the actin cytoskeleton and pMLC levels.…”

“…In vitro studies in mammalian cell lines have revealed that mechanical stresses can be sensed via the actin cytoskeleton and modify YAP/TAZ activity [ 12 , 13 ]. More recent data have demonstrated a novel mechanism by which hepatocytes sense organ size during liver regeneration by means of changes in the apical actomyosin network that trigger YAP nuclear translocation [ 14 ]. The relationship of YAP/Yki and actin cytoskeleton is bidirectional, with studies indicating that the Hippo pathway regulates actin cytoskeleton in Drosophila [ 10 , 15 , 16 , 17 , 18 , 19 ].…”