Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany.
Mol Syst Biol. 2020 Feb;16(2):e8985. doi: 10.15252/msb.20198985.
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.
器官大小控制的机制仍知之甚少。一个关键问题是细胞如何集体感知组织的整体状态。我们通过聚焦于小鼠肝再生来解决这个问题。通过数字组织重建和定量图像分析，我们发现形成胆小管网络的肝细胞的顶膜在 F-肌动蛋白和磷酸肌球蛋白增加的情况下扩张，以补偿胆汁酸的过载。这些变化被 Hippo 转录共激活因子 YAP 感知，YAP 定位于顶膜富含 F-肌动蛋白的区域，并依赖于肌动蛋白细胞骨架的完整性向核内易位。该机制在组织稳态下耐受适度的胆汁酸波动，但在持续的胆汁酸过载时激活 YAP。通过胆汁压力和 Hippo 信号的综合生物物理-生物化学模型，我们通过存在机械敏感机制来解释这种行为，该机制以开关方式激活 YAP。我们提出，肝细胞的顶膜作为一种自我调节的机械敏感系统，以胆汁酸的临界水平作为组织状态的读出。
