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.

中文翻译：

---

在肝脏再生过程中，胆小管重塑通过肌动蛋白细胞骨架激活 YAP。

器官大小控制的机制仍然知之甚少。一个关键问题是细胞如何集体感知组织的整体状态。我们解决这个问题的重点是小鼠肝脏再生。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顶端表面随着 F-肌动蛋白和磷酸肌球蛋白的增加而扩张，以补偿胆汁酸的过载。这些变化由 Hippo 转录共激活因子 YAP 感知，YAP 定位于富含 F 肌动蛋白的顶端区域，并根据肌动蛋白细胞骨架的完整性易位至细胞核。这种机制可以耐受组织稳态下的适度胆汁酸波动，但会激活 YAP 以应对持续的胆汁酸超负荷。使用胆汁压力和 Hippo 信号传导的集成生物物理生化模型，我们通过机械感觉机制的存在来解释这种行为，该机械感觉机制以类似开关的方式激活 YAP。我们提出，肝细胞的顶面充当自我调节的机械感觉系统，对胆汁酸的临界水平做出反应，作为组织状态的读数。