Background & Aims: Partial hepatectomy (PHx)-induced liver regeneration causes the increase in relative blood flow rate within the liver, which dilates hepatic sinusoids and applies mechanical stretch on liver sinusoidal endothelial cells (LSECs). Heparin-binding EGF-like growth factor (HB-EGF) is a crucial growth factor during liver regeneration. We aimed to investigate whether this sinusoidal dilation-induced stretch promotes HB-EGF secretion in LSECs and what the related molecular mechanism is. Approach & Results: In vivo PHx, ex vivo liver perfusion and in vitro LSEC mechanical stretch were applied to detect HB-EGF expression in LSECs and hepatocyte proliferation. Knockdown or inhibition of mechanosensitive proteins were used to unravel the molecular mechanism in response to stretch. This stretch triggers amplitude- and duration-dependent HB-EGF up-regulation in LSECs, which is mediated by Yes-associated protein (YAP) nuclear translocation and binding to TEAD. This YAP translocation is achieved in two ways: On one hand, F-actin polymerization-mediated expansion of nuclear pores promotes YAP entry into nucleus passively. On the other hand, F-actin polymerization up-regulates the expression of BAG family molecular chaperone regulator 3 (BAG-3), which binds with YAP to enter nucleus cooperatively. In this process, β1-integrin serves as a target mechanosensory in stretch-induced signaling pathways. This HB-EGF secretion-promoted liver regeneration after 2/3 PHx is attenuated in endothelial cell-specific Yap1-deficient mice. Conclusions: Our findings indicate that mechanical stretch-induced HB-EGF up-regulation in LSECs via YAP translocation can promote the hepatocyte proliferation during liver regeneration through a mechanocrine manner, which deepens the understanding of the mechanical-biological coupling in liver regeneration.

中文翻译：

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拉伸诱导的肝内皮机械分泌促进肝细胞增殖


背景和目标：部分肝切除术（PHx）诱导的肝脏再生导致肝脏内相对血流速率的增加，从而扩张肝窦细胞并对肝窦内皮细胞（LSECs）施加机械拉伸。肝素结合 EGF 样生长因子 （HB-EGF） 是肝脏再生过程中的关键生长因子。我们旨在研究这种正弦扩张诱导的拉伸是否促进 LSEC 中 HB-EGF 的分泌以及相关的分子机制是什么。方法和结果：体内PHx、离体肝脏灌注和体外LSEC机械拉伸用于检测LSECs中的HB-EGF表达和肝细胞增殖。使用机械敏感蛋白的敲低或抑制来揭示响应拉伸的分子机制。这种拉伸触发 LSEC 中振幅和持续时间依赖性的 HB-EGF 上调，这是由 Yes 相关蛋白 （YAP） 核转位和与 TEAD 结合介导的。这种 YAP 易位是通过两种方式实现的：一方面，F-肌动蛋白聚合介导的核孔扩张促进 YAP 被动进入细胞核。另一方面，F-肌动蛋白聚合上调 BAG 家族分子伴侣调节因子 3 （BAG-3） 的表达，该调节因子与 YAP 结合以协同进入细胞核。在此过程中，β1-整合素在拉伸诱导的信号通路中充当靶标机械感应。这种 HB-EGF 分泌促进的 2/3 PHx 后肝脏再生在内皮细胞特异性 Yap1 缺陷小鼠中减弱。 结论： 我们的研究结果表明，通过 YAP 易位在 LSECs 中机械拉伸诱导的 HB-EGF 上调可以通过机械分泌方式促进肝再生过程中的肝细胞增殖，这加深了对肝脏再生中机械-生物耦合的理解。