Wu Yi, Li Linda, Li Wang, Li Ning, Zhang Xiaoyu, Zheng Lu, Zhong Shaoyu, Lü Shouqin, Shu Xinyu, Zhou Jin, Ai Ding, Gao Ming, Liu Sijin, Lü Dongyuan, Long Mian
Center for Biomechanics and Bioengineering, Beijing Key Laboratory of Engineered Construction and Mechanobiology and Key Laboratory of Microgravity (National Microgravity Laboratory), Institute of Mechanics, Chinese Academy of Sciences, Beijing, China.
School of Engineering Science, University of Chinese Academy of Sciences, Beijing, China.
Hepatology. 2025 Aug 1;82(2):370-387. doi: 10.1097/HEP.0000000000001082. Epub 2024 Sep 6.
Partial hepatectomy-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 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.
In vivo partial hepatectomy, 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 was used to unravel the molecular mechanism in response to stretch. This stretch triggers amplitude-dependent and duration-dependent HB-EGF upregulation in LSECs, which is mediated by Yes-associated protein (YAP) nuclear translocation and binding to TEA domain family. This YAP translocation is achieved in 2 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 upregulates the expression of BAG family molecular chaperone regulator 3, which binds with YAP to enter the 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 partial hepatectomy is attenuated in endothelial cell-specific Yap1 -deficient mice.
Our findings indicate that mechanical stretch-induced HB-EGF upregulation in LSECs through YAP translocation can promote hepatocyte proliferation during liver regeneration through a mechanocrine manner, which deepens the understanding of the mechanical-biological coupling in liver regeneration.
部分肝切除诱导的肝再生会导致肝脏内相对血流速率增加，这会使肝血窦扩张并对肝窦内皮细胞（LSECs）施加机械牵张。肝素结合表皮生长因子样生长因子是肝再生过程中的一种关键生长因子。我们旨在研究这种血窦扩张诱导的牵张是否会促进LSECs中HB-EGF的分泌以及相关的分子机制是什么。
采用体内部分肝切除、体外肝脏灌注以及体外LSECs机械牵张来检测LSECs中HB-EGF的表达和肝细胞增殖。通过敲低或抑制机械敏感蛋白来揭示对牵张反应的分子机制。这种牵张会触发LSECs中HB-EGF的上调，其依赖于幅度和持续时间，这是由Yes相关蛋白（YAP）核转位并与TEA结构域家族结合介导的。这种YAP转位通过两种方式实现：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的表达，其与YAP结合协同进入细胞核。在此过程中，β1整合素作为牵张诱导信号通路中的靶机械感受器。在2/3部分肝切除后，这种HB-EGF分泌促进的肝再生在内皮细胞特异性Yap1缺陷小鼠中减弱。
我们的研究结果表明，机械牵张通过YAP转位诱导LSECs中HB-EGF上调，可通过机械分泌方式促进肝再生过程中的肝细胞增殖，这加深了对肝再生中机械-生物学耦合的理解。
