Stretch-induced hepatic endothelial mechanocrine promotes hepatocyte proliferation

Background and Aims: 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. Approach and Results: 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. Conclusions: 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.