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.