Hepatocyte-Sourced Gankyrin Orchestrates Hepatocyte And Liver Sinusoidal Endothelial Cell To Promote Liver Regeneration

Liver regeneration is an intricate, evolutionarily conserved process involving the interactions of various hepatic cell types, which contribute to hepatocyte proliferation and hepatovasular mass reconstitution. However, it remains unclear how hepatocytes coordinate with liver sinusoidal endothelial cells(LSECs) to initiate and restore liver regeneration. Various liver injury-induced hepatocyte proliferation were accompanied by Gankyrin expression. In PHx or iterative CCl4 injection model, Gankyrin deficiency in hepatocytes impairs the early burst of hepatocyte proliferation through reductive response to HGF, and resultant reconstitution of the hepatovascular mass. Remarkably,in vitro co-cultures, multicytokines analysis showed that gankyrin-absent hepatocyte diminished VEGF release and lessened endothelial cell proliferation. Accordingly,administration of VEGFA164 can restore the defective endothelial proliferation, but also correct the deficient hepatovascular regeneration seen in gankyrin knockout mice.Moreover, reduced hypoxia inducible factor-1?(HIF-1?) in Gankyrin-/- hepatocytes caused deceleration of later angiogenic phase of liver regeneration. Indeed, transduction of HIF-1? in Gankyrin-/- hepatocytes re-provokes proliferative endothelial cells and inductive angiogenesis. The close interrelationships between Gankyrin, VEGF and HIF-1? were also presented in clinical cirrhosis specimens. Our data establish hepatocytes as an inductor of liver regeneration, orchestrating hepatocyte and LSEC proliferation, and motivating hepatovascular regeneration through Gankyrin.Therapeutic transplantation of Gankyrin-modified hepatocytes combined with VEGF injection provides an efficient strategy to achieve durable hepatic regeneration.