Balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution in postoperative liver regeneration

Post-hepatectomy liver failure (PHLF) leads to poor prognosis in patients receiving hepatectomy, where hepatic-vascular reconstitution plays a critical role. However, the regulators of hepatic-vascular reconstitution remain unclear. This study aimed to investigate the regulatory mechanisms of hepatic-vascular reconstitution and identify biomarkers predicting PHLF in patients underwent hepatectomy.Candidate genes that were associated with hepatic vascular reconstitution were screened in adeno-associated virus 8 (AAV8) combining Alb-Cre-CRISPR/Cas9 mice underwent partial hepatectomy. The biological activities of candidate genes were estimated using endothelial precursors transfusion and an associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) model. The level of candidates was detected in biopsies from ALPPS patients. Risk factors of PHLF were also screened using retrospective data.The downregulation of Gata3 and upregulation of Ramp2 in hepatocytes promoted the proliferation of liver sinusoidal endothelial cells (LSECs) and hepatic revascularization. Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor A (VEGFA) played opposite roles in regulating the migration of endothelial precursors from bone marrow and the formation of new sinusoids after hepatectomy. Gata3 restricted endothelial cell function in patient-derived hepatic-organoids, which was abrogated by Gata3 inhibitor. Moreover, overexpression of Gata3 led to higher mortality in ALPPS mice, which was improved by PEDF-neutralizing antibody. The expression of Gata3/Ramp2 and PEDF/VEGFA tended to have negative correlation in ALPPS patients. A nomogram model incorporating multiple factors such as serum PEDF/VEGF index (SPVI) was constructed and could efficiently predict the risk of PHLF.The balance of Gata3 and Ramp2 in hepatocytes regulated the proliferation of LSECs and hepatic revascularization via shifting PEDF to VEGFA, which provided potential targets for the prevention and treatment of PHLF.In this study, we revealed a novel mechanism that the balance of Gata3 and Ramp2 in hepatocyte regulated hepatic vascular reconstitution via shifting PEDF to VEGFA during hepatectomy- or ALLPS-induced liver regeneration. We also identified serum PEDF/VEGFA index (SPVI) as a potential predictor for post-hepatectomy liver failure (PHLF) in patients who underwent hepatectomy. This study will provide a better understanding on how hepatocytes contribute to liver regeneration and new targets for the prevention and treatment of PHLF.