CD177⁺ neutrophils drive extracellular matrix remodelling and HGF-alpha release in ALPPS-induced liver regeneration.

Abstract

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively induces rapid liver hypertrophy in patients with initially unresectable liver tumours, yet the immunological mechanisms remain unclear. We aim to elucidate the immune alterations and underlying mechanisms driving liver regeneration following ALPPS. The cohort study included single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics on remnant liver tissues from ALPPS patients. Neutrophil infiltration was validated by flow cytometry and histological analyses in the world's largest ALPPS clinical cohort and mouse ALPPS models. Functional validation, including neutrophil depletion, matrix metalloproteinase 9 (MMP9) inhibition and CD177 blockade, as well as <i>Cd177</i> knockout and CD177⁺ neutrophil infusion in vivo. scRNA-seq revealed substantial neutrophil infiltration following stage 1 ALPPS. Depletion of neutrophils impaired liver regeneration. Among subsets, CD177⁺ neutrophils were metabolically active with enhanced neutrophil extracellular traps formation and secreted MMP9. MMP9 inhibition disrupted extracellular matrix (ECM) degradation and hepatocyte growth factor alpha (HGF-α) release, impairing regeneration. CD177⁺ neutrophils interacted with endothelial cells via CD177-PECAM1 to facilitate transmigration, while hepatic stellate cell-derived CXCL8 promoted neutrophil chemotaxis via CXCL8-CXCR1/2. Cd177 deficiency attenuated neutrophil infiltration and regenerative growth, while CD177⁺ neutrophil infusion restored regeneration, which was abolished in Cd177^-/^- mice. CD177⁺ neutrophils drive liver regeneration by promoting endothelial transmigration, ECM degradation and HGF-α release. These findings reveal a neutrophil-mediated mechanism driving surgical liver regeneration and support the potential of CD177⁺ neutrophil infusion to establish a proregenerative hepatic environment for therapeutic strategies in liver failure.