Gliotoxin‐induced changes in rat liver regeneration after partial hepatectomy

Background Hepatic non‐parenchymal cells ( NPC s), encompassing hepatic stellate cells ( HSC s), macrophages and endothelial cells, synthesize new hepatocyte growth factor ( HGF ) during liver regeneration ( LR ), and also play an important function in matrix production at the end of regeneration. Aims The aim of this study was to determine whether ablating NPC s either during hepatocyte proliferation or during matrix resynthesis will have any effect on LR . Methods Rats were injected with either gliotoxin (which induces NPC apoptosis) or vehicle control at various stages during partial hepatectomy ( PH ). NPC s and hepatocytes were also treated in vitro with gliotoxin. Results Proliferating cells were abundant in control livers 24 h after PH , while in gliotoxin‐treated rats, mitosis was absent, apoptotic NPC s were apparent and HGF was decreased. In vitro studies demonstrated a > 50% decrease in cell viability in NPC cultures, while hepatocyte viability and proliferation were unaffected. Chronic elimination of NPC s over a period of 5 days after PH led to increased desmin‐positive HSC s and fewer alpha smooth muscle actin‐expressing HSC s. Finally, there was continued proliferation of hepatocytes and decreased collagen I and TGF ‐β when HSC s, the matrix‐producing NPC s, were ablated during later stages of LR . Conclusions Ablation of NPC s at early time points after PH interferes with liver regeneration, while their ablation at late stages causes impairment in the termination of LR , demonstrating a time‐dependent regulatory role of NPC s in the regenerative process.