Gliotoxin‐induced changes in rat liver regeneration after partial hepatectomy

Abstract

Hepatic non-parenchymal cells (NPCs), encompassing hepatic stellate cells (HSCs), 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. The aim of this study was to determine whether ablating NPCs either during hepatocyte proliferation or during matrix resynthesis will have any effect on LR. Rats were injected with either gliotoxin (which induces NPC apoptosis) or vehicle control at various stages during partial hepatectomy (PH). NPCs and hepatocytes were also treated in vitro with gliotoxin. Proliferating cells were abundant in control livers 24 h after PH, while in gliotoxin-treated rats, mitosis was absent, apoptotic NPCs 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 NPCs over a period of 5 days after PH led to increased desmin-positive HSCs and fewer alpha smooth muscle actin-expressing HSCs. Finally, there was continued proliferation of hepatocytes and decreased collagen I and TGF-β when HSCs, the matrix-producing NPCs, were ablated during later stages of LR. Ablation of NPCs 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 NPCs in the regenerative process.