Netrin-1 promotes liver regeneration possibly by facilitating vagal nerve repair after partial hepatectomy in mice

Abstract

Hepatic regeneration after hepatectomy is a great concern in clinical practice. Recently, the neuronal guidance protein netrin-1 has been reported to enhance regeneration after nerve injury. The goal of this study was to preliminarily investigate whether netrin-1 stimulates vagus nerve regeneration to promote liver regeneration after partial hepatectomy in mice. The expression of netrin-1 in murine remnant livers after partial hepatectomy (PHx) was evaluated in initial studies. C57BL/6 mice that received exogenous netrin-1 after PHx were used to examine liver regeneration. PHx was performed in wild-type mice after adeno-associated virus injection (Ntn1 gene silencing) to detect the impact of endogenous netrin-1. After PHx and hepatic branch vagotomy (HV), the mice were injected with or without netrin-1 to evaluate the effects on hepatic regeneration and vagal nerve recovery. Significant reductions in netrin-1 at the transcript and protein levels in murine liver tissue after hepatectomy were observed. Subsequent studies of netrin-1 administration revealed the promotion of hepatocyte proliferation and specific growth factors contributing to liver repair and a decrease in hepatic-specific injury enzymes. Furthermore, the opposite results were observed in the netrin-1 knockdown group. HV delayed liver regeneration after PHx. However, this retardation was reversed by exogenous netrin-1 supplementation. In addition, the results of nerve growth and vagal nerve repair in the remnant liver suggested that netrin-1 promoted vagal nerve regeneration after hepatectomy. Netrin-1 accelerates liver regeneration after partial hepatectomy in mice, and the potential mechanism is related to the promotion of vagus nerve repair and regeneration.