Wnt agonist stimulates liver regeneration after small-for-size liver transplantation in rats

Liver regeneration is inhibited in small-for-size grafts, which plays a role in the failure of partial liver grafts after transplantation. The Wnt/β-catenin signaling pathway plays a critical role in liver development, regeneration and homeostasis. In this study, we investigated whether pharmacological activation of Wnt signaling improves liver regeneration after small-for-size liver transplantation.

The livers of male Sprague-Dawley rats were reduced to approximately 50% and 30% of their original sizes and transplanted. A Wnt agonist (2-amino-4-[3,4-[methylenedioxy]benzylamino]-6-[3-methoxyphenyl] pyrimidine], 5 mg/kg bodyweight) or an equal volume of vehicle was administrated i.p. into the donor 1 h before the transplantation. Tissue and blood samples were collected at various times after transplantation, and a survival study was performed.

Hepatic expression of active β-catenin and its downstream target gene Axin2 were decreased in 30% of liver grafts after transplantation while the Wnt agonist increased their expression similar to the 50% liver grafts. The Wnt agonist reversed inhibition of cyclin D1 expression and adenosine triphosphate production in the 30% liver grafts compared with the 50% grafts. The Wnt agonist also attenuated hepatocellular injury and increased the hepatocyte proliferation response, liver regeneration rate and survival after transplantation of the 30% liver graft.

Activation of Wnt/β-catenin signaling in liver grafts by pharmacological pretreatment can accelerate regeneration in a partial liver transplant model.