Wnt/β-catenin Signaling and Liver Regeneration: Circuit, Biology and Opportunities.

The liver is uniquely bestowed with an ability to regenerate following a surgical or toxicant insult. One of the most researched models to demonstrate the regenerative potential of this organ is the partial hepatectomy model where two-thirds of the liver is surgically resected. The remnant liver replenishes the lost mass within 10-14 days in mice. The distinctive ability of the liver to regenerate has allowed living donor and split liver transplantation. One signaling pathway shown to be activated during the process of regeneration to contribute towards the mass and functional recovery of the liver is Wnt/β-catenin pathway. Very early after any insult to the liver, the cell-molecule circuitry of Wnt/β-catenin pathway is set into motion with the release of specific Wnt ligands from sinusoidal endothelial cells and macrophages, which in a paracrine manner, engage Frizzled and LDL-Related Protein-5/6 co-receptors on hepatocytes to stabilize β-catenin inducing its nuclear translocation. Nuclear β-catenin interacts with T-cell factor family of transcription factors to induce target genes including Cyclin D1 for proliferation, and others, for regulating hepatocyte function. Working in collaboration with other signaling pathways, Wnt/β-catenin signaling contributes to the restoration process without any compromise of function at any stage. Also, stimulation of this pathway through innovative means, induces liver regeneration when this process is exhausted or compromised, and thus has applications in the treatment of End Stage Liver Disease and in the field of liver transplantation. Thus, Wnt/β-catenin signaling pathway is highly relevant in the discipline of hepatic regenerative medicine.