Wnt/-Catenin Signaling and Liver Regeneration: Circuit, Biology, and Opportunities

Abstract

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 1014 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 toward the mass and functional recovery of the liver is the Wnt/-catenin pathway. Very early after any insult to the liver, the cellmolecule circuitry of the Wnt/-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 coreceptors on hepatocytes to stabilize -catenin inducing its nuclear translocation. Nuclear -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/-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/-catenin signaling pathway is highly relevant in the discipline of hepatic regenerative medicine.

Figure 1

Cell–molecule circuitry of Wnt/β-catenin signaling during liver regeneration. Wnt/β-catenin is a major regulator of hepatic repair. After insult, sinusoidal endothelial cell-secreted Wnts bind to Frizzled receptors (Fzd) and low-density lipoprotein (LDL)-related protein-5/6 coreceptors (LRP5/6) on hepatocytes, stabilize β-catenin, induce cyclin D1 expression, and promote hepatocyte proliferation. Shear stress and hypoxia are most likely the drivers of Wnt expression and secretion from endothelial cells after PH. RSPO–LGR4/5–ZNRF3/RNF43 module and heparan sulfate proteoglycans (HSPGs) potentiate Wnt/β-catenin by dispersal of hydrophobic Wnt ligands, by stabilization of Wnt receptors on the membrane, and by fine-tuning interactions of ligands and receptors. Modulators like transmembrane protein 9 (TMEM9) and lncRNA are also involved in this process. Several drugs, including GC-1/Sobetirome, AMBMP, pan-Fzd agonist, and bispecific RSPO are under evaluation and stand as promising candidates for hepatic regenerative medicine due to their positive impact on Wnt/β-catenin signaling at various key nodes in the cell-molecule circuitry of the pathway.

Figure 2

Distinct role of endothelial cell- and macrophage-secreted Wnts in regulating proliferation and compensation of hepatic functions during liver regeneration. Following PH, hepatocytes bifurcate into two populations: one (left), under the control of Wnt2 and Wnt9b from sinusoidal endothelial cells, expresses cyclin D1 and enters cell cycle, contributing to the regain of hepatic mass through proliferation; second (right), under the control of Wnts from macrophages, expresses GS, cyp2e1, and other metabolic, biosynthetic, and detoxification-related genes, thus ensuring continual hepatic function.