The RSPO‐LGR4/5‐ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease

Abstract

WNT/β‐catenin signaling plays pivotal roles during liver development, homeostasis, and regeneration. Likewise, its deregulation disturbs metabolic liver zonation and is responsible for the development of a large number of hepatic tumors. Liver fibrosis, which has become a major health burden for society and a hallmark of NASH, can also be promoted by WNT/β‐catenin signaling. Upstream regulatory mechanisms controlling hepatic WNT/β‐catenin activity may constitute targets for the development of novel therapies addressing these life‐threatening conditions. The R‐spondin (RSPO)–leucine‐rich repeat‐containing G protein‐coupled receptor (LGR) 4/5–zinc and ring finger (ZNRF) 3/ring finger 43 (RNF43) module is fine‐tuning WNT/β‐catenin signaling in several tissues and is essential for hepatic WNT/β‐catenin activity. In this review article, we recapitulate the role of the RSPO‐LGR4/5‐ZNRF3/RNF43 module during liver development, homeostasis, metabolic zonation, regeneration, and disease. We further discuss the controversy around LGR5 as a liver stem cell marker.

Bipotent transitional liver progenitor cells contribute to liver regeneration

“…10c and Supplementary Table 1). Although WNT/β-catenin signaling is a well-known pro-proliferative signal [48][49][50] , cell cycle gene signatures were not increased in Ctnnb1 lox(ex3)/+ BECs (Fig. 7e).…”

Wnt-β-catenin in hepatobiliary homeostasis, injury, and repair

“…LRG4 and LRG5 are expressed in pericentral hepatocytes with high Wnt activity, and the loss of these 2 receptors abrogates Wnt signaling and results in the loss of metabolic liver zonation 49 . Furthermore, RSPO blockade disrupts zonation, while recombinant RSPO1 expanded Wnt signaling into periportal hepatocytes, demonstrating that the RSPO-LGR4/5-ZNRF3/RNF43 module is essential in regulating hepatic Wnt signaling and metabolic zonation 49,50 …”

“…Furthermore, the deletion of Wnt7b from both cholangiocytes and hepatocytes improved biliary injury and decreased inflammation by promoting hepatocyte-to-cholangiocyte reprogramming, which compensated for the inability of cholangiocytes to proliferate due to the lack of Wnt7b 115 . Although Wnt ligands play an important role in biliary regeneration, several groups have shown that this proliferation is β-catenin independent, thus indicating that canonical Wnt signaling is dispensable for expansion of the biliary compartment during cholestasis 50,108,112,116–118 …”

“…[49] Furthermore, RSPO blockade disrupts zonation, while recombinant RSPO1 expanded Wnt signaling into periportal hepatocytes, demonstrating that the RSPO-LGR4/5-ZNRF3/RNF43 module is essential in regulating hepatic Wnt signaling and metabolic zonation. [49,50] Perturbation of the Wnt-β-catenin circuit not only causes impairment of zone-3 gene expression but also leads to expansion of genes normally restricted to zone-1. [42,45] In fact, single-cell spatial transcriptomics performed on mice where endothelial cell-Wnt2-9b or the hepatocyte-LRP5/6 or β-catenin axis was perturbed resulted in the appearance of zone-1 genes in zone-3 hepatocytes.…”

“…[115] Although Wnt ligands play an important role in biliary regeneration, several groups have shown that this proliferation is β-catenin independent, thus indicating that canonical Wnt signaling is dispensable for expansion of the biliary compartment during cholestasis. [50,108,112,[116][117][118] Another potential source of Wnts during cholestasis is the inflammatory cells surrounding the ducts. In PSC, ductular proliferation is associated with sustained expression of Wnt ligands in inflammatory cells.…”