Cell-to-cell signaling cross-talk in liver regeneration: A prostaglandin-Wnt axis

The ability of the liver to regenerate after either surgical resection or injury is fundamental to its homeostasis.1,2 The liver is constantly exposed to noxious chemicals and infectious agents, which lead to various injuries. The extraordinary regenerative capacity of the liver is essential to repair such damage and maintain function. Liver regeneration is a highly complicated process regulated by several well-orchestrated and often redundant pathways involving chemokines, cytokines, growth factors, and endogenous chemicals such as bile acids, nuclear receptors, and various intracellular signaling pathways.1,2 Despite decades of research, which has uncovered a wealth of information, studies such as the one published by Li et al3 in this issue of the Journal are constantly revealing new mechanistic details that regulate liver regeneration. Li et al demonstrated that the secretion of prostaglandin D2 (PGD2) is highly induced after partial hepatectomy (PHX) in mice. Initial studies using whole-body knockout mice demonstrated that PGD2 signals through the prostaglandin D receptor 1 (DP1) in the liver. Further studies using cell-specific deletion of DP1 revealed that PGD2-DP1 signaling in resident KCs plays a critical role in liver regeneration. Deletion of DP1 in resident KCs using Clec4f-cre resulted in significantly lower cell proliferation in the liver after PHX. A focused gene expression analysis demonstrated that KC-specific deletion of DP1 resulted in lower expression of Wnt2, a ligand that activates canonical Wnt/β-catenin signaling, which is an important regulator of liver regeneration. Further, ChIP analysis and pharmacological and genetic manipulations showed that activation of DP1 results in Wnt2 induction through protein kinase A (PKA)/CREB signaling. Finally, treatment of a synthetic DP1 agonist, BW245C, promoted liver regeneration after 85% PHX, a model where normal liver regeneration is inhibited. Taken together, these studies by Li et al have uncovered a novel PGD2-DP1-PKA/CREb-Wnt2 signaling axis in liver regeneration that is active in resident KCs. Prostaglandins are fatty acid derivatives that play a major role in pathophysiology, including in vasodilation and inflammation.4 Whereas previous studies have implicated prostaglandins in liver regeneration,5 the specific role of various prostaglandins and the exact mechanism by which they induce cell proliferation in the liver are not clear. Prostaglandins signal through prostaglandin receptors, and often, the physiological effects of prostaglandin secretion are determined by the receptor they choose for signaling. Li et al found that PGD2 signaling, specifically through the DP1 receptor, affects liver regeneration, while deletion of the DP2 receptor did not affect liver regeneration after PHX. Such granularity in obtaining data on mechanisms of liver regeneration is the next step in this field of research, where extensive work is published each year. The proliferation of hepatocytes is at the center of liver regeneration and gets the most attention because hepatocytes are the most abundant cells in the liver and perform the majority of the liver functions. However, recent studies have increasingly revealed the role of nonparenchymal cells in the regulation of hepatocyte function and regeneration.6 The role of HSCs and KCs has been explored in various liver diseases and liver regeneration. KCs, the resident macrophages in the liver, are essential for maintaining liver health and homeostasis. Previous studies have demonstrated that KCs are required for liver regeneration.7–9 Similarly, the orientation and maturation of infiltrating monocytes that turn into KCs impact liver regeneration.10 However, specific molecular signaling that drives KC-mediated activation of cell proliferation in the hepatocytes has not been completely revealed. These studies by Li et al further add solid evidence that activation of specific pro-regenerative signaling initiated in the KCs, ie, Wnt2 production, is driven by prostaglandins, which in turn activates Wnt/β-catenin pathway leading to hepatocyte proliferation. These data provide new evidence supporting the hypothesized cross-talk between KCs and hepatocytes during liver regeneration and highlight new therapeutic opportunities. Wnt/β-catenin signaling plays a central role in liver pathobiology and is involved in every aspect, including development, regeneration, and disease.11 Extensive research has shown that Wnt ligands, which generally act in paracrine fashion because of their lipoprotein chemistry, are secreted by the nonparenchymal cells in the liver, including HSC and endothelial cells. Studies by Li et al add valuable evidence that KCs are also a source of Wnt ligands during liver regeneration and that Wnt2 produced by the KC activates canonical Wnt signaling in the hepatocytes. Further, previous studies have shown the role of PGE2 in the regulation of Wnt signaling.12 A novel finding of these studies is the regulation of the Wnt2 gene by PGD2, opening the possibility that prostaglandins and perhaps other eicosanoids may be involved in the activation of this important signaling mechanism. In summary, the studies by Li et al add significant detail and granularity to our understanding of signaling mechanisms involved in liver regeneration. These studies have identified several new therapeutic targets, including the endogenous lipid signaling pathways initiated in the nonparenchymal cells that ultimately regulate hepatocyte proliferation in liver regeneration. The next frontier and challenge in the field of liver regeneration is to translate the vast mechanistic information into novel regenerative therapies for patients with liver disease, and studies by Li et al are initial stepping stones in that direction.