Wnt-driven communication between macrophages and hepatic stellate cells within the ductular reaction - Pro-fibrotic or pro-regenerative?
Public Health, Healthcare Research, Social and Occupational Medicine
Final Report Abstract
Wnt signalling plays a significant role in liver fibrosis development as well as liver regeneration and fibrosis regression. Macrophages have clear roles in both fibrosis progression and resolution, and macrophage-derived Wnt molecules are implicated in multiple phases of the dynamic process of liver fibrosis development, through cross-talk with other hepatic cells including HSCs. During the fellowship I demonstrated that Wnt signalling has distinct effects in the liver depending on stage of fibrosis and the inflammatory tissue microenvironment. Macrophage-derived Wnts appear to have anti-fibrotic effects, possibly through inducing the expression of matrix remodelling enzymes (Mmps), and global inhibition of Wnt secretion decreased collagen expression and HSC activation, suggesting that macrophages are an important source of Wnt proteins in the liver. Overall, mice lacking general or macrophage-derived Wnt molecule secretion tend to show an increased accumulation of extracellular matrix during fibrosis development due to an imbalance between matrix secretion and degradation. Wnt proteins may differentially regulate macrophage recruitment during different stages of fibrosis, with global inhibition of Wnt secretion/signalling preventing inflammatory monocyte recruitment, whereas a lack of macrophage-derived Wnt production later in the disease process was associated with increased monocyte infiltration and alternative macrophage activation. Whilst Wnt proteins are one potential mechanism by which macrophages modulate the dynamic process of liver fibrosis, reprogramming macrophages to an anti-fibrotic, pro-restorative phenotype is the ultimate therapeutic goal. By administering a stabilised colony stimulating factor 1 (CSF-1) during liver fibrosis resolution in mice, I was able to prime circulating monocytes and macrophages to a more regenerative phenotype enhancing Mmp expression and matrix degradation, and increasing liver regeneration, as indicated by liver growth and hepatocyte replication. Moreover, along with the monocyte recruitment to the liver, Wnt signalling was also modulated by CSF-1 administration. CSF-1 shows a high potential as a new therapeutical approach to support liver fibrosis resolution and regeneration. In in vitro studies focused on HSCs, the main collagen producing cell during liver fibrosis, I have demonstrated that miRNA-25-3p decreases TGF-β signalling and subsequent collagen expression as well as expression of several Wnt molecules, especially Wnt5a, in HSCs. Hence, miRNA-25 could be another promising anti-fibrotic approach in chronic liver disease. In summary, the impact of Wnt signalling and its inhibition on liver fibrosis development and regression is diverse depending on the producing and responding cell types and the stage of disease. Therefore, there is no clear answer to the question whether Wnt-driven cell-cell interaction in the liver is anti-fibrotic or pro-regenerative. In order to determine the impact of Wnt-directed therapy in CLD, it is imperative to further investigate the role of individual Wnt molecules and receptors on different liver cells to understand the specific Wnts and Wnt receptors, and molecular mechanisms, involved.
