WISP1: A novel extracellular matrix remodeling protein in liver fibrosis

Liver diseases are a global burden and a better understanding of factors controlling disease progression is required. In the last decade, great knowledge has been developed regarding the biological role of the extracellular matrix composition. Alterations in this dynamic structure can either facilitate or impair the repairmen of damaged liver tissue. That is why, novel components like matricellular proteins from the CCN family, have emerged as new targets in liver pathophysiology. These highly conserved secreted proteins specifically interact with and signal through various extracellular partners, like integrins, which enable them to play crucial roles in various processes including development, wound healing and diseases such as cancer and fibrosis.

We have discovered that WISP1 (Wnt-induced secreted protein-1) also named CCN4, is induced upon CCl4-induced liver damage and may play an important role in the remodeling process of the extracellular matrix. Thus, we aim to study WISP1 cell source and its influence in cell migration and fibrosis model in WISP1 KO mice.

Isolation of individual liver cell types and quantification of WISP1 expression and secretion showed a higher mRNA expression and TGF-β-induced secretion of WISP1 in non-parenchymal cells, especially in stellate cells but also in liver sinusoidal endothelial cells compared to hepatocytes. Furthermore, WISP1 facilitates the migration of isolated mouse hepatic stellate cells through collagen lattices, suggesting the interaction of WISP1 with one of the main components of the extracellular matrix. Additionally, gene expression analysis and Sirius Red staining showed differences in the development of CCl4-induced fibrosis between WISP1 wild type and knockout mice. Upregulation of collagen type I and α-SMA is reduced in WISP1 KO mice and less breaching of the collagen deposition is also observed.

In conclusion, WISP1 is mainly expressed and secreted by stellate cells which may influence their migration upon chronic liver injury.