Hepatic stellate cells: balancing homeostasis, hepatoprotection and fibrogenesis in health and disease.

In the past decades, the pathogenic role of hepatic stellate cells (HSCs) in the development of liver fibrosis and its complications has been deeply characterized, rendering HSCs a primary target for antifibrotic therapies. By contrast, the beneficial roles of HSCs in liver homeostasis and liver disease are only beginning to emerge, revealing critical regulatory and fibrosis-independent functions in hepatic zonation, metabolism, injury, regeneration and non-parenchymal cell identity. Here, we review how HSC mediators, such as R-spondin 3, hepatocyte growth factor and bone morphogenetic proteins, regulate critical and homeostatic liver functions in health and disease via cognate receptors in hepatocytes, Kupffer cells and endothelial cells. We highlight how the balance shifts from protective towards fibropathogenic HSC mediators during the progression of chronic liver disease (CLD) and the impact of this shifted balance on patient outcomes. Notably, the protective roles of HSCs are not accounted for in current therapeutic concepts for CLD. We discuss the concept that reverting the HSC balance from fibrogenesis towards hepatoprotection might represent a novel holistic treatment approach to inhibit fibrogenesis and restore epithelial health in CLD simultaneously.