Hepatic stellate cells in the injured liver: Perspectives beyond hepatic fibrosis

Over the last two decades, our understanding of the pathological role of hepatic stellate cells (HSCs) in fibrotic liver disease has increased dramatically. As HSCs are identified as the principal collagen-producing cells in the injured liver, several experimental and clinical studies have targeted HSCs to treat liver fibrosis. However, HSCs also play a critical role in developing nonfibrotic liver diseases such as cholestasis, portal hypertension, and hepatocellular carcinoma (HCC). Therefore, this review exclusively focuses on the role of activated HSCs beyond hepatic fibrosis. In cholestasis conditions, elevated bile salts and bile acids activate HSCs to secrete collagen and other extracellular matrix products, which cause biliary fibrosis and cholangitis. In the chronically injured liver, autocrine and paracrine signaling from liver sinusoidal endothelial cells activates HSCs to induce portal hypertension via endothelin-1 release. In the tumor microenvironment (TME), activated HSCs are the major source of cancer-associated fibroblasts (CAF). The crosstalk between activated HSC/CAF and tumor cells is associated with tumor cell proliferation, migration, metastasis, and chemoresistance. In TME, activated HSCs convert macrophages to tumor-associated macrophages and induce the differentiation of dendritic cells (DCs) and monocytes to regulatory DCs and myeloid-derived suppressor cells, respectively. This differentiation, in turn, increases T cells proliferation and induces their apoptosis leading to reduced immune surveillance in TME. Thus, HSCs activation in chronically injured liver is a critical process involved in the progression of cholestasis, portal hypertension, and liver cancer.