Hepatic stellate cells and astrocytes: Stars of scar formation and tissue repair

Abstract

Scar formation inhibits tissue repair and regeneration in the liver and central nervous system. Activation of hepatic stellate cells (HSCs) after liver injury or of astrocytes after nervous system damage is considered to drive scar formation. HSCs are the fibrotic cells of the liver, as they undergo activation and acquire fibrogenic properties after liver injury. HSC activation has been compared to reactive gliosis of astrocytes, which acquire a reactive phenotype and contribute to scar formation after nervous system injury, much like HSCs after liver injury. It is intriguing that a wide range of neuroglia-related molecules are expressed by HSCs. We identified an unexpected role for the p75 neurotrophin receptor in regulating HSC activation and liver repair. Here we discuss the molecular mechanisms that regulate HSC activation and reactive gliosis and their contributions to scar formation and tissue repair. Juxtaposing key mechanistic and functional similarities in HSC and astrocyte activation might provide novel insight into liver regeneration and nervous system repair.

Figure 1

Expression of GFAP in HSCs and astrocytes. Differentiation of HSCs into activated myofibroblasts (left) is a hallmark of fibrotic liver disease of different etiologies, such as viral hepatitis and chronic alcohol consumption. In chronic liver disease, perpetuation of HSC activation leads to excessive collagen and ECM deposition, resulting in liver fibrosis. Thus, sustained activation of HSCs is a target for the treatment of liver fibrosis. Astrocytes (right) become reactive in response to all forms of CNS injury or disease, causing cellular hypertrophy, scar formation and production of inhibitory CSPGs., CSPG removal from the injured CNS area offers promise for therapies to improve axonal regeneration after CNS injury.

Figure 2

Dual role of HSCs and astrocytes in tissue repair. HSC activation and reactive astrogliosis after tissue injury each lead to deposition of growth factors, cytokines and ECM proteins that control cell survival, proliferation, growth and regeneration in an autocrine and paracrine manner. In both liver and CNS injury there is a dual role for HSC activation and reactive astrogliosis, respectively. The balance of protective and damaging effects of HSCs and astrocytes may be related to the mechanisms that regulate their cross-talk with hepatocytes and neurons, respectively; as well as the stage and context of injury.