Hepatic stellate cells as key target in liver fibrosis

Abstract

Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or "activation") of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

Keywords: Alcoholic liver disease; Cirrhosis; Hepatitis; Myofibroblast; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis.

Figure 1. Extracellular regulation of HSC activation

HSC activation is promoted (sharp arrow) or inhibited (blocked arrow) by liver resident cells, ECM, and circulating cells via paracrine factors. Red and blue font colors indicate positive and negative regulators of HSC activation, respectively. Pharmacological intervention to each candidate target is shown in parenthesis.

Figure 2. Cellular signaling pathways involved in HSC activation and deactivation

A variety of cell surface receptor-, nuclear receptor-, and intracellular signal transmitter-mediated mechanisms of HSC activation has been identified. Dysregulation of cellular homeostasis and epigenetic modifications also regulate HSC activation. HSC deactivation can be induced via specific targets. Red and blue font colors indicate positive and negative regulators of HSC activation, respectively. Black font color indicates involvement in both pro- and anti-fibrogenic functions depending on biological context or undetermined role in HSC activation. Pharmacological intervention to each candidate target is shown in parenthesis.