Galectin-3 regulates myofibroblast activation and hepatic fibrosis

TLDR

Fibrogenesis and organ scarring depend on fibroblast activation into matrix‑secreting myofibroblasts. In vivo siRNA knockdown of Galectin‑3 inhibited myofibroblast activation after hepatic injury, suggesting a therapeutic approach to prevent and treat liver fibrosis. Galectin‑3 is up‑regulated in human fibrotic liver and is required for TGF‑β–mediated myofibroblast activation and procollagen‑I production; loss of Galectin‑3 blocks these processes, markedly reduces fibrosis despite unchanged injury or inflammation, and exogenous Galectin‑3 restores the phenotype, supporting its role as a therapeutic target.

Abstract

Central to fibrogenesis and the scarring of organs is the activation of fibroblasts into matrix-secreting myofibroblasts. We demonstrate that Galectin-3 expression is up-regulated in established human fibrotic liver disease and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the Galectin-3 gene blocks myofibroblast activation and procollagen (I) expression in vitro and in vivo , markedly attenuating liver fibrosis. Addition of exogenous recombinant Galectin-3 in vitro reversed this abnormality. The reduction in hepatic fibrosis observed in the Galectin-3 −/− mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-β. TGF-β failed to transactivate Galectin-3 −/− hepatic stellate cells, in contrast with WT hepatic stellate cells; however, TGF-β-stimulated Smad-2 and -3 activation was equivalent. These data suggest that Galectin-3 is required for TGF-β mediated myofibroblast activation and matrix production. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation after hepatic injury and may therefore provide an alternative therapeutic approach to the prevention and treatment of liver fibrosis.