A WISP1 Antibody Inhibits MRTF Signaling to Prevent the Progression of Established Liver Fibrosis

Abstract

Fibrosis or cirrhosis is the major risk factor associated with morbidity and mortality in patients with non-alcoholic steatohepatitis (NASH)-driven chronic liver disease. While numerous efforts have been made to identify mediators of the initiation of liver fibrosis, the molecular underpinnings of fibrosis progression remain poorly understood and anti-fibrotic therapies to arrest liver fibrosis progression and promote resolution are elusive. Here, we identify a pathway involving WNT1 inducible signaling pathway protein 1 (WISP1) and myocardin related transcription factor (MRTF), as a central mechanism driving liver fibrosis progression through transcriptional reprogramming of myofibroblast cytoskeleton and motility. WISP1 expression is highly correlated with MRTF activity in human cirrhotic livers and can activate MRTF signaling in vitro. In mice, WISP1 deficiency protects against fibrosis progression but not fibrosis onset and leads to reduced myofibroblast accumulation in tissue interstitial areas and diminished expression of MRTF target cytoskeleton genes. WISP1 activates MRTF signaling via multiple integrins including αVβ1/3/5/8 and α11β1. Moreover, therapeutic administration of a novel antibody blocking WISP1-MRTF signaling axis halted the progression of existing liver fibrosis. These findings implicate the WISP1-MRTF axis as a crucial determinant of liver fibrosis progression and support targeting this pathway by antibody-based therapy for the treatment of NASH fibrosis and its associated complications.