Scar-associated endothelial-stellate cellular crosstalk drives fibrosis resolution in MASH

TL;DR

The study identifies a cellular communication pathway in the liver that helps resolve fibrosis, a common cause of death in industrialized countries.

Contribution

The paper introduces a novel Wnt9b-Sfrp2 crosstalk mechanism between endothelial and stellate cells that drives fibrosis resolution in MASH.

Findings

A Wnt9b-Sfrp2 crosstalk emerges during fibrosis resolution in MASH.

Endo4 endothelial cells are the source of Wnt9b and are associated with fibrotic scars.

VWF+ vasculature interacts with activated stellate cells and shows protease activity in fibrotic tissue.

Abstract

Fibrosis contributes to ~40% of mortality in the industrialized world. Fibrosis in the liver can spontaneously resolve when injury terminates. In this study, we establish a robust mouse model of fibrosis regression in MASH (metabolic dysfunction-associated steatohepatitis), a highly prevalent chronic liver disease world-wide, and perform single-cell and in situ molecular profiling to define the molecular drivers of fibrosis regression. Prediction of cell-cell communication identifies a Wnt9b-Sfrp2 crosstalk that emerges as fibrosis resolves, the perturbation of which attenuates spontaneous fibrosis regression. We further identify a subset of liver endothelial cells termed “Endo4” as the source of Wnt9b. Immunostaining for the Endo4 marker VWF using tissue clearing and 3D imaging reveals VWF+ vasculature juxtaposing activated hepatic stellate cells that penetrate deep into the fibrotic septa and exhibit in situ protease activity, establishing them as de facto scar-associated endothelial cells and a regulatory node in murine MASH fibrosis regression.

A fibrosis scar can spontaneously resolve in the liver when injury terminates. Modeling fibrosis regression in mice, Li et al. identify a molecular crosstalk between scar-associated liver cells that drives fibrosis regression.

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