Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 15, Issue 677, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.add3949
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Using single-nucleus RNA sequencing and tissue clearing in a murine NASH model, we identified a repertoire of antifibrotic drug targets underlying advanced fibrosis, including an autocrine HSC signaling circuit composed of 68 receptor-ligand interactions conserved between murine and human NASH. Inhibiting one such autocrine interaction reversed advanced murine NASH fibrosis and inhibited human HSC activation in culture, suggesting the potential for stage-specific therapies in patients with advanced hepatic fibrosis.
Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies. To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model. In advanced fibrosis, we found that an autocrine HSC signaling circuit emerged that was composed of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions were supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, neurotrophic receptor tyrosine kinase 3-neurotrophin 3, inhibited human HSC activation in culture and reversed advanced murine NASH fibrosis. In summary, we uncovered a repertoire of antifibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a therapeutic paradigm in which stage-specific therapies could yield enhanced antifibrotic efficacy in patients with advanced hepatic fibrosis.
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