An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis

Shuang Wang, Kenneth Li, Eliana Pickholz, Ross Dobie, Kylie P. Matchett, Neil C. Henderson, Chris Carrico, Ian Driver, Martin Borch Jensen, Li Chen, Mathieu Petitjean, Dipankar Bhattacharya, Maria I. Fiel, Xiao Liu, Tatiana Kisseleva, Uri Alon, Miri Adler, Ruslan Medzhitov, Scott L. Friedman

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Article numbereadd3949
Number of pages12
JournalScience Translational Medicine
Volume15
Issue number677
DOIs
StatePublished - 4 Jan 2023

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