TY - JOUR
T1 - An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis
AU - Wang, Shuang
AU - Li, Kenneth
AU - Pickholz, Eliana
AU - Dobie, Ross
AU - Matchett, Kylie P.
AU - Henderson, Neil C.
AU - Carrico, Chris
AU - Driver, Ian
AU - Borch Jensen, Martin
AU - Chen, Li
AU - Petitjean, Mathieu
AU - Bhattacharya, Dipankar
AU - Fiel, Maria I.
AU - Liu, Xiao
AU - Kisseleva, Tatiana
AU - Alon, Uri
AU - Adler, Miri
AU - Medzhitov, Ruslan
AU - Friedman, Scott L.
PY - 2023/1/4
Y1 - 2023/1/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85145537197&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.add3949
DO - 10.1126/scitranslmed.add3949
M3 - Article
C2 - 36599008
AN - SCOPUS:85145537197
SN - 1946-6234
VL - 15
SP - eadd3949
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 677
ER -