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 - Jensen, Martin Borch
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.
N1 - Funding Information:
We thank J. Gregory at Mount Sinai for illustrations and N. Tzavaras and D. L. Benson at the Mount Sinai Microscope Core for assistance with Confocal and Lightsheet imaging; K. Beaumont, R. Sebra, and the team at the Mount Sinai Genomics Core for assistance with single-nucleus RNA sequencing; and the Biorepository and Pathology CoRE for procurement of human tissue samples at Mount Sinai. We express our gratitude to all of the anonymous organ donors and their families for giving both the gift of life and the gift of knowledge by their donations. We thank Donor Network West for cooperation in this project. We thank H. Zhao for technical support. Microscopy and image analysis was performed at the Microscopy and Advanced Bioimaging CoRE at the Icahn School of Medicine at Mount Sinai. Funding was provided by NIH grants R01DK56621, R01DK128289, TR004419, and P30CA196521 (S.L.F.); Scleroderma Research Foundation (R.M.); Wellcome Trust Senior Research Fellowship in Clinical Science 219542/Z/19/Z (N.C.H.); American Gastroenterological Association Research Scholar AGA2020-13-03 and Pilot grant AGA2021-21-02 (S.W.); Cancer Research UK C19767/A27145 (U.A.); NIH grants R01DK101737, R01DK099205, R01DK111866, R01AA028550, P50AA011999, P30 DK120515, and U01AA029019 (T.K.); and a Fulbright Scholar Fellowship, the Zuckerman STEM leadership program, the Israel National Postdoctoral Award Program for Advancing Women in Science, and the European Molecular Biology Organization (EMBO) Long Term Fellowship (ALTF 304-2019) (M.A.).
Publisher Copyright:
© 2023 The Authors, some rights reserved.
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
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 677
M1 - eadd3949
ER -