TY  - JOUR
AU  - De Angelis Rigotti, Francesca
AU  - Wiedmann, Lena
AU  - Hubert, Max Ole
AU  - Vacca, Margherita
AU  - Hasan, Sana S
AU  - Moll, Iris
AU  - Carvajal, Silvia
AU  - Jiménez, Wladimiro
AU  - Starostecka, Maja
AU  - Billeter, Adrian T
AU  - Müller-Stich, Beat
AU  - Wolff, Gretchen
AU  - Ekim-Üstünel, Bilgen
AU  - Herzig, Stephan
AU  - Fandos-Ramo, Cristina
AU  - Krätzner, Ralph
AU  - Reich, Maria
AU  - Keitel-Anselmino, Verena
AU  - Heikenwälder, Mathias
AU  - Mogler, Carolin
AU  - Fischer, Andreas
AU  - Rodriguez-Vita, Juan
TI  - Semaphorin 3C exacerbates liver fibrosis.
JO  - Hepatology
VL  - 78
IS  - 4
SN  - 0270-9139
CY  - New York [u.a.]
PB  - Wiley Interscience
M1  - DKFZ-2023-00746
SP  - 1092-1105
PY  - 2023
N1  - #EA:A270#LA:A270# / 2023 Oct 1;78(4):1092-1105
AB  - Chronic liver disease is a growing epidemic, leading to fibrosis and cirrhosis. TGF-β is the pivotal pro-fibrogenic cytokine which activates hepatic stellate cells (HSC), yet, other molecules can modulate TGF-β signaling during liver fibrosis. Expression of the axon guidance molecules Semaphorins (SEMAs), which signal through Plexins and Neuropilins (NRPs), have been associated with liver fibrosis in HBV-induced chronic hepatitis. This study aims at determining their function in the regulation of HSCs. We analyzed publicly available patient databases and liver biopsies. We employed transgenic mice, in which genes are deleted only in activated HSCs to perform ex vivo analysis and animal models. SEMA3C is the most enriched member of the Semaphorin family in liver samples from cirrhotic patients. Higher expression of SEMA3C in patients with NASH, alcoholic hepatitis or HBV-induced hepatitis discriminates those with a more pro-fibrotic transcriptomic profile. SEMA3C expression is also elevated in different mouse models of liver fibrosis and in isolated HSCs upon activation. In keeping with this, deletion of SEMA3C in activated HSCs reduces myofibroblast marker expression. Conversely, SEMA3C overexpression exacerbates TGF-β-mediated myofibroblast activation, as shown by increased SMAD2 phosphorylation and target gene expression. Among SEMA3C receptors, only NRP2 expression is maintained upon activation of isolated HSCs. Interestingly, lack of NRP2 in those cells reduces myofibroblast marker expression. Finally, deletion of either SEMA3C or NRP2, specifically in activated HSCs, reduces liver fibrosis in mice. SEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis.
LB  - PUB:(DE-HGF)16
C6  - pmid:37055018
DO  - DOI:10.1097/HEP.0000000000000407
UR  - https://inrepo02.dkfz.de/record/275423
ER  -