Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Semaphorin 3C exacerbates liver fibrosis

View ORCID ProfileFrancesca De Angelis Rigotti, Lena Wiedmann, Max Ole Hubert, Margherita Vacca, Sana S. Hasan, Iris Moll, Silvia Carvajal, Wladimiro Jiménez, View ORCID ProfileMaja Starostecka, Adrian T Billeter, Beat Müller-Stich, Gretchen Wolff, Bilgen Ekim-Üstünel, Stephan Herzig, Carolin Mogler, View ORCID ProfileAndreas Fischer, View ORCID ProfileJuan Rodriguez-Vita
doi: https://doi.org/10.1101/2021.07.29.454292
Francesca De Angelis Rigotti
1Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Francesca De Angelis Rigotti
Lena Wiedmann
1Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
2Faculty of Biosciences, University of Heidelberg, 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Max Ole Hubert
1Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
3European Center for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Margherita Vacca
1Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sana S. Hasan
1Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Iris Moll
1Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Silvia Carvajal
4Service of Biochemistry and Molecular Genetics, Hospital Clinic Universitari, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wladimiro Jiménez
4Service of Biochemistry and Molecular Genetics, Hospital Clinic Universitari, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maja Starostecka
1Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
2Faculty of Biosciences, University of Heidelberg, 69120 Heidelberg, Germany
5European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69126 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Maja Starostecka
Adrian T Billeter
6Department of General, Visceral and Transplantation Surgery, University of Heidelberg Hospital, 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Beat Müller-Stich
6Department of General, Visceral and Transplantation Surgery, University of Heidelberg Hospital, 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gretchen Wolff
7Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Centre Munich, Neuherberg, Germany
8Joint Heidelberg-IDC Translational Diabetes Program, Department of Internal Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
9German Center for Diabetes Research (DZD), Neuherberg, Germany, and Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bilgen Ekim-Üstünel
7Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Centre Munich, Neuherberg, Germany
8Joint Heidelberg-IDC Translational Diabetes Program, Department of Internal Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
9German Center for Diabetes Research (DZD), Neuherberg, Germany, and Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephan Herzig
7Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Centre Munich, Neuherberg, Germany
8Joint Heidelberg-IDC Translational Diabetes Program, Department of Internal Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
9German Center for Diabetes Research (DZD), Neuherberg, Germany, and Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carolin Mogler
10Institute of Pathology, Technical University of Munich, 81675 Munich, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andreas Fischer
1Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
3European Center for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
11Department of Medicine 1 and Clinical Chemistry, University Hospital of Heidelberg, 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andreas Fischer
  • For correspondence: a.fischer@dkfz.de j.rodriguezvita@dkfz.de
Juan Rodriguez-Vita
1Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Juan Rodriguez-Vita
  • For correspondence: a.fischer@dkfz.de j.rodriguezvita@dkfz.de
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Background 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 substantially modulate TGF-β signalling in the course of 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. However, their function in the regulation of HSCs has not yet been described.

Results 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 SMAD2/3 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.

Conclusion SEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted July 29, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Semaphorin 3C exacerbates liver fibrosis
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Semaphorin 3C exacerbates liver fibrosis
Francesca De Angelis Rigotti, Lena Wiedmann, Max Ole Hubert, Margherita Vacca, Sana S. Hasan, Iris Moll, Silvia Carvajal, Wladimiro Jiménez, Maja Starostecka, Adrian T Billeter, Beat Müller-Stich, Gretchen Wolff, Bilgen Ekim-Üstünel, Stephan Herzig, Carolin Mogler, Andreas Fischer, Juan Rodriguez-Vita
bioRxiv 2021.07.29.454292; doi: https://doi.org/10.1101/2021.07.29.454292
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Semaphorin 3C exacerbates liver fibrosis
Francesca De Angelis Rigotti, Lena Wiedmann, Max Ole Hubert, Margherita Vacca, Sana S. Hasan, Iris Moll, Silvia Carvajal, Wladimiro Jiménez, Maja Starostecka, Adrian T Billeter, Beat Müller-Stich, Gretchen Wolff, Bilgen Ekim-Üstünel, Stephan Herzig, Carolin Mogler, Andreas Fischer, Juan Rodriguez-Vita
bioRxiv 2021.07.29.454292; doi: https://doi.org/10.1101/2021.07.29.454292

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Pathology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3585)
  • Biochemistry (7539)
  • Bioengineering (5494)
  • Bioinformatics (20724)
  • Biophysics (10292)
  • Cancer Biology (7946)
  • Cell Biology (11609)
  • Clinical Trials (138)
  • Developmental Biology (6584)
  • Ecology (10161)
  • Epidemiology (2065)
  • Evolutionary Biology (13573)
  • Genetics (9511)
  • Genomics (12811)
  • Immunology (7900)
  • Microbiology (19490)
  • Molecular Biology (7632)
  • Neuroscience (41969)
  • Paleontology (307)
  • Pathology (1254)
  • Pharmacology and Toxicology (2189)
  • Physiology (3258)
  • Plant Biology (7017)
  • Scientific Communication and Education (1293)
  • Synthetic Biology (1946)
  • Systems Biology (5417)
  • Zoology (1112)