Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation

Author:

Györfi Andrea-Hermina12ORCID,Matei Alexandru-Emil12ORCID,Fuchs Maximilian3ORCID,Liang Chunguang3ORCID,Rigau Aleix Rius12ORCID,Hong Xuezhi12ORCID,Zhu Honglin124ORCID,Luber Markus12ORCID,Bergmann Christina12ORCID,Dees Clara12ORCID,Ludolph Ingo5ORCID,Horch Raymund E.5ORCID,Distler Oliver6ORCID,Wang Jiucun789ORCID,Bengsch Bertram1011ORCID,Schett Georg12ORCID,Kunz Meik3ORCID,Distler Jörg H.W.12ORCID

Affiliation:

1. Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany

2. Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany

3. Medical Informatics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany

4. Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China

5. Department of Plastic and Hand Surgery, Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany

6. Department of Rheumatology, Center of Experimental Rheumatology, University Hospital of Zurich, Zurich, Switzerland

7. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China

8. Human Phenome Institute, Fudan University, Shanghai, P.R. China

9. Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, P.R. China

10. Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany

11. BIOSS Centre for Biological Signaling Studies, Freiburg, Germany

Abstract

Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.

Funder

German Research Foundation

Interdisciplinary Center for Clinical Research

Else Kröner-Fresenius Foundation

ELAN-Foundation Erlangen

German Ministry of Education and Research

Ernst Jung Foundation

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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