Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation

Györfi AH, Matei AE, Fuchs M, Liang C, Rigau A, Hong X, Zhu H, Luber M, Bergmann C, Dees C, Ludolph I, Horch RE, Distler O, Wang J, Bengsch B, Schett G, Kunz M, Distler J (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Journal of Experimental Medicine Rockefeller University Press

Book Volume: 218

Article Number: e20201916

Journal Issue: 9

DOI: 10.1084/jem.20201916

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.

Authors with CRIS profile

Andrea-Hermina Györfi Department of Medicine 3 – Rheumatology and Immunology Alexandru-Emil Matei Department of Medicine 3 – Rheumatology and Immunology Maximilian Fuchs Lehrstuhl für Medizinische Informatik Aleix Rius Rigau Department of Medicine 3 – Rheumatology and Immunology Xuezhi Hong Professur für Molekulare Mechanismen der Organfibrose Christina Bergmann Department of Medicine 3 – Rheumatology and Immunology Clara Dees Department of Medicine 3 – Rheumatology and Immunology Ingo Ludolph Department of Plastic and Hand Surgery Raymund Horch Professur für Plastische Chirurgie und Handchirurgie Georg Schett Lehrstuhl für Innere Medizin III Meik Kunz Lehrstuhl für Medizinische Informatik Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung (IZKF)

Related research project(s)

A079: The nuclear receptor TR4 regulates TGFbeta-induced fibroblast activation and tissue fibrosis Jan. 1, 2021 - June 30, 2023

Involved external institutions

Universitätsspital Zürich (USZ) CH Switzerland (CH) Universitätsklinikum Freiburg DE Germany (DE) Fudan University / 复旦大学 CN China (CN)

How to cite

APA:

Györfi, A.-H., Matei, A.-E., Fuchs, M., Liang, C., Rigau, A., Hong, X.,... Distler, J. (2021). Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation. Journal of Experimental Medicine, 218(9). https://doi.org/10.1084/jem.20201916

MLA:

Györfi, Andrea-Hermina, et al. "Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation." Journal of Experimental Medicine 218.9 (2021).

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