Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation

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 TGF...

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Bibliographic Details
Published in:The Journal of experimental medicine 2021-09, Vol.218 (9)
Main Authors: Györfi, Andrea-Hermina, Matei, Alexandru-Emil, Fuchs, Maximilian, Liang, Chunguang, Rigau, Aleix Rius, Hong, Xuezhi, Zhu, Honglin, Luber, Markus, Bergmann, Christina, Dees, Clara, Ludolph, Ingo, Horch, Raymund E, Distler, Oliver, Wang, Jiucun, Bengsch, Bertram, Schett, Georg, Kunz, Meik, Distler, Jörg H W
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Autoimmunity
Case-Control Studies
Cell Differentiation - physiology
Cytoskeleton - genetics
Cytoskeleton - metabolism
Female
Gene Expression Regulation
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Male
Mice
Mice, Knockout
Middle Aged
Myofibroblasts - cytology
Myofibroblasts - pathology
Myofibroblasts - physiology
rho-Associated Kinases - metabolism
Scleroderma, Systemic - pathology
Skin - pathology
Transforming Growth Factor beta - metabolism
Young Adult
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Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20201916