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.
Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation
Disclosures: C. Bergmann reported personal fees from Boehringer Ingelheim and Pfizer during the conduct of the study. O. Distler reported personal fees from Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Böhringer Ingelheim, ChemomAb, Corbus Pharmacheuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon Pharmaceuticals, Inventiva, Iqvia, Italfarmaco, Iqone, Kymera Therapeutics, Lupin Pharmaceuticals, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Roivant, Sanofi, Serodapharm, Topadur, Target Bioscience, and UCB during the conduct of the study; in addition, O. Distler had a patent to mir-29 for the treatment of systemic sclerosis issued (US8247389, EP2331143). J.H.W. Distler reported personal fees from Janssen, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Galapagos, GSK, Inventiva, Novartis, and UCB; grants from Anamar, ARXX, aTyr, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, Inventiva, Kiniksa, and UCB outside the submitted work; and owns stock in 4D Science. No other disclosures were reported.
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Andrea-Hermina Györfi, Alexandru-Emil Matei, Maximilian Fuchs, Chunguang Liang, Aleix Rius Rigau, Xuezhi Hong, Honglin Zhu, Markus Luber, Christina Bergmann, Clara Dees, Ingo Ludolph, Raymund E. Horch, Oliver Distler, Jiucun Wang, Bertram Bengsch, Georg Schett, Meik Kunz, Jörg H.W. Distler; Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation. J Exp Med 6 September 2021; 218 (9): e20201916. doi: https://doi.org/10.1084/jem.20201916
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