| First Author | Györfi AH | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 9 | PubMed ID | 34259830 |
| Mgi Jnum | J:346569 | Mgi Id | MGI:6887331 |
| Doi | 10.1084/jem.20201916 | Citation | Gyorfi AH, et al. (2021) Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation. J Exp Med 218(9):e20201916 |
| abstractText | Transforming growth factor-beta (TGFbeta) 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 TGFbeta signaling in myofibroblast differentiation: TGFbeta induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFbeta. 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. |
