Open AccessEngrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation
Author(s) -
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
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20201916
Subject(s) - myofibroblast , fibroblast , microbiology and biotechnology , transforming growth factor , transforming growth factor beta , biology , fibrosis , cytoskeleton , cancer research , in vitro , pathology , cell , medicine , genetics
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.