Myofibroblasts (MFBs) are differentiated from fibroblasts by transforming growth factor (TGF)-β1 and mediate the pathogenesis of fibrotic disease. As eukaryotic initiation factor 6 (eIF6) has recently been proposed to be involved in scar formation and contraction, Jun Wu, Gao-xing Luo and colleagues (p. ), decided to investigate the mechanism by which eIF6 regulates TGF-β1 and MFB differentiation. They show that TGF-β1 levels are increased in fibroblasts derived from eIF6+/− mice, but reduced upon eIF6 overexpression. Surprisingly, the authors discover reduced levels of the histone H2A.Z variant and increased recruitment of the general transcriptional activator Sp1 at the TGF-β1 promoter in eIF6+/− fibroblasts. Furthermore, TGF-β1 signalling is more active and MFB characteristics more pronounced when eIF6 levels are reduced. In fact, pharmacological inhibition of TGF-β1 in eIF6+/− fibroblasts prevented their differentiation into MFBs, confirming that effects of eIF6 on MFB differentiation are mediated by TGF-β1. The authors then extend these findings in vivo by showing that wound closure, which reflects MFB differentiation, is faster in eIF6+/− mice and that eIF6 expression is significantly lower in scar-derived fibroblasts than in normal fibroblasts. Finally, overexpression of eIF6 in scar-derived fibroblasts decreased MFB differentiation. These results are the first demonstration of a role for eIF6 in MFB differentiation and, as such, provide important new insights into our understanding of fibrotic disease pathology.
