TGF-β-SNAIL axis induces Müller glial-mesenchymal transition in the pathogenesis of idiopathic epiretinal membrane

Abstract

The epithelial-mesenchymal transition (EMT) is a key process in fibrogenic diseases where transdifferentiated myofibroblasts produce excessive amounts of extracellular matrix, resulting in organ dysfunction. Idiopathic epiretinal membrane (iERM) is a vision-threatening disorder characterized by fibrocellular proliferation and contraction on the central retina. Müller glial cells, which regulate retinal physiology and structure, are the major cellular components in the iERM tissue; however, the pathological role of this cell type remains incompletely understood. Here we revealed the involvement of Müller glial-mesenchymal transition (GMT), as an alternative to EMT, in the pathogenesis of iERM lacking epithelial contribution in nature. Of various pro-fibrotic cytokines, transforming growth factor (TGF)-β1 stimulation to human Müller glial cells exclusively increased mRNA and protein levels of several EMT-related molecular markers, together with the transcription factor SNAIL but not SLUG or TWIST. TGF-β1-stimulated Müller cells also exhibited EMT-related cell motility, while reducing the expression of glutamine synthetase (GS), a Müller glial marker. Notably, all of these TGF-β-induced EMT features were reversed by SNAI1 knockdown in Müller cells. iERM patient specimens demonstrated co-immunolocalization of SNAIL with TGF-β1, GS, and smooth muscle protein 22. Our data implicated a critical role of the TGF-β-SNAIL axis in Müller GMT to promote iERM formation.

Effect of axial length and age on the visual outcome of patients with idiopathic epiretinal membrane after pars plana vitrectomy

“…4a). Moreover, iERM is gradually modified by the migration of Müller glial cells and cytokines such as transforming growth factor-beta from the retina, as reported previously 38 . The cell migration becomes easier when the tractional force is greater, and cytokines are reported to be concentrated in eyes with a shorter AL 39 , most probably because vitreous liquefaction has not progressed much; this slows the turnover of soluble factors 40 .…”

Heat Shock Protein 90 Involvement in the Development of Idiopathic Epiretinal Membranes

“… 9 , 10 Interestingly, αSMA can be expressed by cells derived from retinal pigment epithelial cells and hyalocytes, respectively, after a process of epithelial-mesenchymal transition or transdifferentiation, 4 , 11 , 12 and by Müller cells 13 , 14 after a process of glial-mesenchymal transition. 15 In practice, all cell types that have been proposed to give rise to ERM cells can transdifferentiate into a myofibroblast-like phenotype because reactive astrocytes can also express αSMA. 16 …”

Involvement of Müller Glial Autoinduction of TGF-β in Diabetic Fibrovascular Proliferation Via Glial–Mesenchymal Transition

“…6,7 As concerns the cellular source of myofibroblasts in epiretinal fibrocellular proliferation seen in idiopathic epiretinal membrane, we recently revealed that Müller glial cells are equipped with fibrogenic EMT program for the expression of TβR, SNAIL, and smooth muscle protein (SM)22, which would thus be termed the Müller glialmesenchymal transition (GMT) as an alternative to EMT. 9 In fibrovascular proliferation associated with PDR, however, little is yet known about the involvement of Müller GMT promoted by the TGF-β-SNAIL axis, although Müller glial cells in patient tissues were suggested to bear a contractile phenotype expressing α-smooth muscle actin (SMA). 10 It is also yet to be elucidated whether Müller glial cells have any capacity for the profibrotic TGF-β autoinduction as seen in RPE cells during subretinal fibrovascular proliferation.…”