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.

Highlights

  • The epithelial-mesenchymal transition (EMT) is a complex biological process characterized by the transdifferentiation of epithelial cells into motile mesenchymal cells[1,2,3,4]

  • Fibrogenic processes estimated from Idiopathic epiretinal membrane (iERM) tissue samples[10,11,12] appear to be equivalent with Type 2 EMT featuring myofibroblasts[1,4,5], the precise mechanism of myofibroblastic differentiation remains largely elusive in the pathogenesis of iERM that lacks epithelial contribution in nature

  • The present study demonstrated, for the first time to our knowledge, that Müller glial cells are equipped with the Type 2 EMT program driven by the transforming growth factor (TGF)-β-SNAIL axis

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Summary

Introduction

The epithelial-mesenchymal transition (EMT) is a complex biological process characterized by the transdifferentiation of epithelial cells into motile mesenchymal cells[1,2,3,4]. We checked the aforementioned parameters of the Type 2 EMT program by screening pro-fibrotic cytokines that transdifferentiate Müller cells into myofibroblasts, analyzing whether the transdifferentiated cells exhibit fibrogenic phenotypes (cell motility, ECM productivity, and cytoskeleton contractility), and determining which transcription factor governs these Type 2 EMT features in human Müller glial cells. These in vitro data were further supported by immunohistochemistry for iERM patient specimens

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