Role of epithelial–mesenchymal transition in proliferative vitreoretinopathy
Introduction
Proliferative vitreoretinopathy (PVR) is an ocular fibrotic complication that occurs following corrective surgery for rhegmatogenous retinal detachment or posterior segment trauma (Pastor et al., 2002). Aberrant wound healing and/or persistent inflammation is believed to contribute to the formation of epiretinal membranes (ERMs). Contraction of ERMs results in loss of visual acuity due to retinal wrinkling, retinal folds and traction retinal detachments (TRD). Analyses of ERMs have identified several cell types, including retinal pigment epithelial (RPE) cells, glial cells, fibroblasts, myofibroblasts and immune cells (Pastor et al., 2002). Fibroblasts and myofibroblasts are considered to be the contractile cellular phenotypes within the ERM, and thus, play a prominent role in the contractile phase of PVR. Co-localization of cytokeratin, used as an RPE marker, with vimentin, a mesenchymal marker, in ERM samples obtained from patients with PVR strongly suggests that RPE cells, which are abundant at the early stages (Morino et al., 1990, Yamashita et al., 1986), are capable of undergoing epithelial–mesenchymal transition (EMT) to become fibroblasts (Fig. 1) (Casaroli-Marano et al., 1999). Furthermore, co-localization of cytokeratin with alpha-smooth muscle actin (α-SMA), a myofibroblast marker protein, suggests that RPE cells that have undergone EMT are capable of turning into myofibroblasts (Fig. 1) (Feist et al., 2014), a process referred to as epithelial–myofibroblast transition (EMyT) (Masszi and Kapus, 2011). This review will summarize the molecular mechanisms involved in EMT of RPE cells and the subsequent differentiation into myofibroblasts, as well as the potential role of RPE cells that have undergone EMT/EMyT in PVR.
Section snippets
Epithelial–mesenchymal transition (EMT)
EMT is a process in which epithelial cells adopt a mesenchymal phenotype. In addition to changes in cell morphology, various cellular functions, such as cell motility, proliferation, apoptosis, and protein expression, are altered (Kalluri and Weinberg, 2009). EMT plays key roles during embryonic development, and is also involved in pathophysiological processes such as neoplastic metastasis, as well as increased resistance to apoptosis of cancer cells. While the role of EMT in fibrotic diseases
Role of cell–cell contact in regulating EMT
Cell–cell adhesion, maintained by junctional complexes such as adherens junctions (AJs) and tight junctions (TJs), plays a critical role in maintenance of epithelial layer integrity, and thus, is required for apicobasal polarity and barrier function (Niessen, 2007). One of the mechanisms by which these complexes maintain an epithelial phenotype is by sequestering EMT signaling effectors at the plasma membrane/cytoplasm to prevent nuclear localization (Fig. 3) (Bernascone and Martin-Belmonte,
EMT transcription factors
Transcription factors including Snail 1 and 2, ZEB 1 and 2, twist, and LEF-1 has been demonstrated to be involved in EMT of a variety of cell types (Gonzalez and Medici, 2014). Zeb1, Snail1 and 2 have been detected in RPE cells undergoing EMT but the extent of expression seems to be dependent on the species and/or the experimental setup (Georgiadis et al., 2010, Liu et al., 2009, Palma-Nicolas and Lopez-Colome, 2013). Zeb1 induces EMT by down-regulating transcription factors MITF and Otx2 that
Mechanisms involved in myofibroblast differentiation
Myofibroblasts, which are characterized by the incorporation of α-SMA into stress fibers, are involved in matrix turnover, accumulation of aberrant matrices, and contraction of these newly formed matrices that ultimately results in contracture of the fibrotic tissue. Two key elements are required for full myofibroblast differentiation: transforming growth factor-beta (TGF-β) signaling and mechanical tension resulting from increased stiffness of the underlying ECM (Hinz et al., 2012). TGF-β, a
Role of RPE cells that have undergone EMT/EMyT in PVR
RPE cells undergoing EMT acquire significantly increased capacity to proliferate and migrate. RPE cells injected into vitreous cavity have been shown to undergo proliferation (Mandelcorn et al., 1975, Radtke et al., 1981), and to play a key role in PVR; the severity of PVR has been shown to correlate with the number of RPE cells injected into the vitreous cavity (Fastenberg et al., 1982). However, treatments only targeting proliferation to prevent PVR (Schiff et al., 2007, Wiedemann et al., 1998
Conclusion
In summary, both clinical and experimental evidence demonstrates that RPE cells are capable of undergoing EMT and EMyT to become fibroblasts and myofibroblasts, respectively. Cell–cell adhesion is critical in maintaining the RPE phenotype, and its disruption induces EMT via activation of various signaling pathways and transcription factors to produce proliferative, migratory and contractile fibroblasts. Further differentiation into myofibroblasts involves TGF-β signaling in concert with several
Grant information
Research to Prevent Blindness Unrestricted Grant, New York, NY; the KY Lions Eye Foundation; KY Research Challenge Trust Fund (HJ Kaplan).
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