Role of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium Dysfunction

Abstract

Retinal pigment epithelial (RPE) cells maintain the health and functional integrity of both photoreceptors and the choroidal vasculature. Loss of RPE differentiation has long been known to play a critical role in numerous retinal diseases, including inherited rodcone degenerations, inherited macular degeneration, age-related macular degeneration, and proliferative vitreoretinopathy. Recent studies in post-mortem eyes have found upregulation of critical epithelial-mesenchymal transition (EMT) drivers such as TGFβ, Wnt, and Hippo. As RPE cells become less differentiated, they begin to exhibit the defining characteristics of mesenchymal cells, namely, the capacity to migrate and proliferate. A number of preclinical studies, including animal and cell culture experiments, also have shown that RPE cells undergo EMT. Taken together, these data suggest that RPE cells retain the reprogramming capacity to move along a continuum between polarized epithelial cells and mesenchymal cells. We propose that movement along this continuum toward a mesenchymal phenotype be defined as RPE Dysfunction. Potential mechanisms include impaired tight junctions, accumulation of misfolded proteins and dysregulation of several key pathways and molecules, such as TGF-β pathway, Wnt pathway, nicotinamide, microRNA 204/211 and extracellular vesicles. This review synthesizes the evidence implicating EMT of RPE cells in post-mortem eyes, animal studies, primary RPE, iPSC-RPE and ARPE-19 cell lines.

Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy

“…Therapeutic interventions against RPE EMT have largely been explored in mechanistic experiments using in vitro cell culture and in vivo animal models. To date, some promising drug candidates have been trialed in preclinical studies of PVR, including TGF-β receptor inhibitors, peroxisome proliferator-activated receptor (PPAR)-γ agonists, retinoic acid receptor-γ (RAR-γ) agonists and methotrexate ( Shu, Butcher & Saint-Geniez, 2020 ; Zhou et al, 2020 ). Nassar et al (2014) found that TGF-β receptor 1 inhibitor LY-364947 (LY) attenuates RPE cell transdifferentiation in vitro, and that intravitreal injection of LY completely prevents PVR and TRD in vivo.…”

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

“…The epigenetic transcriptome analyses of human AMD-RPE unveiled an association between RPE senescence and the epigenetic dysregulation, such as a differentiation of methylated SKI proto-oncogene, which is a negative regulator of the TGF-β pathway [ 56 ]. As a consequence, the over-activated TGF-β signaling induces a SIPS in RPE cells [ 69 ] and facilitates an epithelial-mesenchymal transition (EMT), leading to loss of RPE differentiation and compromised cellular function [ 70 ]. We have recently demonstrated that RPE cells deficient in interleukin-1 receptor-associated kinase-M (IRAK-M), a key inhibitor of TLR/IL-1R-mediated inflammation, are more susceptible to oxidative stress-induced senescence, evidenced by elevated SA-β-Gal and p21 CIP1 expression, increased secretion of SASP proteins HMGB1 and IL-6, and decreased nuclear lamina protein LB1.…”

Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration

“…ETM consists in the loss of epithelial cell polarity and cell-cell adhesion and the acquisition of migratory and invasive properties as mesenchymal stem cells. This process RPE-ETM has been found to be linked to TGF-β upregulation, UPR mt dysfunctions, yet, as reported by Zhou et al and Hyttinen et al, NAM treatment prevented ETM in numerous RPE cell models, orchestrating the mechanism responsible for that shift [ 211 , 212 ].…”