Regulation of retinal pigment epithelial cell phenotype by Annexin A8

Lueck, Katharina; Carr, Amanda-Jayne F.; Stampoulis, Dimitrios; Gerke, Volker; Rescher, Ursula; Greenwood, John; Moss, Stephen E.

doi:10.1038/s41598-017-03493-3

Cited by 13 publications

(15 citation statements)

References 50 publications

(59 reference statements)

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“…The UPR principally acts to attenuate global translation via PERK and eif2α phosphorylation 23 . Previous studies have determined that PERK knockdown in mouse embryonic fibroblasts (MEF) results in increased 35 S -labeled cellular protein in the ER, indicative of an impaired attenuation of global translation and an increase of protein binding to GRP78 due to a loss of PERK kinase activity and eif2α phosphorylation 8 . In this context, our findings support the notion that upregulated GRP78 is an adaptive response intended on delaying induction of apoptotic pathways in ARPE-19 cells.…”

Section: Discussionmentioning

confidence: 99%

PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells

Saptarshi

Porter

Paraoan

2022

Sci Rep

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Retinal pigment epithelium (RPE) performs essential functions for ensuring retinal homeostasis and is a key site for pathogenic changes leading to age-related macular degeneration (AMD). Compromised proteostasis in RPE results in ER stress and ER stress-dependent antioxidant, apoptosis and autophagic responses. ER stress induces the unfolded protein response (UPR) in which EIF2AK3, encoding the protein kinase RNA-like ER kinase (PERK), acts as a key regulator. Downregulated EIF2AK3 gene expression has recently been identified in AMD using human donor RPE, however the molecular mechanisms that integrate the various ER-mediated cellular pathways underpinning progressive RPE dysfunction in AMD have not been fully characterised. This study investigated the downstream effects of PERK downregulation in response to Brefeldin A (BFA)-induced ER stress in ARPE-19 cells. PERK downregulation resulted in increased ER stress and impaired apoptosis induction, antioxidant responses and autophagic flux. ARPE-19 cells were unable to efficiently induce autophagy following PERK downregulation and PERK presented a role in regulating the rate of autophagy induction. The findings support PERK downregulation as an integrative event facilitating dysregulation of RPE processes critical to cell survival known to contribute to AMD development and highlight PERK as a potential future therapeutic target for AMD.

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Section: Discussionmentioning

confidence: 99%

PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells

Saptarshi

Porter

Paraoan

2022

Sci Rep

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“…in culture and can be induced to transdifferentiate towards a neuronal-like phenotype upon certain stimuli 11,17 . We recently found that AnxA8 was down-regulated in ARPE-19 cells induced towards a neuronal lineage following treatment with FR, and showed that AnxA8 down-regulation is both necessary and sufficient for RPE transdifferentiation 13 . FR-induced AnxA8 loss also correlated with decreased expression of the Wnt-related genes Frizzled-1, Frizzled-4 and Wnt2b (Table 1), leading us to hypothesize that AnxA8 may regulate RPE phenotype via modulation of Wnt signaling.…”

Section: Fr and Anxa8 Loss Both Induce Neuronal Transdifferentiationmentioning

confidence: 99%

“…A microarray analysis performed on FR-transdifferentiated RPE cells revealed down-regulation of AnxA8 and suppression of several genes involved in Wnt signaling 13 , raising the question of whether cross-talk occurs between AnxA8 and Wnt signaling. Canonical Wnt signaling maintains cell fate specification and proliferation in diverse mammalian cell types 14,15 and it occurs upon binding of secreted Wnt proteins to Frizzled receptors and their co-receptors, lipoprotein receptor-related proteins (LRP)-5 and 6.…”

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confidence: 99%

Annexin A8 regulates Wnt signaling to maintain the phenotypic plasticity of retinal pigment epithelial cells

Lueck¹,

Carr²,

Yu³

et al. 2020

Sci Rep

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Wnt signalling mediates complex cell-cellinteractions during development and proliferation. Annexin A8 (AnxA8), a calcium-dependent phospholipid-binding protein, and canonical Wnt signalling mechanisms have both been implicated in retinal pigment epithelial (RPE) cell differentiation. The aim here was to examine the possibility of cross-talk between AnxA8 and Wnt signalling, as both are downregulated upon fenretinide (FR)-mediated RPE transdifferentiation. AnxA8 suppression in RPE cells via siRNA or administration of FR induced neuronal-like cell transdifferentiation and reduced expression of Wnt-related genes, as measured by real-time PCR and western blotting. AnxA8 gene expression, on the other hand, remained unaltered upon manipulating Wnt signalling, suggesting Wnt-related genes to be downstream effectors of AnxA8. Co-immunoprecipitation revealed an interaction between AnxA8 and β-catenin, which was reduced in the presence of activated TGF-β1. TGF-β1 signalling also reversed the AnxA8 loss-induced cell morphology changes, and induced β-catenin translocation and GSK-3β phosphorylation in the absence of AnxA8. Ectopic over-expression of AnxA8 led to an increase in active β-catenin and GSK-3β phosphorylation. These data demonstrate an important role for AnxA8 as a regulator of Wnt signalling and a determinant of RPE phenotype, with implications for regenerative medicine approaches that utilise stem cell-derived RPE cells to treat conditions such as age-related macular degeneration.In vivo, retinal pigment epithelial (RPE) cell phenotype is sustained by the retinal microenvironment. However, once removed from the retina and placed in culture, RPE cells dedifferentiate within a few rounds of division, losing signature characteristics such as pigment granules and expression of genes such as MerTk and RPE65. The widely used human RPE cell line, ARPE19, is typical in this respect, though several studies have shown that under appropriate culture conditions ARPE19 cells will re-adopt a more mature phenotype that includes restoration of pigment granules and expression of key RPE-associated genes 1-3 . Interest in RPE de-differentiation has also been driven by the need to understand the process in proliferative vitreoretinopathy (PVR) where epithelial mesenchymal transition (EMT) plays a key role in the pathogenesis of this condition. More recently, interest in RPE cell differentiation and maturation has intensified with advances in regenerative medicine that utilize RPE cells derived from embryonic stem (ES) cells or induced pluripotent stem (iPS) cells 4-6 . RPE cells derived from ES or iPS cells exhibit many characteristics of mature fully differentiated RPE cells, and first-in-man transplantation studies in dry and wet age-related macular degeneration (AMD) have yielded encouraging results 7-10 . Key to these clinical advances is a better understanding of the signaling pathways that regulate and maintain RPE cell phenotype.The plasticity of RPE cells in culture is evident from studies showing that not only can they d...

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“…49,50 Retinal pigment epithelium perform a variety of functions to support and protect the retina, including phagocytosis of the PR outer segments, adsorption of free radicals by pigment granules, and maintenance of ocular immune privilege by forming the outer blood-retina barrier. 51…”

Section: Retinal Pigment Epitheliummentioning

confidence: 99%

Mammalian Retinal Cell Quantification

Muthuswamy

Chen

et al. 2020

Toxicol Pathol

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Normal retina and its cell layers are essential for processing visual stimuli, and loss of its integrity has been documented in many disease processes. The numbers and the axonal processes of retinal ganglion cells are reduced substantially in glaucoma, leading to vision loss and blindness. Similarly, selective loss of photoreceptors in age-related macular degeneration and hereditary retinal dystrophies also results in the compromise of visual acuity. Development of genetically modified mice has led to increased understanding of the pathogenesis of many retinal diseases. Similarly, in this digital era, usage of modalities to quantify the retinal cell loss has grown exponentially leading to a better understanding of the suitability of animal models to study human retinal diseases. These quantification modalities provide valuable quantifiable data in studying pathogenesis and disease progression. This review will discuss the immunohistochemical markers for various retinal cells, available automated tools to quantify retinal cells, and present an example of retinal ganglion cell quantification using HALO image analysis platform. Additionally, we briefly review retinal cell types and subtypes, salient features of retina in various laboratory animal species, and a few of the main disease processes that affect retinal cell numbers in humans.

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Regulation of retinal pigment epithelial cell phenotype by Annexin A8

Cited by 13 publications

References 50 publications

PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells

PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells

Annexin A8 regulates Wnt signaling to maintain the phenotypic plasticity of retinal pigment epithelial cells

Mammalian Retinal Cell Quantification

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