scholarly journals Expression of Pro-Angiogenic Markers Is Enhanced by Blue Light in Human RPE Cells

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1154 ◽  
Author(s):  
Concetta Scimone ◽  
Simona Alibrandi ◽  
Sergio Zaccaria Scalinci ◽  
Edoardo Trovato Battagliola ◽  
Rosalia D’Angelo ◽  
...  
Keyword(s):  
Blue Light ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
R Package ◽  
Rpe Cells ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Increased Risk ◽  
Angiogenic Markers

Inherited retinal dystrophies are characterized by photoreceptor death. Oxidative stress usually occurs, increasing vision loss, and oxidative damage is often reported in retinitis pigmentosa (RP). More than 300 genes have been reported as RP causing. In contrast, choroidal neovascularization (CNV) only occasionally develops in the late stages of RP. We herein study the regulation of RP causative genes that are likely linked to CNV onset under oxidative conditions. We studied how the endogenous adduct N-retinylidene-N-retinylethanolamine (A2E) affects the expression of angiogenic markers in human retinal pigment epithelium (H-RPE) cells and a possible correlation with RP-causing genes. H-RPE cells were exposed to A2E and blue light for 3 and 6h. By transcriptome analysis, genes differentially expressed between A2E-treated cells and untreated ones were detected. The quantification of differential gene expression was performed by the Limma R package. Enrichment pathway analysis by the FunRich tool and gene prioritization by ToppGene allowed us to identify dysregulated genes involved in angiogenesis and linked to RP development. Two RP causative genes, AHR and ROM1, can be associated with an increased risk of CNV development. Genetic analysis of RP patients affected by CNV will confirm this hypothesis.

scholarly journals Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies

2021 ◽  
Vol 13 ◽  
pp. 251584142199719
Author(s):  
Simranjeet Singh Grewal ◽  
Joseph J. Smith ◽  
Amanda-Jayne F. Carr
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
Underlying Disease ◽  
Incomplete Penetrance ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
High Acuity ◽  
Induced Pluripotent

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum of disorders is caused by mutations in bestrophin1 ( BEST1), a protein thought to act as a Ca2+-activated Cl- channel in the retinal pigment epithelium (RPE) of the eye. Although bestrophinopathies are rare, over 250 individual pathological mutations have been identified in the BEST1 gene, with many reported to have various clinical expressivity and incomplete penetrance. With no current clinical treatments available for patients with bestrophinopathies, understanding the role of BEST1 in cells and the pathological pathways underlying disease has become a priority. Induced pluripotent stem cell (iPSC) technology is helping to uncover disease mechanisms and develop treatments for RPE diseases, like bestrophinopathies. Here, we provide a comprehensive review of the pathophysiology of bestrophinopathies and highlight how patient-derived iPSC-RPE are being used to test new genomic therapies in vitro.

scholarly journals A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor–RPE interface

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Cynthia Tang ◽  
Jimin Han ◽  
Sonal Dalvi ◽  
Kannan Manian ◽  
Lauren Winschel ◽  
...  
Keyword(s):  
Photoreceptor Cell ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Loss ◽  
Human Model ◽  
Lysosomal Storage ◽  
Rpe Cells ◽  
Cln3 Disease

AbstractMutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy.

scholarly journals PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

2018 ◽  
Vol 19 (8) ◽  
pp. 2317 ◽  
Author(s):  
Kai Kaarniranta ◽  
Jakub Kajdanek ◽  
Jan Morawiec ◽  
Elzbieta Pawlowska ◽  
Janusz Blasiak
Keyword(s):  
Oxidative Stress ◽  
Cellular Senescence ◽  
Mitochondrial Biogenesis ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Sirtuin 1 ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Age Related

PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes. PGC-1α can decrease oxidative stress, a key factor of AMD pathogenesis related to senescence, through upregulation of antioxidant enzymes and DNA damage response. PGC-1α is an important regulator of VEGF (vascular endothelial growth factor), which is targeted in the therapy of wet AMD, the most devastating form of AMD. Dysfunction of mitochondria induces cellular senescence associated with AMD pathogenesis. PGC-1α can improve mitochondrial biogenesis and negatively regulate senescence, although this function of PGC-1α in AMD needs further studies. Post-translational modifications of PGC-1α by AMPK (AMP kinase) and SIRT1 (sirtuin 1) are crucial for its activation and important in AMD pathogenesis.

scholarly journals Dorzolamide in a management of cystoid macular edema in a patient with retinitis pigmentosa sine pigmento

2017 ◽  
Vol 145 (5-6) ◽  
pp. 296-300
Author(s):  
Jelena Karadzic ◽  
Igor Kovacevic ◽  
Aleksandra Radosavljevic ◽  
Ivan Stefanovic
Keyword(s):  
Retinitis Pigmentosa ◽  
Macular Edema ◽  
Cystoid Macular Edema ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Visual Field Loss ◽  
Ophthalmological Examination ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Advanced Stages

Introduction. Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies caused by mutations in various genes. The disease leads to progressive photoreceptors loss (rods predominantly) and retinal pigment epithelium alteration. RP can lead to blindness in the advanced stages of the disease, when the central retina is involved, mostly due to the presence of cystoid macular edema (CME). Several therapeutic approaches for CME in RP patients have been attempted but responses have been variable. Case outline. A 51-year-old man was referred due to progressive six-month-long blurring of vision in both eyes. The patient underwent complete ophthalmological examination at baseline. Based on the clinical presentation of mottled mid periphery of the retina and characteristic tubular visual field loss, hence typical fluorescein angiography and optical coherence tomography (OCT) findings, the patient was diagnosed as bilateral retinitis pigmentosa sine pigmento with CME. In an attempt to control the edema, treatment was started with dorzolamide, instilled three times daily in each eye, which resulted in reduction of macular edema in a one-month-period, as documented by OCT. This effect was further monitored for five months and was stable. Conclusion. In the presented case, we investigate the six-month therapeutic efficacy of dorzolamide for dealing with the CME secondary to RP. Topical carbonic anhydrase inhibitors are considered as the first option for treatment of CME in RP patients, due to their high efficacy and safety.

scholarly journals CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway

2021 ◽  
Vol 22 (16) ◽  
pp. 8727
Author(s):  
Angela Armento ◽  
Tiziana L. Schmidt ◽  
Inga Sonntag ◽  
David A. Merle ◽  
Mohamed Ali Jarboui ◽  
...  
Keyword(s):  
Complement System ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Major Pathway ◽  
Rpe Cells ◽  
Age Related

Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism of CFH dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., C3, CFB upregulation, and C5 downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype.

scholarly journals The HDAC/HSP90 Inhibitor G570 Attenuated Blue Light-Induced Cell Migration in RPE Cells and Neovascularization in Mice through Decreased VEGF Production

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4359
Author(s):  
Tai-Ju Hsu ◽  
Kunal Nepali ◽  
Chi-Hao Tsai ◽  
Zuha Imtiyaz ◽  
Fan-Li Lin ◽  
...  
Keyword(s):  
Cell Migration ◽  
Blue Light ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Hsp90 Inhibitor ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Age Related ◽  
Proven Efficacy ◽  
Wet Amd

Age-related macular degeneration (AMD) occurs due to an abnormality of retinal pigment epithelium (RPE) cells that leads to gradual degeneration of the macula. Currently, AMD drug pipelines are endowed with limited options, and anti-VEGF agents stand as the dominantly employed therapy. Despite the proven efficacy of such agents, the evidenced side effects associated with their use underscore the need to elucidate other mechanisms involved and identify additional molecular targets for the sake of therapy improvement. The previous literature provided us with a solid rationale to preliminarily explore the potential of selective HDAC6 and HSP90 inhibitors to treat wet AMD. Rather than furnishing single-target agents (either HDAC6 or HSP90 inhibitor), this study recruited scaffolds endowed with the ability to concomitantly modulate both targets (HDAC6 and HSP90) for exploration. This plan was anticipated to accomplish the important goal of extracting amplified benefits via dual inhibition (HDAC6/HSP90) in wet AMD. As a result, G570 (indoline-based hydroxamate), a dual selective HDAC6-HSP90 inhibitor exerting its effects at micromolar concentrations, was pinpointed in the present endeavor to attenuate blue light-induced cell migration and retinal neovascularization by inhibiting VEGF production. In addition to the identification of a potential chemical tool (G570), the outcome of this study validates the candidate HDAC6-HSP90 as a compelling target for the development of futuristic therapeutics for wet AMD.

scholarly journals Implication of N-methyl-D-aspartate receptor In Homocysteine Induced Age related Macular Degeneration

2021 ◽  
Author(s):  
Yara A. Samra ◽  
Dina Kira ◽  
Pragya Rajpurohit ◽  
Riyaz Mohamed ◽  
Leah Owen ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Mice Model ◽  
Rpe Cells ◽  
Aspartate Receptor ◽  
Age Related ◽  
Retinal Structure

Abstract Background: Age related macular degeneration (AMD) is a leading cause of vision loss in old people. Elevated homocysteine (Hcy), known as Hyperhomocysteinemia (HHcy) was reported in association with AMD. We previously reported that HHcy induces AMD like features. The current study suggests activation of N-Methyl-D-aspartate receptor (NMDAR) in retinal pigment epithelium (RPE) cells as a mechanism for HHcy-induced AMD. Serum Hcy and cystathione-β-synthase enzyme (CBS) were assessed by ELISA in AMD patients. The involvement of NMDAR in Hcy’s induced AMD features were evaluated 1)-In-vitro using ARPE-19 cells, primary RPE isolated from mice model of HHcy (CBS) and mouse choroidal endothelial cells (MCEC). 2)-In-vivo using wild type mice and mice deficient in RPE cells NMDAR (NMDARR -/-) with/without intravitreal injection of Hcy. Expression of retinal isolectin-B4, Ki67, HIF-1α, VEGF, NMDAR1 and albumin were assessed by immunofluorescence (IF), Western blot (WB), Optical coherence tomography (OCT), and fluorescein angiography (FA) to evaluate retinal structure, fluorescein leakage and development of choroidal neovascularization (CNV) in living mice. Results: Serum of the neovascular AMD patients showed significant increase in Hcy and decrease in CBS levels. Moreover, Hcy significantly increased angiogenic markers; HIF-1α, VEGF and NMDAR in RPE cells and Ki67 in MCEC. Hcy-injected WT mice showed disrupted retinal morphology and development of CNV. Knocking down NMDAR in RPE improved retinal structure and CNV induction.Conclusion: Our findings underscore the potential role for NMDAR in RPE cells in mediating Hcy-induced features of AMD and CNV induction, thus NMDAR inhibition could provide a promising therapeutic target for AMD.

scholarly journals AAV-mediated gene augmentation therapy restores critical functions in mutant iPSC-derived PRPF31+/- cells

2019 ◽  
Author(s):  
Elizabeth M. Brydon ◽  
Revital Bronstein ◽  
Adriana Buskin ◽  
Majlinda Lako ◽  
Eric A. Pierce ◽  
...  
Keyword(s):  
Barrier Function ◽  
Vision Loss ◽  
Cell Structure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Photoreceptor Cells ◽  
Good Evidence ◽  
Incomplete Penetrance ◽  
Augmentation Therapy ◽  
Rpe Cells

ABSTRACTRetinitis pigmentosa (RP) is the most common form of inherited vision loss and is characterized by degeneration of retinal photoreceptor cells and the retinal pigment epithelium (RPE). Mutations in pre-mRNA processing factor 31 (PRPF31) cause dominant RP via haploinsufficiency with incomplete penetrance. There is good evidence that the diverse severity of this disease is a result of differing levels of expression of the wild type allele among patients. Thus, we hypothesize that PRPF31-related RP will be amenable to treatment by adeno-associated virus (AAV)-mediated gene augmentation therapy. To test this hypothesis, we used induced pluripotent stem cells (iPSC) with mutations in PRPF31 and differentiated them into RPE cells. The mutant PRPF31 iPSC-RPE cells recapitulate the cellular phenotype associated with the PRPF31 pathology, including defective cell structure, diminished phagocytic function, defects in ciliogenesis, and compromised barrier function. Treatment of the mutant PRPF31 iPSC-RPE cells with AAV-PRPF31 restored normal phagocytosis and cilia formation, and partially restored structure and barrier function. These results provide proof-of concept that AAV-based gene therapy can be used to treat patients with PRPF31-related RP.

scholarly journals CFH loss in human RPE cells leads to inflammation and complement system dysregulation via the NF-ƙB pathway

2021 ◽  
Author(s):  
Angela Armento ◽  
Tiziana Luisa Schmidt ◽  
Inga Sonntag ◽  
David Merle ◽  
Mohamed-ali Jarboui ◽  
...  
Keyword(s):  
Complement System ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Major Pathway ◽  
Rpe Cells ◽  
Age Related

Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease and chronic inflammatory processes may be involved. Besides ageing and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism by which CFH dysregulation confers such a great risk for AMD and its role in RPE cells homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g. IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g. C3, CFB upregulation and C5 downregulation) that are known to play a role in AMD. Moreover, we identified the NF-ƙB pathway as the major pathway involved in the regulation of these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-ƙB pathway work in synergy to maintain inflammatory and complement balance and in case either one of them is dysregulated, the RPE microenvironment changes towards a pro-inflammatory AMD-like phenotype.

scholarly journals Scaffold-Free Retinal Pigment Epithelium Microtissues Exhibit Increased Release of PEDF

2021 ◽  
Vol 22 (21) ◽  
pp. 11317
Author(s):  
Abdullah Al-Ani ◽  
Derek Toms ◽  
Saud Sunba ◽  
Kayla Giles ◽  
Yacine Touahri ◽  
...  
Keyword(s):  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Age Related ◽  
Wide Range ◽  
And Function

The retinal pigmented epithelium (RPE) plays a critical role in photoreceptor survival and function. RPE deficits are implicated in a wide range of diseases that result in vision loss, including age-related macular degeneration (AMD) and Stargardt disease, affecting millions worldwide. Subretinal delivery of RPE cells is considered a promising avenue for treatment, and encouraging results from animal trials have supported recent progression into the clinic. However, the limited survival and engraftment of transplanted RPE cells delivered as a suspension continues to be a major challenge. While RPE delivery as epithelial sheets exhibits improved outcomes, this comes at the price of increased complexity at both the production and transplant stages. In order to combine the benefits of both approaches, we have developed size-controlled, scaffold-free RPE microtissues (RPE-µTs) that are suitable for scalable production and delivery via injection. RPE-µTs retain key RPE molecular markers, and interestingly, in comparison to conventional monolayer cultures, they show significant increases in the transcription and secretion of pigment-epithelium-derived factor (PEDF), which is a key trophic factor known to enhance the survival and function of photoreceptors. Furthermore, these microtissues readily spread in vitro on a substrate analogous to Bruch’s membrane, suggesting that RPE-µTs may collapse into a sheet upon transplantation. We anticipate that this approach may provide an alternative cell delivery system to improve the survival and integration of RPE transplants, while also retaining the benefits of low complexity in production and delivery.

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