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16 pages, 7673 KiB

Open AccessArticle

Transcriptional and Distributional Profiling of Microglia in Retinal Angiomatous Proliferation

by Anja Schlecht, Julian Wolf, Stefaniya Boneva, Gabriele Prinz, Barbara M. Braunger, Peter Wieghofer, Hansjürgen Agostini, Günther Schlunck and Clemens Lange

Int. J. Mol. Sci. 2022, 23(7), 3443; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073443 - 22 Mar 2022

Cited by 2 | Viewed by 1825

Abstract

Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC [...] Read more.

Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC to the myeloid cell pool at RAP sites and their exact functions remain unknown. In this study, we combined a microglia-specific reporter mouse line with a mouse model for RAP to identify the contribution of MG and MAC to myeloid cell accumulation at RAP and determined the transcriptional profile of MG using RNA sequencing. We found that MG are the most abundant myeloid cell population around RAP, whereas MAC are rarely, if ever, associated with late stages of RAP. RNA sequencing of RAP-associated MG showed that differentially expressed genes mainly contribute to immune-associated processes, including chemotaxis and migration in early RAP and proliferative capacity in late RAP, which was confirmed by immunohistochemistry. Interestingly, MG upregulated only a few angiomodulatory factors, suggesting a rather low angiogenic potential. In summary, we showed that MG are the dominant myeloid cell population at RAP sites. Moreover, MG significantly altered their transcriptional profile during RAP formation, activating immune-associated processes and exhibiting enhanced proliferation, however, without showing substantial upregulation of angiomodulatory factors. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 3.0)

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20 pages, 35194 KiB

Open AccessArticle

Regulation of ABCA1 by AMD-Associated Genetic Variants and Hypoxia in iPSC-RPE

by Florian Peters, Lynn J. A. Ebner, David Atac, Jordi Maggi, Wolfgang Berger, Anneke I. den Hollander and Christian Grimm

Int. J. Mol. Sci. 2022, 23(6), 3194; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063194 - 16 Mar 2022

Cited by 8 | Viewed by 3430

Abstract

Age-related macular degeneration (AMD) is a progressive disease of the macula characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor degeneration, leading to severe vision loss at advanced stages in the elderly population. Impaired reverse cholesterol transport (RCT) as well as [...] Read more.

Age-related macular degeneration (AMD) is a progressive disease of the macula characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor degeneration, leading to severe vision loss at advanced stages in the elderly population. Impaired reverse cholesterol transport (RCT) as well as intracellular lipid accumulation in the RPE are implicated in AMD pathogenesis. Here, we focus on ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transport protein in the RPE, and analyze conditions that lead to ABCA1 dysregulation in induced pluripotent stem cell (iPSC)-derived RPE cells (iRPEs). Our results indicate that the risk-conferring alleles rs1883025 (C) and rs2740488 (A) in ABCA1 are associated with increased ABCA1 mRNA and protein levels and reduced efficiency of cholesterol efflux from the RPE. Hypoxia, an environmental risk factor for AMD, reduced expression of ABCA1 and increased intracellular lipid accumulation. Treatment with a liver X receptor (LXR) agonist led to an increase in ABCA1 expression and reduced lipid accumulation. Our data strengthen the homeostatic role of cholesterol efflux in the RPE and suggest that increasing cellular cholesterol export by stimulating ABCA1 expression might lessen lipid load, improving RPE survival and reducing the risk of developing AMD. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 3.0)

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15 pages, 20258 KiB

Open AccessArticle

Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

by Anja Schlecht, Adrian Thien, Julian Wolf, Gabriele Prinz, Hansjürgen Agostini, Günther Schlunck, Peter Wieghofer, Stefaniya Boneva and Clemens Lange

Int. J. Mol. Sci. 2021, 22(24), 13318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413318 - 10 Dec 2021

Cited by 8 | Viewed by 3053

Abstract

Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1 [...] Read more.

Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1^GFP^/+ mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 3.0)

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17 pages, 1833 KiB

Open AccessArticle

Differential Circulating MicroRNA Expression in Age-Related Macular Degeneration

by Hanan ElShelmani, Ian Brennan, David J. Kelly and David Keegan

Int. J. Mol. Sci. 2021, 22(22), 12321; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212321 - 15 Nov 2021

Cited by 7 | Viewed by 2313

Abstract

This study explored the expression of several miRNAs reported to be deregulated in age-related macular degeneration (AMD). Total RNA was isolated from sera from patients with dry AMD (n = 12), wet AMD (n = 14), and controls (n = [...] Read more.

This study explored the expression of several miRNAs reported to be deregulated in age-related macular degeneration (AMD). Total RNA was isolated from sera from patients with dry AMD (n = 12), wet AMD (n = 14), and controls (n = 10). Forty-two previously investigated miRNAs were selected based on published data and their role in AMD pathogenesis, such as angiogenic and inflammatory effects, and were co-analysed using a miRCURY LNA miRNA SYBR^® Green PCR kit via quantitative real-time polymerase chain reaction (qRT-PCR) to validate their presence. Unsupervised hierarchical clustering indicated that AMD serum specimens have a different miRNA profile to healthy controls. We successfully validated the differentially regulated miRNAs in serum from AMD patients versus controls. Eight miRNAs (hsa-let-7a-5p, hsa-let-7d-5p, hsa-miR-23a-3p, hsa-miR-301a-3p, hsa-miR-361-5p, hsa-miR-27b-3p, hsa-miR-874-3p, hsa-miR-19b-1-5p) showed higher expression in the serum of dry AMD patients than wet AMD patients and compared with healthy controls. Increased quantities of certain miRNAs in the serum of AMD patients indicate that these miRNAs could potentially serve as diagnostic AMD biomarkers and might be used as future AMD treatment targets. The discovery of significant serum miRNA biomarkers in AMD patients would provide an easy screening tool for at-risk populations. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 3.0)

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13 pages, 2207 KiB

Open AccessArticle

A Novel Method of Mouse RPE Explant Culture and Effective Introduction of Transgenes Using Adenoviral Transduction for In Vitro Studies in AMD

by Peng Shang, Nadezda A. Stepicheva, Haitao Liu, Olivia Chowdhury, Jonathan Franks, Ming Sun, Stacey Hose, Sayan Ghosh, Meysam Yazdankhah, Anastasia Strizhakova, Donna Beer Stolz, J. Samuel Zigler, Jr. and Debasish Sinha

Int. J. Mol. Sci. 2021, 22(21), 11979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111979 - 05 Nov 2021

Cited by 4 | Viewed by 2905

Abstract

Degeneration of retinal pigment epithelium (RPE) is one of the most critical phenotypic changes of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. While cultured polarized RPE cells with original properties are valuable in in vitro models to [...] Read more.

Degeneration of retinal pigment epithelium (RPE) is one of the most critical phenotypic changes of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. While cultured polarized RPE cells with original properties are valuable in in vitro models to study RPE biology and the consequences of genetic and/or pharmacological manipulations, the procedure to establish mouse primary PRE cell culture or pluripotent stem cell-derived RPE cells is time-consuming and yields a limited number of cells. Thus, establishing a mouse in situ RPE culture system is highly desirable. Here we describe a novel and efficient method for RPE explant culture that allows for obtaining biologically relevant RPE cells in situ. These RPE explants (herein referred to as RPE flatmounts) are viable in culture for at least 7 days, can be efficiently transduced with adenoviral constructs, and/or treated with a variety of drugs/chemicals followed by downstream analysis of the signaling pathways/biological processes of interest, such as assessment of the autophagy flux, inflammatory response, and receptor tyrosine kinases stimulation. This method of RPE explant culture is highly beneficial for pharmacological and mechanistic studies in the field of RPE biology and AMD research. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 3.0)

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19 pages, 3869 KiB

Open AccessArticle

VEGF-R2/Caveolin-1 Pathway of Undifferentiated ARPE-19 Retina Cells: A Potential Target as Anti-VEGF-A Therapy in Wet AMD by Resvega, an Omega-3/Polyphenol Combination

by Flavie Courtaut, Alessandra Scagliarini, Virginie Aires, Clarisse Cornebise, Jean-Paul Pais de Barros, Céline Olmiere and Dominique Delmas

Int. J. Mol. Sci. 2021, 22(12), 6590; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126590 - 19 Jun 2021

Cited by 8 | Viewed by 2773

Abstract

Age-related macular degeneration (AMD) is one of the main causes of deterioration in vision in adults aged 55 and older. In spite of therapies, the progression of the disease is often observed without reverse vision quality. In the present study, we explored whether, [...] Read more.

Age-related macular degeneration (AMD) is one of the main causes of deterioration in vision in adults aged 55 and older. In spite of therapies, the progression of the disease is often observed without reverse vision quality. In the present study, we explored whether, in undifferentiated ARPE-19 retinal cells, a disruption of the VEGF receptors (VEGF-R)/caveolin-1 (Cav-1)/protein kinases pathway could be a target for counteracting VEGF secretion. We highlight that Resvega^®, a combination of omega-3 fatty acids with an antioxidant, resveratrol, inhibits VEGF-A secretion in vitro by disrupting the dissociation of the VEGF-R2/Cav-1 complex into rafts and subsequently preventing MAPK activation. Moreover, DNA ChIP analysis reveals that this combination prevents the interaction between AP-1 and vegf-a and vegf-r2 gene promoters. By these pathways, Resvega could present a potential interest as nutritional complementation against AMD. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 3.0)

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Review

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14 pages, 752 KiB

Open AccessReview

The Role of Dysregulated miRNAs in the Pathogenesis, Diagnosis and Treatment of Age-Related Macular Degeneration

by Karolina Urbańska, Piotr Witold Stępień, Katarzyna Natalia Nowakowska, Martyna Stefaniak, Natalia Osial, Tomasz Chorągiewicz, Mario Damiano Toro, Katarzyna Nowomiejska and Robert Rejdak

Int. J. Mol. Sci. 2022, 23(14), 7761; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147761 - 14 Jul 2022

Cited by 8 | Viewed by 2030

Abstract

Age-related macular degeneration (AMD) is an eye disease causing damage to the macular region of the retina where most of the photoreceptors responsible for central visual acuity are located. MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that negatively regulate genes by silent [...] Read more.

Age-related macular degeneration (AMD) is an eye disease causing damage to the macular region of the retina where most of the photoreceptors responsible for central visual acuity are located. MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that negatively regulate genes by silent post-transcriptional gene expressions. Previous studies have shown that changes in specific miRNAs are involved in the pathogenesis of eye diseases, including AMD. Altered expressions of miRNAs are related to disturbances of regulating oxidative stress, inflammation, angiogenesis, apoptosis and phagocytosis, which are known factors in the pathogenesis of AMD. Moreover, dysregulation of miRNA is involved in drusen formation. Thus, miRNAs may be used as potential molecular biomarkers for the disease and, furthermore, tailoring therapeutics to particular disturbances in miRNAs may, in the future, offer hope to prevent irreversible vision loss. In this review, we clarify the current state of knowledge about the influence of miRNA on the pathogenesis, diagnosis and treatment of AMD. Our study material consisted of publications, which were found in PubMed, Google Scholar and Embase databases using “Age-related macular degeneration”, “miRNA”, “AMD biomarkers”, “miRNA therapeutics” and “AMD pathogenesis” as keywords. Paper search was limited to articles published from 2011 to date. In the section “Retinal, circulating and vitreous body miRNAs found in human studies”, we limited the search to studies with patients published in 2016–2021. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 3.0)

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23 pages, 631 KiB

Open AccessReview

Exudative versus Nonexudative Age-Related Macular Degeneration: Physiopathology and Treatment Options

by Ana Rita Fernandes, Aleksandra Zielińska, Elena Sanchez-Lopez, Tiago dos Santos, Maria Luisa Garcia, Amelia M. Silva, Jacek Karczewski and Eliana B. Souto

Int. J. Mol. Sci. 2022, 23(5), 2592; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052592 - 26 Feb 2022

Cited by 28 | Viewed by 5695

Abstract

Age-related macular degeneration (AMD) is an eye disease typically associated with the aging and can be classified into two types—namely, the exudative and the nonexudative AMD. Currently available treatments for exudative AMD use intravitreal injections, which are associated with high risk of infection [...] Read more.

Age-related macular degeneration (AMD) is an eye disease typically associated with the aging and can be classified into two types—namely, the exudative and the nonexudative AMD. Currently available treatments for exudative AMD use intravitreal injections, which are associated with high risk of infection that can lead to endophthalmitis, while no successful treatments yet exist for the nonexudative form of AMD. In addition to the pharmacologic therapies administered by intravitreal injection already approved by the Food and Drug Administration (FDA) in exudative AMD, there are some laser treatments approved that can be used in combination with the pharmacological therapies. In this review, we discuss the latest developments of treatment options for AMD. Relevant literature available from 1993 was used, which included original articles and reviews available in PubMed database and also information collected from Clinical Trials Gov website using “age-related macular degeneration” and “antiangiogenic therapies” as keywords. The clinical trials search was limited to ongoing trials from 2015 to date. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 3.0)

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