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Cells
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Cell Biology of Age-Related Macular Degeneration
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Cell Biology of Age-Related Macular Degeneration

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (25 May 2023) | Viewed by 10594

Special Issue Editor

Dr. Imre Lengyel

E-Mail Website
Guest Editor
The Wellcome-Wolfson Institute, For Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
Interests: retina; pigment epithelium; choroid; drusen; age-related macular degeneration; zinc; mineralisation; calcification; trace elements; Alzheimer's disease; multiple sclerosis; down syndrome; eye imaging

Special Issue Information

Dear Colleagues,

Age-related macular degeneration (AMD) is a complex disease that primarily affects central vision, although peripheral retinal abnormalities are also observed. A variety of cellular changes are involved in the initiation and progression of AMD, and patient-derived cells with a varied genetic background now highlight further complexities. Given the emergence of gene and cell therapy approaches to combat irreversible visual loss, a better understanding of the role different cells play in AMD is paramount.

This Special Issue will focus on cell biology studies on this complex disease. Results on any of the retinal or choroidal cells are welcome as this issue aims to reflect the complexity of AMD through cell biology approaches. We hope that the combination of a variety of original experimental and bioinformatics papers and focused reviews will become a useful resource for developing new approaches to slow the progression or prevent the development of AMD.

Dr. Imre Lengyel
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cell biology of the retinal pigment epithelium and choroidal endothelium
  • mineralisation
  • trace element research
  • translational vision research

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Published Papers (4 papers)

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Research

20 pages, 2293 KiB  
Article
Exploring the Therapeutic Potential of Elastase Inhibition in Age-Related Macular Degeneration in Mouse and Human
by Soumya Navneet, Carlene Brandon, Kit Simpson and Bärbel Rohrer
Cells 2023, 12(9), 1308; https://doi.org/10.3390/cells12091308 - 3 May 2023
Cited by 5 | Viewed by 2537
Abstract
Abnormal turnover of the extracellular matrix (ECM) protein elastin has been linked to AMD pathology. Elastin is a critical component of Bruch’s membrane (BrM), an ECM layer that separates the retinal pigment epithelium (RPE) from the underlying choriocapillaris. Reduced integrity of BrM’s elastin [...] Read more.
Abnormal turnover of the extracellular matrix (ECM) protein elastin has been linked to AMD pathology. Elastin is a critical component of Bruch’s membrane (BrM), an ECM layer that separates the retinal pigment epithelium (RPE) from the underlying choriocapillaris. Reduced integrity of BrM’s elastin layer corresponds to areas of choroidal neovascularization (CNV) in wet AMD. Serum levels of elastin-derived peptides and anti-elastin antibodies are significantly elevated in AMD patients along with the prevalence of polymorphisms of genes regulating elastin turnover. Despite these results indicating significant associations between abnormal elastin turnover and AMD, very little is known about its exact role in AMD pathogenesis. Here we report on results that suggest that elastase enzymes could play a direct role in the pathogenesis of AMD. We found significantly increased elastase activity in the retinas and RPE cells of AMD mouse models, and AMD patient-iPSC-derived RPE cells. A1AT, a protease inhibitor that inactivates elastase, reduced CNV lesion sizes in mouse models. A1AT completely inhibited elastase-induced VEGFA expression and secretion, and restored RPE monolayer integrity in ARPE-19 monolayers. A1AT also mitigated RPE thickening, an early AMD phenotype, in HTRA1 overexpressing mice, HTRA1 being a serine protease with elastase activity. Finally, in an exploratory study, examining archival records from large patient data sets, we identified an association between A1AT use, age and AMD risk. Our results suggest that repurposing A1AT may have therapeutic potential in modifying the progression to AMD. Full article
(This article belongs to the Special Issue Cell Biology of Age-Related Macular Degeneration)
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25 pages, 3282 KiB  
Article
Zinc Supplementation Induced Transcriptional Changes in Primary Human Retinal Pigment Epithelium: A Single-Cell RNA Sequencing Study to Understand Age-Related Macular Degeneration
by Eszter Emri, Oisin Cappa, Caoimhe Kelly, Elod Kortvely, John Paul SanGiovanni, Brian S. McKay, Arthur A. Bergen, David A. Simpson and Imre Lengyel
Cells 2023, 12(5), 773; https://doi.org/10.3390/cells12050773 - 28 Feb 2023
Cited by 1 | Viewed by 2783
Abstract
Zinc supplementation has been shown to be beneficial to slow the progression of age-related macular degeneration (AMD). However, the molecular mechanism underpinning this benefit is not well understood. This study used single-cell RNA sequencing to identify transcriptomic changes induced by zinc supplementation. Human [...] Read more.
Zinc supplementation has been shown to be beneficial to slow the progression of age-related macular degeneration (AMD). However, the molecular mechanism underpinning this benefit is not well understood. This study used single-cell RNA sequencing to identify transcriptomic changes induced by zinc supplementation. Human primary retinal pigment epithelial (RPE) cells could mature for up to 19 weeks. After 1 or 18 weeks in culture, we supplemented the culture medium with 125 µM added zinc for one week. RPE cells developed high transepithelial electrical resistance, extensive, but variable pigmentation, and deposited sub-RPE material similar to the hallmark lesions of AMD. Unsupervised cluster analysis of the combined transcriptome of the cells isolated after 2, 9, and 19 weeks in culture showed considerable heterogeneity. Clustering based on 234 pre-selected RPE-specific genes divided the cells into two distinct clusters, we defined as more and less differentiated cells. The proportion of more differentiated cells increased with time in culture, but appreciable numbers of cells remained less differentiated even at 19 weeks. Pseudotemporal ordering identified 537 genes that could be implicated in the dynamics of RPE cell differentiation (FDR < 0.05). Zinc treatment resulted in the differential expression of 281 of these genes (FDR < 0.05). These genes were associated with several biological pathways with modulation of ID1/ID3 transcriptional regulation. Overall, zinc had a multitude of effects on the RPE transcriptome, including several genes involved in pigmentation, complement regulation, mineralization, and cholesterol metabolism processes associated with AMD. Full article
(This article belongs to the Special Issue Cell Biology of Age-Related Macular Degeneration)
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18 pages, 2270 KiB  
Article
Relative Leukocyte Telomere Length and Genetic Variants in Telomere-Related Genes and Serum Levels Role in Age-Related Macular Degeneration
by Alvita Vilkeviciute, Greta Gedvilaite, Mantas Banevicius, Loresa Kriauciuniene, Dalia Zaliuniene, Olivija Dobiliene and Rasa Liutkeviciene
Cells 2022, 11(23), 3847; https://doi.org/10.3390/cells11233847 - 30 Nov 2022
Cited by 2 | Viewed by 1565
Abstract
Telomere shortening is well known to be associated with ageing. Age is the most decisive risk factor for age-related macular degeneration (AMD) development. The older the individual, the higher the AMD risk. For this reason, we aimed to find any associations between telomere [...] Read more.
Telomere shortening is well known to be associated with ageing. Age is the most decisive risk factor for age-related macular degeneration (AMD) development. The older the individual, the higher the AMD risk. For this reason, we aimed to find any associations between telomere length, distribution of genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TRF2, and TNKS2), and serum TERF-1 and TERF2 levels on AMD development. Methods: Our study enrolled 342 patients with AMD and 177 healthy controls. Samples of DNA from peripheral blood leukocytes were extracted by DNA salting-out method. The genotyping of TERT rs2736098, rs401681 in TERT-CLPTM1 locus, TRF1 rs1545827, rs10107605, TNKS2 rs10509637, rs10509639, and TRF2 rs251796 and relative leukocyte telomere length (T/S) measurement were carried out using the real-time polymerase chain reaction method. Serum TERF-1 and TERF2 levels were measured by enzymatic immunoassay (ELISA). Results: We found longer telomeres in early AMD patients compared to the control group. Additionally, we revealed that minor allele C at TRF1 rs10107605 was associated with decreases the odds of both early and exudative AMD. Each minor allele G at TRF2 rs251796 and TRF1 rs1545827 C/T genotype and C/T+T/T genotypes, compared to the C/C genotype, increases the odds of having shorter telomeres. Furthermore, we found elevated TERF1 serum levels in the early AMD group compared to the control group. Conclusions: In conclusion, these results suggest that relative leukocyte telomere length and genetic variants of TRF1 and TRF2 play a role in AMD development. Additionally, TERF1 is likely to be associated with early AMD. Full article
(This article belongs to the Special Issue Cell Biology of Age-Related Macular Degeneration)
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16 pages, 1432 KiB  
Article
Retinal Pigment Epithelium-Secreted VEGF-A Induces Alpha-2-Macroglobulin Expression in Endothelial Cells
by Guillermo L. Lehmann, Michael Ginsberg, Daniel J. Nolan, Cristina Rodríguez, José Martínez-González, Shemin Zeng, Andrew P. Voigt, Robert F. Mullins, Shahin Rafii, Enrique Rodriguez-Boulan and Ignacio Benedicto
Cells 2022, 11(19), 2975; https://doi.org/10.3390/cells11192975 - 24 Sep 2022
Cited by 4 | Viewed by 2765
Abstract
Alpha-2-macroglobulin (A2M) is a protease inhibitor that regulates extracellular matrix (ECM) stability and turnover. Here, we show that A2M is expressed by endothelial cells (ECs) from human eye choroid. We demonstrate that retinal pigment epithelium (RPE)-conditioned medium induces A2M expression specifically in ECs. [...] Read more.
Alpha-2-macroglobulin (A2M) is a protease inhibitor that regulates extracellular matrix (ECM) stability and turnover. Here, we show that A2M is expressed by endothelial cells (ECs) from human eye choroid. We demonstrate that retinal pigment epithelium (RPE)-conditioned medium induces A2M expression specifically in ECs. Experiments using chemical inhibitors, blocking antibodies, and recombinant proteins revealed a key role of VEGF-A in RPE-mediated A2M induction in ECs. Furthermore, incubation of ECs with RPE-conditioned medium reduces matrix metalloproteinase-2 gelatinase activity of culture supernatants, which is partially restored after A2M knockdown in ECs. We propose that dysfunctional RPE or choroidal blood vessels, as observed in retinal diseases such as age-related macular degeneration, may disrupt the crosstalk mechanism we describe here leading to alterations in the homeostasis of choroidal ECM, Bruch’s membrane and visual function. Full article
(This article belongs to the Special Issue Cell Biology of Age-Related Macular Degeneration)
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