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An in vitro model of chronic wounding and its implication for age-related macular degeneration

Bailey-Steinitz, LJ; Shih, Y-H; Radeke, MJ; Coffey, PJ; (2020) An in vitro model of chronic wounding and its implication for age-related macular degeneration. PLoS ONE , 15 (7) 10.1371/journal.pone.0236298. Green open access

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Abstract

Degeneration of the retinal pigment epithelium (RPE) plays a central role in age-related macular degeneration (AMD). Throughout life, RPE cells are challenged by a variety of cytotoxic stressors, some of which are cumulative with age and may ultimately contribute to drusen and lipofuscin accumulation. Stressors such as these continually damage RPE cells resulting in a state of chronic wounding. Current cell-based platforms that model a state of chronic RPE cell wounding are limited, and the RPE cellular response is not entirely understood. Here, we used the electric cell-substrate impedance sensing (ECIS) system to induce a state of acute or chronic wounding on differentiated human fetal RPE cells to analyze changes in the wound repair response. RPE cells surrounding the lesioned area employ both cell migration and proliferation to repair wounds but fail to reestablish their original cell morphology or density after repetitive wounding. Chronically wounded RPE cells develop phenotypic AMD characteristics such as loss of cuboidal morphology, enlarged size, and multinucleation. Transcriptomic analysis suggests a systemic misregulation of RPE cell functions in bystander cells, which are not directly adjacent to the wound. Genes associated with the major RPE cell functions (LRAT, MITF, RDH11) significantly downregulate after wounding, in addition to differential expression of genes associated with the cell cycle (CDK1, CDC6, CDC20), inflammation (IL-18, CCL2), and apoptosis (FAS). Interestingly, repetitive wounding resulted in prolonged misregulation of genes, including FAS, LRAT, and PEDF. The use of ECIS to induce wounding resulted in an over-representation of AMD-associated genes among those dysregulated genes, particularly genes associated with advanced AMD. This simple system provides a new model for further investigation of RPE cell wound response in AMD pathogenesis.

Type: Article
Title: An in vitro model of chronic wounding and its implication for age-related macular degeneration
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0236298
Publisher version: http://dx.doi.org/10.1371/journal.pone.0236298
Language: English
Additional information: Copyright: © 2020 Bailey-Steinitz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: RETINAL-PIGMENT EPITHELIUM, ENDOTHELIAL GROWTH-FACTOR, GEOGRAPHIC ATROPHY, OXIDATIVE STRESS, CELLS, EXPRESSION, SECRETION, CULTURE, DRUSEN, INFLAMMATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10128212
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