Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model

Age-related Macular degeneration (AMD) is a degenerative disease of the macula affecting the elderly population. Treatment options are limited, partly due to the lack of understanding of AMD pathology and the lack of suitable research models that replicate the complexity of the human macula and the...

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Autores principales:	Angela Armento, Aparna Murali, Julia Marzi, Ana C Almansa-Garcia, Blanca Arango-Gonzalez, Ellen Kilger, Simon J Clark, Katja Schenke-Layland, Charmaine A Ramlogan-Steel, Jason C Steel, Marius Ueffing
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	age-related macular degeneration (AMD) complement factor H (CFH) retinal pigment epithelium (RPE) cells retinal degeneration co-culture porcine retinal explants Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/536089fdaf7f41d9979efdbcd4ffd47f
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spelling	oai:doaj.org-article:536089fdaf7f41d9979efdbcd4ffd47f2021-11-25T16:52:56ZComplement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model10.3390/biom111116212218-273Xhttps://doaj.org/article/536089fdaf7f41d9979efdbcd4ffd47f2021-11-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1621https://doaj.org/toc/2218-273XAge-related Macular degeneration (AMD) is a degenerative disease of the macula affecting the elderly population. Treatment options are limited, partly due to the lack of understanding of AMD pathology and the lack of suitable research models that replicate the complexity of the human macula and the intricate interplay of the genetic, aging and lifestyle risk factors contributing to AMD. One of the main genetic risks associated with AMD is located on the Complement Factor H (<i>CFH</i>) gene, leading to an amino acid substitution in the Factor H (FH) protein (Y402H). However, the mechanism of how this FH variant promotes the onset of AMD remains unclear. Previously, we have shown that FH deprivation in RPE cells, via <i>CFH</i> silencing, leads to increased inflammation, metabolic impairment and vulnerability toward oxidative stress. In this study, we established a novel co-culture model comprising <i>CFH</i> silenced RPE cells and porcine retinal explants derived from the visual streak of porcine eyes, which closely resemble the human macula. We show that retinae exposed to FH-deprived RPE cells show signs of retinal degeneration, with rod cells being the first cells to undergo degeneration. Moreover, via Raman analyses, we observed changes involving the mitochondria and lipid composition of the co-cultured retinae upon FH loss. Interestingly, the detrimental effects of FH loss in RPE cells on the neuroretina were independent of glial cell activation and external complement sources. Moreover, we show that the co-culture model is also suitable for human retinal explants, and we observed a similar trend when RPE cells deprived of FH were co-cultured with human retinal explants from a single donor eye. Our findings highlight the importance of RPE-derived FH for retinal homeostasis and provide a valuable model for AMD research.Angela ArmentoAparna MuraliJulia MarziAna C Almansa-GarciaBlanca Arango-GonzalezEllen KilgerSimon J ClarkKatja Schenke-LaylandCharmaine A Ramlogan-SteelJason C SteelMarius UeffingMDPI AGarticleage-related macular degeneration (AMD)complement factor H (CFH)retinal pigment epithelium (RPE) cellsretinal degenerationco-cultureporcine retinal explantsMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1621, p 1621 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	age-related macular degeneration (AMD) complement factor H (CFH) retinal pigment epithelium (RPE) cells retinal degeneration co-culture porcine retinal explants Microbiology QR1-502
spellingShingle	age-related macular degeneration (AMD) complement factor H (CFH) retinal pigment epithelium (RPE) cells retinal degeneration co-culture porcine retinal explants Microbiology QR1-502 Angela Armento Aparna Murali Julia Marzi Ana C Almansa-Garcia Blanca Arango-Gonzalez Ellen Kilger Simon J Clark Katja Schenke-Layland Charmaine A Ramlogan-Steel Jason C Steel Marius Ueffing Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model
description	Age-related Macular degeneration (AMD) is a degenerative disease of the macula affecting the elderly population. Treatment options are limited, partly due to the lack of understanding of AMD pathology and the lack of suitable research models that replicate the complexity of the human macula and the intricate interplay of the genetic, aging and lifestyle risk factors contributing to AMD. One of the main genetic risks associated with AMD is located on the Complement Factor H (<i>CFH</i>) gene, leading to an amino acid substitution in the Factor H (FH) protein (Y402H). However, the mechanism of how this FH variant promotes the onset of AMD remains unclear. Previously, we have shown that FH deprivation in RPE cells, via <i>CFH</i> silencing, leads to increased inflammation, metabolic impairment and vulnerability toward oxidative stress. In this study, we established a novel co-culture model comprising <i>CFH</i> silenced RPE cells and porcine retinal explants derived from the visual streak of porcine eyes, which closely resemble the human macula. We show that retinae exposed to FH-deprived RPE cells show signs of retinal degeneration, with rod cells being the first cells to undergo degeneration. Moreover, via Raman analyses, we observed changes involving the mitochondria and lipid composition of the co-cultured retinae upon FH loss. Interestingly, the detrimental effects of FH loss in RPE cells on the neuroretina were independent of glial cell activation and external complement sources. Moreover, we show that the co-culture model is also suitable for human retinal explants, and we observed a similar trend when RPE cells deprived of FH were co-cultured with human retinal explants from a single donor eye. Our findings highlight the importance of RPE-derived FH for retinal homeostasis and provide a valuable model for AMD research.
format	article
author	Angela Armento Aparna Murali Julia Marzi Ana C Almansa-Garcia Blanca Arango-Gonzalez Ellen Kilger Simon J Clark Katja Schenke-Layland Charmaine A Ramlogan-Steel Jason C Steel Marius Ueffing
author_facet	Angela Armento Aparna Murali Julia Marzi Ana C Almansa-Garcia Blanca Arango-Gonzalez Ellen Kilger Simon J Clark Katja Schenke-Layland Charmaine A Ramlogan-Steel Jason C Steel Marius Ueffing
author_sort	Angela Armento
title	Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model
title_short	Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model
title_full	Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model
title_fullStr	Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model
title_full_unstemmed	Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model
title_sort	complement factor h loss in rpe cells causes retinal degeneration in a human rpe-porcine retinal explant co-culture model
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/536089fdaf7f41d9979efdbcd4ffd47f
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Complement Factor H Loss in RPE Cells Causes Retinal Degeneration in a Human RPE-Porcine Retinal Explant Co-Culture Model

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