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Complement factor H loss in RPE cells causes retinal degeneration in a human RPE-porcine retinal explant co-culture model

journal contribution
posted on 14.11.2021, 22:44 by Angela Armento, Aparna Murali, Julia Marzi, Ana C Almansa-Garcia, Blanca Arango-Gonzalez, Ellen Kilger, Simon J Clark, Katja Schenke-Layland, Charmaine Ramlogan-SteelCharmaine Ramlogan-Steel, Jason SteelJason Steel, Marius Ueffing
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 (CFH) 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 CFH silencing, leads to increased inflammation, metabolic impairment and vulnerability toward oxidative stress. In this study, we established a novel co-culture model comprising CFH 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 involv-ing 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 high-light the importance of RPE-derived FH for retinal homeostasis and provide a valuable model for AMD research.

History

Volume

11

Issue

11

Start Page

1

End Page

19

Number of Pages

19

eISSN

2218-273X

Publisher

MDPI

Additional Rights

CC BY 4.0

Language

en

Peer Reviewed

Yes

Open Access

Yes

Acceptance Date

29/10/2021

External Author Affiliations

Eberhard Karls University of Tübingen,

Era Eligible

Yes

Journal

Biomolecules

Article Number

1621