title: Quantitative metabolomics of photoreceptor degeneration and the effects of stem cell-derived retinal pigment epithelium transplantation.
abstract: Photoreceptor degeneration is characteristic of vision-threatening diseases including age-related macular degeneration. Photoreceptors are metabolically demanding cells in the retina, but specific details about their metabolic behaviours are unresolved. The quantitative metabolomics of retinal degeneration could provide valuable insights and inform future therapies. Here, we determined the metabolomic 'fingerprint' of healthy and dystrophic retinas in rat models using optimized metabolite extraction techniques. A number of classes of metabolites were consistently dysregulated during degeneration: vitamin A analogues, fatty acid amides, long-chain polyunsaturated fatty acids, acyl carnitines and several phospholipid species. For the first time, a distinct temporal trend of several important metabolites including DHA (4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid), all-trans-retinal and its toxic end-product N-retinyl-N-retinylidene-ethanolamine were observed between healthy and dystrophic retinas. In this study, metabolomics was further used to determine the temporal effects of the therapeutic intervention of grafting stem cell-derived retinal pigment epithelium (RPE) in dystrophic retinas, which significantly prevented photoreceptor atrophy in our previous studies. The result revealed that lipid levels such as phosphatidylethanolamine in eyes were restored in those animals receiving the RPE grafts. In conclusion, this study provides insight into the metabolomics of retinal degeneration, and further understanding of the efficacy of RPE transplantation.This article is part of the themed issue 'Quantitative mass spectrometry'.
authors.affiliation: Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Junhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA The Lowy Medical Research Institute, 3366 N. Torrey Pines Court, Suite 300, La Jolla, CA 92037, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Westenskow
authors.affiliation: Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA School of Civil and Environmental Engineering, Nanyang Technological University, Singapore.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA friedlan@scripps.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
authors.affiliation: Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA siuzdak@scripps.edu.
authors.forename: Gary
authors.identifier: http://orcid.org/0000-0002-4749-0014
authors.initials: G
authors.lastname: Siuzdak
mesh_terms: D000818:Animals; D055432:Metabolomics; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000637:transplantation*; D012172:Retinaldehyde / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
chemical_list: D012172:Retinaldehyde
keywords: bioinformatics; cell-based therapy; lipidomics; metabolomics; retinal degeneration; stem cell-derived retinal pigment epithelium