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      Autofluorescent Granules of the Human Retinal Pigment Epithelium: Phenotypes, Intracellular Distribution, and Age-Related Topography

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          Abstract

          Purpose

          The human retinal pigment epithelium (RPE) accumulates granules significant for autofluorescence imaging. Knowledge of intracellular accumulation and distribution is limited. Using high-resolution microscopy techniques, we determined the total number of granules per cell, intracellular distribution, and changes related to retinal topography and age.

          Methods

          RPE cells from the fovea, perifovea, and near-periphery of 15 human RPE flat mounts were imaged using structured illumination microscopy (SIM) and confocal fluorescence microscopy in young (≤51 years, n = 8) and older (>80 years, n = 7) donors. Using custom FIJI plugins, granules were marked with computer assistance, classified based on morphological and autofluorescence properties, and analyzed with regard to intracellular distribution, total number per cell, and granule density.

          Results

          A total of 193,096 granules in 450 RPE cell bodies were analyzed. Based on autofluorescence properties, size, and composition, the RPE granules exhibited nine different phenotypes (lipofuscin, two; melanolipofuscin, five; melanosomes, two), distinguishable by SIM. Overall, lipofuscin (low at the fovea but increases with eccentricity and age) and melanolipofuscin (equally distributed at all three locations with no age-related changes) were the major granule types. Melanosomes were under-represented due to suboptimal visualization of apical processes in flat mounts.

          Conclusions

          Low lipofuscin and high melanolipofuscin content within foveal RPE cell bodies and abundant lipofuscin at the perifovea suggest a different genesis, plausibly related to the population of overlying photoreceptors (fovea, cones only; perifovea, highest rod density). This systematic analysis provides further insight into RPE cell and granule physiology and links granule load to cell autofluorescence, providing a subcellular basis for the interpretation of clinical fundus autofluorescence.

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          Near-infrared autofluorescence imaging of the fundus: visualization of ocular melanin.

          François C Delori, Claudia Keilhauer (2006)
          To evaluate the origin of the near-infrared autofluorescence (AF) of the fundus detected by scanning laser ophthalmoscopy and compare the distribution of this AF with that of lipofuscin. AF [787] fundus images (excitation [Exc.] 787 nm; emission [Emi.] >800 nm) were recorded with a confocal scanning laser ophthalmoscope, in 85 normal subjects (ages: 11-77 years) and in 25 patients with AMD and other retinal diseases. Standard AF [488] images (Exc. 488 nm; Emi. >500 nm) were recorded in a subset of the population. The fovea exhibits higher AF[787] than the perifovea in an area approximately 8 degrees in diameter, roughly equivalent to the area of higher RPE melanin seen in AF[488] and color images. The ratio of foveal to perifoveal AF[787] decreases with age (P < 0.0001) and is higher in subjects with light irides (P = 0.04). Higher AF[787] emanates from hyperpigmentation, from the choroidal pigment (nevi, outer layers) and from the pigment epithelium and stroma of the iris. Low AF[787] is observed in geographic atrophy particularly in subjects with light irides. AF[787] originates from the RPE and to a varying degree from the choroid. Oxidized melanin, or compounds closely associated with melanin, contributes substantially to this AF, but other fluorophores cannot be excluded at this stage. Confocal AF[787] imaging may provide a new modality to visualize pathologic features of the RPE and the choroid, and, together with AF[488] imaging, offers a new tool to study biological changes associated with aging of the RPE and pathology.
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            Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium.

            Thomas Ach, Carrie Huisingh, Gerald McGwin … (2014)
            Lipofuscin (LF) accumulation within RPE cells is considered pathogenic in AMD. To test whether LF contributes to RPE cell loss in aging and to provide a cellular basis for fundus autofluorescence (AF) we created maps of human RPE cell number and histologic AF.
            Article 0 comments Cited 92 times – based on 0 reviews     Review now
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              The cone-specific visual cycle.

              Jin-Shan Wang, Vladimir J. Kefalov (2011)
              Cone photoreceptors mediate our daytime vision and function under bright and rapidly-changing light conditions. As their visual pigment is destroyed in the process of photoactivation, the continuous function of cones imposes the need for rapid recycling of their chromophore and regeneration of their pigment. The canonical retinoid visual cycle through the retinal pigment epithelium cells recycles chromophore and supplies it to both rods and cones. However, shortcomings of this pathway, including its slow rate and competition with rods for chromophore, have led to the suggestion that cones might use a separate mechanism for recycling of chromophore. In the past four decades biochemical studies have identified enzymatic activities consistent with recycling chromophore in the retinas of cone-dominant animals, such as chicken and ground squirrel. These studies have led to the hypothesis of a cone-specific retina visual cycle. The physiological relevance of these studies was controversial for a long time and evidence for the function of this visual cycle emerged only in very recent studies and will be the focus of this review. The retina visual cycle supplies chromophore and promotes pigment regeneration only in cones but not in rods. This pathway is independent of the pigment epithelium and instead involves the Müller cells in the retina, where chromophore is recycled and supplied selectively to cones. The rapid supply of chromophore through the retina visual cycle is critical for extending the dynamic range of cones to bright light and for their rapid dark adaptation following exposure to light. The importance of the retina visual cycle is emphasized also by its preservation through evolution as its function has now been demonstrated in species ranging from salamander to zebrafish, mouse, primate, and human. Copyright © 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Invest Ophthalmol Vis Sci
                Journal ID (iso-abbrev): Invest. Ophthalmol. Vis. Sci
                Journal ID (pmc): iovs
                Journal ID (publisher-id): IOVS
                Title: Investigative Ophthalmology & Visual Science
                Publisher: The Association for Research in Vision and Ophthalmology
                ISSN (Print): 0146-0404
                ISSN (Electronic): 1552-5783
                Publication date (Electronic): 20 May 2020
                Publication date Collection: May 2020
                Volume: 61
                Issue: 5
                Electronic Location Identifier: 35
                Affiliations
                [ 1 ]Department of Ophthalmology, University Hospital Würzburg, Würzburg, Germany
                [ 2 ]Leibniz Institute of Photonic Technology, Jena, Germany
                [ 3 ]Institute of Physical Chemistry and Abbe Center of Photonics, Friedrich-Schiller University Jena, Jena, Germany
                [ 4 ]Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama, United States
                Author notes
                Correspondence: Thomas Ach, Department of Ophthalmology, University Hospital Würzburg, Josef Schneider Strasse 11, 97080 Würzburg, Germany; thomas.ach@ 123456ukbonn.de.
                Article
                Publisher ID: IOVS-20-29315
                DOI: 10.1167/iovs.61.5.35
                PMC ID: 7405767
                PubMed ID: 32433758
                SO-VID: 4c814e37-b50e-4d5f-9aa7-e6842b58d3ce
                Copyright © Copyright 2020 The Authors
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                Date accepted : 09 April 2020
                Date received : 18 January 2020
                Page count
                Pages: 12
                Categories
                Subject: Retinal Cell Biology
                Subject: Retinal Cell Biology

                Keywords: retinal pigment epithelium,autofluorescence,lipofuscin,melanolipofuscin,melanosome
                Data availability:
                Keywords: retinal pigment epithelium, autofluorescence, lipofuscin, melanolipofuscin, melanosome

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