Retinal phagocytes in age-related macular degeneration

Kim, Soo Young

doi:10.14800/macrophage.698

Cited by 12 publications

(8 citation statements)

References 68 publications

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“…A notable indication observed in our data is that a significant phagocytic dysfunction (~ 50% of age-matched normal), far more than attributable to aging, was present in the RPE from a relatively young AMD patient (65 years old). Anomalies in any stage of the POS shedding and phagocytosis have been thought to cause various ocular disorders, including retinitis pigmentosa (RP) and AMD [ 64 – 67 ]. One of the earliest hypotheses of retinal degeneration, including AMD, was that accumulation of abnormal quantities of POS breakdown products in RPE lead to cellular dysfunction and degeneration [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells

Inana

Murat

et al. 2018

J Transl Med

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BackgroundAge-related macular degeneration (AMD) is a leading cause of blindness among the elderly characterized by retinal pigment epithelium (RPE) degeneration with accumulation of abnormal intracellular deposits (lipofuscin) and photoreceptor death. RPE is vital for the retina and integrity of photoreceptors through its phagocytic function which is closely linked to formation of lipofuscin through daily phagocytosis of discarded photoreceptor outer segments (POS). Although phagocytosis has been implicated in AMD, it has not been directly shown to be altered in AMD. RPE phagocytic defect was previously shown to be rescued by subretinal injection of human umbilical tissue derived cells (hUTC) in a rodent model of retinal degeneration (RCS rat) through receptor tyrosine kinase (RTK) ligands and bridge molecules. Here, we examined RPE phagocytic function directly in the RPE from AMD patients and the ability and mechanisms of hUTC to affect phagocytosis in the human RPE.MethodsHuman RPE was isolated from the post-mortem eyes of normal and AMD-affected subjects and cultured. RPE phagocytic function was measured in vitro using isolated POS. The effects of hUTC conditioned media, recombinant RTK ligands brain-derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and glial cell-derived neurotrophic factor (GDNF), as well as bridge molecules milk-fat-globule-EGF-factor 8 (MFG-E8), thrombospondin (TSP)-1, and TSP-2 on phagocytosis were also examined in phagocytosis assays using isolated POS. RNA was isolated from normal and AMD RPE treated with hUTC conditioned media and subjected to transcriptome profiling by RNA-Seq and computational analyses.ResultsRPE phagocytosis, while showing a moderate decline with age, was significantly reduced in AMD RPE, more than expected for age. hUTC conditioned media stimulated phagocytosis in the normal human RPE and significantly rescued the phagocytic dysfunction in the AMD RPE. RTK ligands and bridge molecules duplicated the rescue effect. Moreover, multiple molecular pathways involving phagocytosis, apoptosis, oxidative stress, inflammation, immune activation, and cholesterol transport were affected by hUTC in the RPE.ConclusionsWe demonstrated for the first time RPE phagocytic dysfunction in AMD, highlighting its likely importance in AMD, and the ability of hUTC to correct this dysfunction, providing insights into the therapeutic potential of hUTC for AMD.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1434-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells

Inana

Murat

et al. 2018

J Transl Med

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“…As rhodopsin staining and markers involved in phagosome maturation in the RPE can be readily identified by IF and further assessed in detail at the high resolution achievable by EM, this approach could be highly beneficial for future studies. These studies include examining phagosome maturation in greater detail in human tissue samples and retinal degenerative disease models to determine how this process can become defective and lead to retinal disease [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Correlative light and immuno-electron microscopy of retinal tissue cryostat sections

et al. 2018

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Correlative light-electron microscopy (CLEM) is a powerful technique allowing localisation of specific macromolecules within fluorescence microscopy (FM) images to be mapped onto corresponding high-resolution electron microscopy (EM) images. Existing methods are applicable to limited sample types and are technically challenging. Here we describe novel methods to perform CLEM and immuno-electron microscopy (iEM) on cryostat sections utilising the popular FM embedding solution, optimal cutting temperature (OCT) compound. Utilising these approaches, we have (i) identified the same phagosomes by FM and EM in the retinal pigment epithelium (RPE) of retinal tissue (ii) shown the correct localisation of rhodopsin on photoreceptor outer segment disc like-structures in iPSC derived optic cups and (iii) identified a novel interaction between peroxisomes and melanosomes as well as phagosomes in the RPE. These data show that cryostat sections allow easy characterisation of target macromolecule localisation within tissue samples, thus providing a substantial improvement over many conventional methods that are limited to cultured cells. As OCT embedding is routinely used for FM this provides an easily accessible and robust method for further analysis of existing samples by high resolution EM.

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“…Maladaptive inflammatory responses of microglia contribute to the progression of various chronic neurodegenerative diseases, promote cell death 13 and can to lead to degeneration of photoreceptors 14 . Numerous clinical and basic studies have implicated age-related alterations of the RPE layer and glial dysfunction in the development AMD 15 , but the mechanisms of the transition of normal age-related changes to the pathological phenotypes in AMD are incompletely understood.…”

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confidence: 99%

Contributions of age-related alterations of the retinal pigment epithelium and of glia to the AMD-like pathology in OXYS rats

Telegina

Kozhevnikova

Bayborodin

et al. 2017

Sci Rep

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Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the molecular pathogenesis of early events of AMD is poorly understood. It is known that age-related alterations of retinal pigment epithelium (RPE) cells and of glial reactivity are early hallmarks of AMD. Here we evaluated contributions of the age-related alterations of the RPE and of glia to the development of AMD-like retinopathy in OXYS rats. We showed that destructive alterations in RPE cells are a primary change during the development of retinopathy in OXYS rats. Furthermore, a defect of retinal maturation and decreased immune function at the preclinical stage of retinopathy were observed in OXYS rats in addition to the impairment of RPE cell proliferation and of their capacity for division. At the active stage of the disease, the atrophic alterations increased, and reactive gliosis was observed when disease progressed, but immune function stayed weakened. Unexpectedly, we did not observe migration of microglia and macrophages into the photoreceptor layer. These results and the wide spectrum of age-related retinal alterations in humans as well as individual differences in the risk of AMD may be attributed to genetic factors and to differences in the underlying molecular events.

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Retinal phagocytes in age-related macular degeneration

Cited by 12 publications

References 68 publications

RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells

RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells

Correlative light and immuno-electron microscopy of retinal tissue cryostat sections

Contributions of age-related alterations of the retinal pigment epithelium and of glia to the AMD-like pathology in OXYS rats

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