2 – 4 It contains numerous components, including a complex mixture of bisretinoids derived from covalent linkage of monoretinoids used in the visual cycle, oxidized lipid products, and cross-linked protein. 1 Lipofuscin accumulates over a lifetime, occupying major portions of the RPE cell in elderly individuals. Incomplete degradation of OS material contributes, in part, to the development of autofluorescent intracellular inclusions termed lipofuscin. As the RPE is a mostly postmitotic tissue, the phagocytic burden for each cell over a lifetime is immense. The daily ingestion of shed OS tips from photoreceptors by the RPE is critical for photoreceptor health and function. Our results suggest that healthy RPE may adequately adapt to and tolerate lipofuscin accumulation. Furthermore, while UAM alters hfRPE phenotype, the effects are modest, consistent with conflicting reports in the literature on the toxicity of lipofuscin. HfRPE demonstrates a remarkable resistance to UAM accumulation, suggesting mechanisms for efficient OS processing that may be lost in other RPE culture models. However, it had no effects on mitochondrial oxygen consumption rate, certain other RPE differentiation markers, secretion of drusen components or polarity markers, nor cell death. UAM accumulation mildly reduced transepithelial electrical resistance, ketogenesis, certain RPE differentiation markers, and phagocytosis efficiency, while inducing senescence and rare, focal pockets of epithelial-mesenchymal transition. Accumulated UAM in hfRPE initially resembled the morphology of lipofuscin from AMD eyes, but compacted and shifted spectrum over time to resemble lipofuscin from healthy aged human RPE. Effects of UAM on multiple RPE phenotypes were assessed.Ĭompared to ARPE-19, hfRPE were markedly less susceptible to UAM buildup. The emission spectrum, composition, and morphology of resulting UAM were measured and compared to in vivo lipofuscin. Unmodified and photo-oxidized OS were fed daily to confluent cultures of ARPE-19 RPE or hfRPE. We therefore investigated the effects of UAM in highly differentiated human fetal RPE (hfRPE) cultures. Whether this accumulated waste is toxic is unclear. Lipofuscin derives, in part, from the incomplete degradation of phagocytized photoreceptor outer segments (OS). The accumulation of undigestible autofluorescent material (UAM), termed lipofuscin in vivo, is a hallmark of aged RPE.
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