The appearance of hyperreflective foci (HRF) above drusenoid pigment epithelial detachments (d-PEDs) on optical coherence tomography (OCT) imaging strongly predicts drusen collapse and subsequent progression to geographic atrophy (GA) in age-related macular degeneration (AMD) [1,2,3,4,5,6] (Fig. 1A, B). Here, we provide literature and laboratory evidence supporting the hypothesis that HRF represent RPE undergoing a pathologic epithelial-to-mesenchymal transition (EMT) and that this phenotypic change results in a decrease in the RPE’s secretion of drusen-sustaining components, leading to drusen collapse just before GA onset.
Most evidence points to HRF above d-PEDs as RPE migrating above the RPE monolayer into the neural retina [7,8,9]. RPE cells that lose contact with the RPE monolayer undergo a phenotypic change, termed an EMT [10]. EMT results in RPE proliferation and increased fibrotic capacity [10, 11], accompanied by a decline in photoreceptor-supporting functions [12]. The extreme clinical example of RPE EMT is proliferative vitreoretinopathy, where RPE released from the monolayer undergoes massive proliferation and fibrosis [11], but more subtle RPE EMT has been demonstrated in AMD as well [10, 13]. Mild RPE EMT may lead to photoreceptor loss and an inability to fill-in gaps in the RPE monolayer after EMT-RPE migrates into the neural retina, thereby triggering GA [10].
d-PED collapse often heralds GA onset [8, 14, 15]. To understand this phenomenon, we first note that d-PEDs are dynamic structures representing an equilibrium between ongoing deposition and egress of drusen material [15]. As RPE sickens, its secretion of the most abundant apolipoprotein component of drusen, apolipoprotein E (apoE) [14], decreases [15], causing a shift in d-PED equilibrium toward egress prior to GA onset.
Here, we hypothesize that RPE undergoing EMT, clinically indicated by HRF above d-PEDs on OCT, also leads to a decrease in secretion of drusen components, further promoting drusen regression prior to GA. To test this hypothesis, we utilized our primary human RPE culture system, previously shown to mimic in vivo RPE [16]. Under normal conditions, our primary human RPE culture maintains a cobblestone morphology (Fig. 1Ci, left). When plated at low density, however, RPE cells fail to make strong cell–cell contacts, triggering EMT and a fibroblastic morphology (Fig. 1Ci, right). EMT-RPE is marked by expression of vimentin (Fig. 1Cii), which is also expressed in degenerating RPE from AMD eyes, further bolstering the concept that AMD involves an RPE EMT shift [17]. Our EMT-RPE also lose their tight-junction integrity, which is critical for establishing the outer retinal–blood barrier (Fig. 1D). Importantly, unlike epithelial RPE cultures, EMT-RPE cultures secrete significantly lower levels of drusen components, including apoE and TIMP-3 (Fig. 1E).
Together, these data support the following model (Fig. 2): as RPE sickens in dry AMD, it undergoes an EMT. Some EMT-RPE may remain in the RPE monolayer but other EMT-RPE migrates into the neural retina, manifesting as HRF on OCT imaging that predict AMD progression. The subsequent decreased secretion of drusen components by sick and EMT-RPE, along with continued efflux of drusen components into the choroid, results in d-PED collapse, followed by GA.
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Acknowledgements
The authors acknowledge the Kellogg Eye Center’s Pre-Residency Fellowship program for funding the basic science aspects of this study. The authors also gratefully acknowledge philanthropic donations from Barbara Dunn as well as Dee and Dickson Brown.
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QZ designed and executed all experiments. JMLM conceived of the study and wrote the manuscript.
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Zhang, Q., Miller, J.M.L. Basic-science observations explain how outer retinal hyperreflective foci predict drusen regression and geographic atrophy in age-related macular degeneration. Eye 36, 1115–1118 (2022). https://doi.org/10.1038/s41433-021-01748-y
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DOI: https://doi.org/10.1038/s41433-021-01748-y
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