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Updated: Aug 11, 2025
Author Spotlight: Ex Vivo OCT-Based Multimodal Imaging of Human Donor Eyes for Research into Age-Related Macular Degeneration
Published on: May 26, 2023
Melanophages give rise to hyperreflective foci in AMD, a disease-progression marker
Sebastien Augustin1, Marion Lam2, Sophie Lavalette1
1Sorbonne Université, INSERM, CNRS, UMR_S 968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
Abstract:
Retinal melanosome/melanolipofuscin-containing cells (MCCs), clinically visible as hyperreflective foci (HRF) and a highly predictive imaging biomarker for the progression of age-related macular degeneration (AMD), are widely believed to be migrating retinal pigment epithelial (RPE) cells. Using human donor tissue, we identify the vast majority of MCCs as melanophages, melanosome/melanolipofuscin-laden mononuclear phagocytes (MPs). Using serial block-face scanning electron microscopy, RPE flatmounts, bone marrow transplantation and in vitro experiments, we show how retinal melanophages form by the transfer of melanosomes from the RPE to subretinal MPs when the "don't eat me" signal CD47 is blocked. These melanophages give rise to hyperreflective foci in Cd47-/--mice in vivo, and are associated with RPE dysmorphia similar to intermediate AMD. Finally, we show that Cd47 expression in human RPE declines with age and in AMD, which likely participates in melanophage formation and RPE decline. Boosting CD47 expression in AMD might protect RPE cells and delay AMD progression.
Insights
Melanosome/melanolipofuscin-containing cells (MCCs), linked to AMD progression, are actually melanophages. These form when CD47 signals are blocked, leading to hyperreflective foci and RPE decline in age-related macular degeneration.
Area of Science:
- Ophthalmology
- Cell Biology
- Immunology
Background:
- Melanosome/melanolipofuscin-containing cells (MCCs) appear as hyperreflective foci (HRF) in the retina.
- HRF are key imaging biomarkers predicting age-related macular degeneration (AMD) progression.
- MCCs were previously thought to be migrating retinal pigment epithelial (RPE) cells.
Purpose of the Study:
- To identify the cellular origin of MCCs.
- To elucidate the mechanism of MCC formation.
- To investigate the role of CD47 in AMD pathogenesis.
Main Methods:
- Human donor eye tissue analysis
- Serial block-face scanning electron microscopy
- Retinal pigment epithelial (RPE) flatmounts
- Bone marrow transplantation
- In vitro cell culture experiments
- Analysis of Cd47 knockout mouse models
Main Results:
- The majority of MCCs are identified as melanophages (mononuclear phagocytes laden with melanosomes/melanolipofuscin).
- Melanophages form via melanosome transfer from RPE to subretinal mononuclear phagocytes when CD47 is blocked.
- Melanophages cause hyperreflective foci in Cd47-/- mice and are linked to RPE abnormalities seen in intermediate AMD.
- Human RPE CD47 expression decreases with age and in AMD, correlating with melanophage formation and RPE decline.
Conclusions:
- Melanophages, not migrating RPE cells, constitute the majority of MCCs.
- CD47 downregulation in RPE cells contributes to melanophage formation and RPE dysfunction in AMD.
- Therapeutic strategies boosting CD47 expression may protect RPE cells and slow AMD progression.
