Melanophages give rise to hyperreflective foci in AMD, a disease-progression marker

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.

Automated summary

Through studying human donor tissue, researchers have discovered that the majority of cells containing retinal melanosome/melanolipofuscin are actually melanophages, rather than migrating retinal pigment epithelial cells. They have also identified the mechanism by which melanophages form, involving the transfer of melanosomes from the retinal pigment epithelial cells to subretinal mononuclear phagocytes when the CD47 signal is blocked. These melanophages result in the formation of hyperreflective foci and are associated with RPE dysmorphia similar to intermediate AMD. Additionally, the study found that CD47 expression in human RPE decreases with age and in AMD, suggesting that boosting CD47 expression may protect RPE cells and delay AMD progression.