Related Experiment Video
Updated: Jul 13, 2025
Generation of Human Microglia to Combine Them with Retinal Organoids for Improved Disease Modeling
Published on: July 26, 2024
Microglia preserve visual function loss in the aging retina by supporting retinal pigment epithelial health
Margarete M Karg1,2, May Moorefield1, Emma Hoffmann1
1Schepens Eye Research Institute of Mass Eye and Ear, 20 Staniford St, Boston, MA, 02114, USA.
Background:
Increased age is a risk factor for the development and progression of retinal diseases including age-related macular degeneration (AMD). Understanding the changes that occur in the eye due to aging is important in enhancing our understanding of AMD pathogenesis and the development of novel AMD therapies. Microglia, the resident brain and retinal immune cells are associated with both maintaining homeostasis and protection of neurons and loss of microglia homeostasis could be a significant player in age related neurodegeneration. One important characteristic of retinal aging is the migration of microglia from the inner to outer retina where they reside in the subretinal space (SRS) in contact with the retinal pigment epithelial (RPE) cells. The role of aged subretinal microglia is unknown. Here, we depleted microglia in aged C57/BL6 mice fed for 6 weeks with a chow containing PLX5622, a small molecule inhibitor of colony-stimulating factor-1 receptor (Csf1r) required for microglial survival.
Results:
The subretinal P2RY12 + microglia in aged mice displayed a highly amoeboid and activated morphology and were filled with autofluorescence droplets reminiscent of lipofuscin. TEM indicates that subretinal microglia actively phagocytize shed photoreceptor outer segments, one of the main functions of retinal pigmented epithelial cells. PLX5622 treatment depleted up to 90% of the retinal microglia and was associated with significant loss in visual function. Mice on the microglia depletion diet showed reduced contrast sensitivity and significantly lower electroretinogram for the c-wave, a measurement of RPE functionality, compared to age-matched controls. The loss of c-wave coincided with a loss of RPE cells and increased RPE swelling in the absence of microglia.
Conclusions:
We conclude that microglia preserve visual function in aged mice and support RPE cell function, by phagocytosing shed photoreceptor outer segments and lipids, therefore compensating for the known age-related decline of RPE phagocytosis.
Insights
In aged mice, microglia in the outer retina support vision and retinal pigment epithelial (RPE) cell function by clearing debris. Depleting these microglia impairs vision and RPE health, highlighting their protective role.
Area of Science:
- Ophthalmology and Vision Science
- Neuroimmunology
- Cellular Biology
Background:
- Aging is a significant risk factor for retinal diseases like age-related macular degeneration (AMD).
- Microglia, the resident immune cells of the retina, play roles in neuronal protection and homeostasis.
- In aged retinas, microglia migrate to the subretinal space (SRS) near retinal pigment epithelial (RPE) cells, but their function there is unknown.
Purpose of the Study:
- To investigate the role of aged subretinal microglia in retinal function and health.
- To determine the impact of microglia depletion on visual function and RPE integrity in aged mice.
Main Methods:
- Aged C57/BL6 mice were fed a chow containing PLX5622, a colony-stimulating factor-1 receptor (Csf1r) inhibitor, for 6 weeks to deplete microglia.
- Visual function was assessed using contrast sensitivity and electroretinography (ERG).
- Retinal structure, including RPE cell health and morphology, was examined using transmission electron microscopy (TEM).
Main Results:
- Subretinal microglia in aged mice exhibited an activated morphology and phagocytosed photoreceptor outer segments.
- PLX5622 treatment depleted up to 90% of retinal microglia, leading to significant vision loss, reduced contrast sensitivity, and lower c-wave ERG amplitudes.
- Microglia depletion resulted in RPE cell loss and increased RPE swelling, indicating impaired RPE function.
Conclusions:
- Microglia are crucial for maintaining visual function in aged mice.
- Subretinal microglia support RPE cell function by phagocytosing shed photoreceptor outer segments and lipids.
- These microglial functions compensate for age-related declines in RPE phagocytic capacity, highlighting their protective role in retinal aging.
