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Updated: Jul 27, 2025
Generation of Human Microglia to Combine Them with Retinal Organoids for Improved Disease Modeling
Published on: July 26, 2024
Microglial and macroglial dynamics in a model of retinitis pigmentosa
Nundehui Díaz-Lezama1, Jacqueline Kajtna1, Jiou Wu1
1Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
Abstract:
In retinal degenerative diseases, such as retinitis pigmentosa (RP), the characteristic photoreceptor cell death is associated with changes of microglia and macroglia cells. Gene therapy, a promising treatment option for RP, is based on the premise that glial cell remodeling does not impact vision rescue. However, the dynamics of glial cells after treatment at late disease stages are not well understood. Here, we tested the reversibility of specific RP glia phenotypes in a Pde6b-deficient RP gene therapy mouse model. We demonstrated an increased number of activated microglia, retraction of microglial processes, reactive gliosis of Müller cells, astrocyte remodelling and an upregulation of glial fibrillary acidic protein (GFAP) in response to photoreceptor degeneration. Importantly, these changes returned to normal following rod rescue at late disease stages. These results suggest that therapeutic approaches restore the homeostasis between photoreceptors and glial cells.
Insights
Gene therapy can reverse glial cell changes in retinitis pigmentosa (RP) even at late stages. This study shows that restoring photoreceptor cells helps normalize microglia and Müller cells, suggesting a return to normal cell balance.
Area of Science:
- Ophthalmology
- Neuroscience
- Genetics
Background:
- Retinal degenerative diseases like retinitis pigmentosa (RP) involve photoreceptor cell death and glial cell alterations.
- The impact of glial cell remodeling on vision rescue after gene therapy, especially in late-stage disease, remains unclear.
Purpose of the Study:
- To investigate the reversibility of glial cell phenotypes in a mouse model of RP following gene therapy.
- To understand the dynamics of microglia and Müller cells after photoreceptor rescue in late-stage disease.
Main Methods:
- Utilized a Pde6b-deficient RP gene therapy mouse model.
- Assessed changes in microglia (activation, process retraction) and Müller cells (reactive gliosis, GFAP upregulation).
- Evaluated these glial changes before and after successful rod photoreceptor rescue.
Main Results:
- Photoreceptor degeneration in RP mice led to activated microglia, retracted microglial processes, reactive Müller cells, and astrocyte remodeling with GFAP upregulation.
- Crucially, these glial abnormalities normalized after gene therapy-induced rod photoreceptor rescue, even when initiated at late disease stages.
Conclusions:
- Glial cell phenotypes associated with RP are reversible following successful gene therapy.
- Therapeutic restoration of photoreceptor cells can re-establish homeostasis between photoreceptors and glial cells in the retina.
