Single-cell analysis reveals a compensatory role of Muller glia in a mouse retinitis pigmentosa model

Abstract

Purpose : Retinitis pigmentosa (RP) is a set of >60 hereditary retinal diseases characterized by degeneration of rod, then cone photoreceptors. It is typically diagnosed in adolescence and patients lose vision during adulthood. Gene therapy has been approved for only one gene in RP and developing gene therapies for >60 genetic causes is time consuming and costly. Therefore, we investigated retinal cellular responses to photoreceptor abnormalities in a mouse RP model to find a potential generic target to treat RP.

Methods : Cellular responses in each major retinal cell type in RP model (P23H; mutation of rhodopsin) and wild-type mice were analyzed using single-cell transcriptomics. Morphological changes were examined in P23H and wild-type mice retinas with OCT and immunohistochemistry (IHC) staining.

Results : OCT analysis showed thinning of the outer nuclear layer (ONL) and IS/OS layer in P23H versus wild-type mice at one-month old (p<0.001). Genes involved in IS/OS segments, photoreceptor cell cilia, and photoreceptor development were significantly decreased in both rod and cone clusters, in line with the structural changes seen with immunohistochemistry. The genes involved in energy production and metabolic pathways associated with this loss were notably decreased in both rods and cones. Furthermore, in the Müller glia/astrocyte cluster, there was a remarkable up-regulation in pathways responsible for photoreceptor maintenance, which was decreased in rods and cones.

Conclusions : Enhancing photoreceptor metabolism and modulating Müller glial responses may potentially serve as a generic approach to protect against retinal degeneration in RP.

This is a 2021 ARVO Annual Meeting abstract.