Abstract
Purpose :
Retinal ganglion cell (RGC) loss subject to elevated intraocular pressure (IOP) represents the leading cause of irreversible vision loss in glaucoma patients. Understanding how different RGC types respond to sustained IOP elevation can provide insight into key molecular players involved in neuroprotection and shed light on potential therapeutic targets for the treatment of glaucoma.
Methods :
Chronic IOP elevation was achieved using the silicone oil-induced ocular hypertension under-detected (SOHU) model. Silicone oil was injected into the anterior chamber of mice 8–10 weeks of age and a saline control into the contralateral eye. The IOP was monitored once weekly for up to 6 weeks after SO injection using the tonometer. AAV-mediated Secreted Phosphoprotein 1 (Spp1) knockdown or overexpression in RGCs occurred at 8 weeks of age. Mice were sacrificed at 1 week and 4 weeks post-SOHU surgery for RGC subtype-specific immunohistochemistry (IHC) analysis. Spp1 expression was also assessed by IHC in post-mortem human retina, as well as an enzyme-linked immunosorbent assay (ELISA) to quantify Spp1 in the aqueous humor (AH) from patients with glaucoma.
Results :
αRGCs and intrinsic-photosensitive RGCs (ipRGCs) are uniquely resilient in the context of chronically elevated IOP. The preferential resiliency was, in part, driven by elevated expression of Spp1. Our past work showed that Spp1 promotes optic nerve regrowth in combination with growth factors. Elimination of Spp1 from RGCs using either a Spp1 mutant or AAV-mediated Spp1 knockdown led to a significant decrease of αRGC survival. In contrast, overexpression of Spp1 in Foxp2-positive RGCs (F-RGCs) led to enhanced neuroprotection of this RGC subclass, which is highly susceptible to increased IOP. In post-mortem human retina, we found that Spp1 is also enriched in human RGC subsets, particularly in the central regions of the retina, as potential markers for human parasol RGCs. SPP1 quantification by ELISA from AH of patients with glaucoma showed that Spp1 levels are correlated with the severity of glaucoma.
Conclusions :
Our study revealed a novel role for Spp1 in promoting RGC resiliency in mouse models of glaucomatous neuropathy. Spp1 levels correlate with the severity of optic neuropathy in patients with glaucoma. Our data indicated that Spp1 may be a relevant biomarker as well as a therapeutic target for promoting neuroprotection in patients with glaucoma.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.