Islets of Langerhans transplantation into the eye anterior chamber improves retinal ganglion cell function and visual behaviors in glaucoma

Abstract

Purpose : Our recent work identified a potent role for insulin on retinal ganglion cell (RGC) dendrite and synapse regeneration. However, the delivery of recombinant insulin has several drawbacks including loss of biological activity and inconsistent levels in the retina. The transplantation of islets of Langerhans (IL) into the eye anterior chamber is a low-invasive strategy that capitalizes on the uniqueness of this site: its accessibility, high oxygen tension, and immune-privilege. Here, we tested the hypothesis that islet-based delivery of insulin is a safe and effective strategy to improve RGC function.

Methods : IL were isolated from donor mice pancreas and transplanted by trans-corneal injection into the anterior chamber (~50 islets/eye). The islets were placed directly onto the iris without blocking the iridocorneal angle. To measure IL-secreted insulin levels, aqueous humor was collected at 1, 2, 3 or 4 weeks after transplantation and analyzed by ELISA. Blood glucose was monitored weekly. To assess IL vascularization, fluorescent dextran was injected retro-orbitally and vessels were imaged with confocal microscopy. Following transplantation and induction of glaucoma (magnetic microbead model), light-evoked single-RGC calcium (Ca²⁺) dynamics were recorded using two-photon microscopy in Thy1.GCaMP6f mice. Optomotor responses were assessed weekly post-transplantation and glaucoma induction.

Results : Transplanted IL rapidly attached to the iris and were stable for several weeks thereafter. Insulin levels increased in the posterior chamber at 2 and 4 weeks after transplantation relative to saline-injected controls (n=4 mice/group, ANOVA, p<0.0001). High resolution imaging of IL revealed dextran-positive vessels suggesting that IL were vascularized by the underlying iris. Blood glucose levels remained unaltered. No signs of ocular abnormalities, inflammation, or adverse effects caused by IL transplantation were detected. IL transplantation restored light-evoked RGC Ca²⁺ dynamics (n=3-6 mice/group, ANOVA, p<0.05) and improved visual behaviors (n=5-16 mice /group, ANOVA, p<0.001) in glaucomatous mice relative to controls.

Conclusions : Our data show that IL transplantation into the eye anterior chamber increases insulin production in situ without adverse effects. IL transplantation restores light-evoked RGC responses and improves visual behaviors during glaucoma.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.