3D human retinal organoid model for the study of early diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is a significant complication of diabetes and a primary cause of visual impairment among working-age individuals. DR is a degenerative condition in which hyperglycaemia results in morphological and functional changes in certain retinal cells. Existing treatments mainly address the advanced stages of the disease, which involve vascular defects such as macular edema or neovascularization. However, it is now known that retinal neurodegeneration and inflammation precede these vascular changes. Therefore, there is a pressing need to identify new therapeutic approaches that target the early stages of DR and prevent its progression. In the last decade, the development of reliable in vitro models resembling the complexity of the retinal tissue has significantly improved. Namely, three-dimensional (3D) retinal organoids derived from human induced-pluripotent stem cells (hiPSCs) recapitulate the cellular organization and complexity of the human retina. Here, we used hiPSCs-derived retinal organoids to generate a model of early DR. In this model, we observe well-established molecular and cellular features of early DR: i) loss of retinal ganglion and amacrine cells; ii) glial reactivity and inflammation, with increased expression of the vascular endothelial-derived growth factor (VEGF) and interleukin-1{beta} (IL-1{beta}), and monocyte chemoattractant protein-1 (MCP-1) secretion; iii) increased levels of reactive oxygen species accompanied by activation of key enzymes involved in antioxidative stress response. The data provided highlight the utility of retinal organoid technology in modelling early-stage DR. This offers new avenues for the development of targeted therapeutic interventions on neurodegeneration and inflammation in the initial phase of DR, potentially slowing the diseases progression.