The Multifaceted Role of Vitreous Hyalocytes: Orchestrating Inflammation, Angiomodulation, and Erythrophagocytosis in Proliferative Diabetic Retinopathy

Despite great advancements in proliferative diabetic retinopathy (PDR) therapy over the last decades, one third of treated patients continue to lose vision. Vitreous macrophages called hyalocytes have been implied in the pathogenesis of vitreoretinal proliferative disease previously but little is known about their role in PDR. In this study, we address molecular and cellular alterations of the PDR vitreous, in order to assess the potential contribution of hyalocytes to PDR development. A total of 55 patients were included in this study encompassing RNA-Sequencing analysis of vitreous hyalocytes from PDR and control patients, multiplex immunoassay and ELISA analysis of undiluted vitreous samples and isolation and immunohistochemical staining of cultured porcine hyalocytes. Our transcriptional analysis revealed an enhanced inflammatory signature of hyalocytes contributing to the cytokine pool within the PDR vitreous by expressing, among others, interleukin-6. The data further indicate an expression shift, involving angiopoietin-2, in PDR hyalocytes converting them to a proangiogenic cellular component, which may mediate formation of retinal neovascularization, hallmark of PDR. Finally, our data suggest a role of vitreous macrophages in erythrophagocytosis and, thereby, removal of vitreous hemorrhage, a severe complication of PDR. Immunomodulation of hyalocytes may thus prove an essential novel therapeutical approach in diabetic vitreoretinal disease.