Abstract
Diabetic retinopathy (DR) is the most common diabetic microvascular complication and major cause of blindness in working-age adults. According to the level of microvascular degeneration and ischemic damage, DR is classified into non-proliferative DR (NPDR), and end-stage, proliferative DR (PDR). Despite advances in the disease etiology and pathogenesis, molecular understanding of end-stage PDR, characterized by ischemia- and inflammation-associated neovascularization and fibrosis, remains incomplete due to the limited availability of ideal clinical samples and experimental research models. Since a great portion of patients do not benefit from current treatments, improved therapies are essential. DR is known to be a complex and multifactorial disease featuring the interplay of microvascular, neurodegenerative, metabolic, genetic/epigenetic, immunological, and inflammation-related factors. Particularly, deeper knowledge on the mechanisms and pathophysiology of most advanced PDR is critical. Lymphatic-like vessel formation coupled with abnormal endothelial differentiation and progenitor cell involvement in the neovascularization associated with PDR are novel recent findings which hold potential for improved DR treatment. Understanding the underlying mechanisms of PDR pathogenesis is therefore crucial. To this goal, multidisciplinary approaches and new ex vivo models have been developed for a more comprehensive molecular, cellular and tissue-level understanding of the disease. This is the first step to gain the needed information on how PDR can be better evaluated, stratified, and treated.
Highlights
The global prevalence of diabetes has nearly doubled in the past three decades, with 425 million individuals affected in 2017 [1]
We found that in the patient-matched surgically-excised fibrovascular proliferative DR (PDR) tissues, vitreous-induced lymphatic endothelial cell (LEC) sprouting is associated with lymphatic marker expression [45]
Lineage tracing approaches in mouse models will be highly beneficial to understand the fate of the different retinal resident and incoming cell types and their contribution to the lymphatic-like neovascular structures arising in PDR
Summary
The global prevalence of diabetes has nearly doubled in the past three decades, with 425 million individuals affected in 2017 [1]. DR is a multifactorial disease involving the complex interplay of microvascular, neurodegenerative, metabolic, genetic/epigenetic, immunological, and inflammation-related factors. Diabetic macular edema (DME), the accumulation of extracellular fluid within the retinal layers around the macular region, often accompanies all stages of DR. The end-stage disease, PDR, is characterized by ischemia- and inflammation-induced neovascularization, coupled with fibrotic responses at the vitreoretinal interface, which, in untreated conditions leads to blindness due to vitreous hemorrhage (VH), retinal fibrosis, tractional retinal detachment (TRD), and neovascular glaucoma [2,3,4]. PDR pathogenesis involves injury of neurons and glial cells, dysfunction of endothelial progenitor cells (EPCs) and accumulation of inflammatory cells [2,5,6]
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