Specialized retinal endothelial cells modulates blood-retina- barrier in diabetic retinopathy
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ABSTRACT:
PROVIDER: PRJNA1016358 | ENA |
REPOSITORIES: ENA
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Project description:Endothelial cells (EC) play essential roles in retinal vascular homeostasis. This study aimed to characterize retinal EC heterogeneity and functional diversity using single-cell RNA sequencing (scRNA-seq). Systematic analysis of cellular compositions and cell-cell interaction networks identified a unique EC cluster with high inflammatory gene expression in the diabetic retina; sphingolipid metabolism in this cluster is a prominent aspect correlated with changes in retinal function. Among the sphingolipid-related genes, alkaline ceramidase 2 (ACER2) showed the most significant increase. We collected plasma and vitreous samples from patients with non-proliferative diabetic retinopathy (NPDR) and PDR for mass spectrometry analysis. Metabolomic profiling revealed that the ceramide levels were significantly elevated in NPDR and further increased in PDR compared with control patients. In vitro analyses showed that the ACER2 overexpression retarded endothelial barrier breakdown induced by ceramide, while silencing of ACER2 further disrupted the injury. Moreover, intravitreal injection of the recombinant ACER2 adeno-associated virus rescued diabetes-induced vessel leakiness, inflammatory response, and neurovascular disease in diabetic mouse models. Together, this study revealed a new diabetes-specific retinal EC population and a negative feedback regulation pathway that reduces ceramide content and endothelial dysfunction by upregulating ACER2 expression. These findings provide insights into cell-type targeted interventions for diabetic retinopathy.
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Project description:The mammalian retina contains an endogenous circadian clock system, located in various cell types. This system enables timing of a broad range of essential retinal functions to anticipate daily changes in environmental lighting conditions. Furthermore, the circadian clocks appear to promote retinal health. A leading cause of blindness in developed countries is diabetic retinopathy. While it is clear that diabetes affects the master clock and its circadian output in the SCN, the effect of diabetic retinopathy on the retinal clock system is unknown. To investigate the influence of diabetic retinopathy on circadian regulation of the retina at a genome-wide level, microarray analysis was used to compare retinal transcriptomes between light- and dark-adapted non-diabetic and diabetic mice.
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Project description:Endothelial tip cells guiding tissue vascularization are primary targets for angiogenic therapies. Whether tip cells require differential signals to develop their complex branching patterns remained unknown. Here we show that diving tip cells invading the neuroretina (D-tip cells) are distinct from tip cells guiding the superficial retinal vascular plexus (S-tip cells). D-tip cells have a unique transcriptional signature, including high TGFβ signaling, and acquire blood-retina barrier properties. Endothelial deletion of TGFβ receptor I (Alk5) inhibits D-tip cell identity acquisition and deep vascular plexus formation. Loss of endothelial ALK5, but not of the canonical SMAD effectors, leads to aberrant contractile pericyte differentiation, and hemorrhagic vascular malformations. Our data reveal stage-specific tip cell heterogeneity as a requirement for retinal vascular development and suggest that noncanonical-TGFβ signaling could improve retinal revascularization and neural function in ischemic retinopathy.
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Project description:Schemic retinopathies such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP), are the main causes of blindness in working age and pediatric populations in industrialized countries. It is estimated that close to 100 million individuals worldwide suffer from DR and 15 million preterm infants born each year are predisposed to ROP. Regrettably, relatively little is known of the cellular processes at play during late stages of pathological angiogenesis in these diseases and consequently current standards of care target all neovascularization. Oxygen-induced retinopathy (OIR) allows to reproduce experimentally in the mouse retina the pathological features observed in human pathological retina such as ischemic avascular regions as well as epi-retinal neovascularization. Using agnostic and orthogonal approaches, in our work we demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cell cycle arrest, resulting in cellular senescence. These findings combined with further genetic and pharmacological approaches provide mechanistic evidence supporting that targeting selectively senescent vessels in DR represents a potential treatment for neovascular retinal disease.
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Project description:Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is essential for the development of new organ systems, but transcriptional control of angiogenesis remains incompletely understood. Here we report that FOXC1 is essential for retinal angiogenesis. Endothelial cell (EC)-specific loss of Foxc1 impairs retinal vascular growth and expression of Slc3a2 and Slc7a5, which encode the heterodimeric CD98 (LAT1/4F2hc) amino acid transporter and regulate the intracellular transport of essential amino acids and activation of the mammalian target of rapamycin (mTOR). EC-Foxc1 deficiency diminishes mTOR activity, while administration of the mTOR agonist MHY-1485 rescues perturbed retinal angiogenesis. EC-Foxc1 expression is required for retinal revascularization and resolution of neovascular tufts in a model of oxygen-induced retinopathy. Foxc1 is also indispensable for pericytes, a critical component of the blood-retina barrier during retinal angiogenesis. Our findings establish FOXC1 as a crucial regulator of retinal vessels and identify therapeutic targets for treating retinal vascular disease.
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Project description:<p>The retina is a notable tissue with high metabolic needs which relies on specialized vascular networks to protect the neural retina while maintaining constant supplies of oxygen, nutrients and dietary essential fatty acids. Here we analyzed the lipidome of the mouse retina under healthy and pathological angiogenesis using the oxygen-induced retinopathy model. By matching lipid profiles to changes in mRNA transcriptome, we identified a lipid signature showing that pathological angiogenesis leads to intense lipid remodeling favoring pathways for neutral lipid synthesis, cholesterol import/export and lipid droplet formation. Noteworthy, it also shows profound changes in pathways for long-chain fatty acid production, vital for retina homeostasis. The net result is accumulation of large quantities of mead acid, a marker of essential fatty acid deficiency, and a potential marker for retinopathy severity. Thus, our lipid signature might contribute to better understand diseases of the retina that lead to vision impairment or blindness.</p>
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