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C57Bl6J retina lysates in oxygen-induced retinopathy

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE158799 | GEO | 2021/02/22

REPOSITORIES: GEO

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C57Bl6J retina lysates

Project description:Diabetic retinopathy (DR) is one of the main causes of blindness in working age populations in industrialized countries. It is estimated that close to 100 million individuals worldwide suffer from DR. Regrettably, relatively little is known of the cellular processes at play during late stages of the disease, especially concerning diabetic macular edema (DME). Streptozotocin-induced diabetic retinopathy (STZ) allows to reproduce experimentally in the mouse retina the retina vascular leakage and neuroegeneration features observed in human pathological retina with non-proliferative DR. Using agnostic and orthogonal approaches, in our work we demonstrate that in contrast to healthy retina, the STZ diabetic retina engages pathways of cell cycle arrest, resulting in cellular senescence. These findings combined with further pharmacological approaches provide mechanistic evidence supporting that targeting selectively senescent vessels in DR represents a potential treatment for high vascular permeability in DME.

2023-12-19 | GSE211583 | GEO

Progenitor cell combination normalizes retinal vascular development by enhancing pericyte ensheathment in the oxygen-induced retinopathy (OIR) model

Project description:Retinopathy of prematurity (ROP) is a disorder of the developing retina of preterm infants. ROP can lead to blindness due to abnormal angiogenesis that is the result of suspended vascular development and vaso-obliteration leading to severe retinal stress and hypoxia. We tested the hypothesis that a combined treatment with two human progenitor populations, the CD34+ cells, bone marrow-derived, and the endothelial colony-forming cells (ECFCs) synergistically protected the developing retinal vasculature in a murine model of ROP, the oxygen-induced retinopathy (OIR)., CD34+ cells alone, ECFCs alone, or a combination thereof were injected intravitreally at either P5 or P12 and pups were euthanized at P17. Retinas from OIR mice injected with ECFCs or the combined treatment revealed formation of the deep vascular plexus (DVP) while still in hyperoxia, with normal appearing connections between the superficial vascular plexus (SVP) and the DVP. The combination therapy prevented aberrant retinal neovascularization and was more effective anatomically and functionally at rescuing the ischemia phenotype than either cell type alone. The beneficial effect of the cell combination was the result of their ability to orchestrate an acceleration of vascular development and more rapid ensheathment of pericytes on the developing vessels.

2019-12-31 | GSE135844 | GEO

A local neuronal clock regulates retinal angiogenesis and neovascularization

Project description:Emerging evidence suggests a link between the circadian clock and retinopathies though the causality has not been established. Circadian clocks in the mammalian retina regulate a diverse range of retinal functions that allow the retina to adapt to the light-dark cycle. We report that clock genes are expressed in the embryonic retina, and the embryonic retina requires light cues to maintain robust circadian expression of the core clock gene, Bmal1. Deletion of Bmal1 and Per2 from the retinal neurons results in retinal angiogenic defects similar to when animals are maintained under constant light conditions. Using two different models to assess pathological neovascularization, we show that neuronal Bmal1 deletion reduces neovascularization with reduced vascular leakage, suggesting that a dysregulated circadian clock primarily drives neovascularization. Chromatin immunoprecipitation sequencing analysis suggests that semaphorin signaling is the dominant pathway regulated by Bmal1. Our data indicate that therapeutic silencing of the retinal clock could be a common approach for the treatment of certain retinopathies like diabetic retinopathy and retinopathy of prematurity.

2022-07-01 | GSE207271 | GEO

Postnatal hyperglycemia alters amino acid profile in retinas

Project description:Nutritional deprivation occurring in most preterm infants postnatally, can induce hyperglycemia, a significant and independent risk factor for suppressing physiological retinal vascularization (Phase I retinopathy of prematurity (ROP)), leading to compensatory but pathological neovascularization. Amino acid supplementation reduces retinal neovascularization in mice. Little is known about amino acid contribution to Phase I ROP. Significant changes in retinal amino acids (including most decreased L-leucine, L-isoleucine and L-valine) were found in mice modeling hyperglycemia-associated Phase I ROP, and parenteral (i.p.) L-isoleucine suppressed physiological retinal vascularization. In premature infants, severe ROP was associated with a higher mean intake of parenteral versus enteral amino acids in the first two weeks of life after adjustment for treatment group, gestational age at birth, birth weight and sex. The number of days with parenteral amino acids support independently predicted severe ROP. Further understanding and modulating amino acids may help improve nutritional intervention and prevent Phase I ROP

2023-02-16 | ST002497 | MetabolomicsWorkbench

FACS-array profiling in retinal endothelial cells from living mouse retinas

Project description:Deregulated retinal angiogenesis directly cause vision loss in many ocular diseases, such as diabetic retinopathy and retinopathy of prematurity. To identify endothelial-specific genes expressed in angiogenic retinal vessels, we purified genetically labeled endothelial cells from Tie2-GFP transgenic mice and performed gene expression profiling using DNA microarray. To find out genes associated with angiogenesis, comparisons of microarray data were carried out between GFP-negative non-endothelial retinal cells and GFP-positive retinal endothelial cells in angiogenic P8 retina. Eighteen arrays are included. Utilizing fluorescence-activated cell sorting (FACS), we isolated endothelial cells as GFP-positive cells from P8 retina in homozygous Tie2-GFP transgenic mice. GFP-negative cells were served as non-endothelial control. RNA extracts from sorted cells were amplified and then hybridized to Affymetrix MGU74v2 series arrays in triplicate.

2011-04-17 | E-GEOD-27238 | biostudies-arrayexpress

FACS-array profiling in retinal endothelial cells from living mouse retinas

2011-04-17 | GSE27238 | GEO

Proteomic phenotyping of stimulated Müller cells uncovers profound pro-inflammatory signaling and antigen-presenting capacity

Project description:Müller cells are the main macroglial cells of the retina exerting a wealth of functions to maintain retinal homoeostasis. Upon pathological changes in the retina, they become gliotic with both protective and detrimental consequences. Accumulating data also provide evidence for a pivotal role of Müller cells in the pathogenesis of diabetic retinopathy (DR). While microglial cells, the resident immune cells of the retina are considered as main players in inflammatory processes associated with DR, the implication of activated Müller cells in chronic retinal inflammation remains to be elucidated. In order to assess the signaling capacity of Müller cells and their role in retinal inflammation, we performed in-depth proteomic analysis of Müller cell proteomes and secretomes after stimulation with INFγ, TNFα, IL-4, IL-6, IL-10, TGFβ1, TGFβ2 and TGFβ3. We used both, primary porcine Müller cells and the human Müller cell line MIO-M1 for our hypothesis generating approach. Our results point towards an intense signaling capacity of Müller cells, which reacted in a highly discriminating manner upon treatment with different cytokines. Stimulation of Müller cells results in a primarily pro-inflammatory phenotype with secretion of cytokines and components of the complement system. Furthermore, we observed evidence for mitochondrial dysfunction, implying oxidative stress after treatment with the various cytokines. Finally, both MIO-M1 cells and primary porcine Müller cells showed several characteristics of atypical antigen-presenting cells, as they are capable of inducing MHC class I and MHC class II with co-stimulatory molecules. In line with this, they express proteins associated with formation and maturation of phagosomes. Thus, our findings underline the importance of Müller cell signaling in the inflamed retina, indicating an active role in chronic retinal inflammation underlying the pathogenesis of diabetic retinopathy.

2022-02-16 | PXD028390 | Pride

Epithelial membrane protein-2 promotes VEGF signaling to promote pathological neovascular growth in retinopathy of prematurity

Project description:Retinopathy of prematurity (ROP) is a leading cause of childhood blindness, and exclusively affects infants born prematurely. In this study, we test the hypothesis that EMP2 contributes to neovascularization in a mouse model of the disease. We show that EMP2 promotes neuronal VEGF signaling and that its downregulation reduces severity of neovascularization.

2021-12-17 | GSE123945 | GEO

Proteomic Analysis of Diabetic Retinas (proteoglycomics data only)

Project description:As a metabolic disease, diabetes often leads to health complications such as heart failure, nephropathy, neurological disorders, and vision loss. Diabetic retinopathy (DR) affects as many as 100 million people worldwide. The mechanism of DR is complex and known to impact both neural and vascular components in the retina. While recent advances in the field have identified major cellular signaling contributing to DR pathogenesis, little has been reported on the protein post-translational modifications (PTM) -known to define protein localization, function, and activity -in the diabetic retina overall. Protein glycosylation is the enzymatic addition of carbohydrates to proteins, which can influence many protein attributes including folding, stability, function, and subcellular localization. Olinked glycosylation is the addition of sugars to an oxygen atom in amino acids with a free oxygen atom in their side chain (i.e., threonine, serine). To date, more than 100 congenital disorders of glycosylation have been described. However, no studies have identified the retinal O-linked glycoproteome in health or disease. With a critical need to expedite the discovery of PTMomics in diabetic retinas, we identified both global changes in protein levels and the retinal O-glycoproteome of control and diabetic mice. Liquid chromatography/mass spectrometry-based glycoproteomics and high throughput screening identified proteins differentially glycosylated in the retinas of wildtype and diabetic mice. Here, we provide evidence that diabetes shifts O-glycosylation of metabolic and synaptic proteins in the retina.

2023-08-16 | PXD044270 | Pride

Proteomic Analysis of Diabetic Retinas

2023-08-16 | PXD044269 | Pride

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