A New Human Blood–Retinal Barrier Model Based on Endothelial Cells, Pericytes, and Astrocytes

Fresta, Claudia G.; Fidilio, Annamaria; Caruso, Giuseppe; Caraci, Filippo; Giblin, Frank J.; Leggio, Gian Marco; Salomone, Salvatore; Drago, Filippo; Bucolo, Claudio

doi:10.3390/ijms21051636

Cited by 60 publications

(64 citation statements)

References 75 publications

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“…Several studies have shown that hyperglycemia represents the main risk factor contributing to the pathogenesis of diabetic retinopathy ( Engerman and Kern, 1986 ; Das et al, 2015 ; Eshaq et al, 2017 ). Furthermore, using a BRB model formed by retinal pericytes, astrocytes and endothelial cells, it has been recently reported that high glucose exposure elicits BRB breakdown, enhances BRB permeability and reduces the levels of junction proteins such as ZO-1 and VE-cadherin ( Fresta et al, 2020 ). Besides, elevated ROS as well as pro-inflammatory mediators (IL-1β, IL-6) and oxidative stress-related enzymes (iNOS, Nox2) have also been shown to be increased ( Fresta et al, 2020 ).…”

Section: Diabetic Retinopathymentioning

confidence: 99%

“…Furthermore, using a BRB model formed by retinal pericytes, astrocytes and endothelial cells, it has been recently reported that high glucose exposure elicits BRB breakdown, enhances BRB permeability and reduces the levels of junction proteins such as ZO-1 and VE-cadherin ( Fresta et al, 2020 ). Besides, elevated ROS as well as pro-inflammatory mediators (IL-1β, IL-6) and oxidative stress-related enzymes (iNOS, Nox2) have also been shown to be increased ( Fresta et al, 2020 ). The major biochemical pathways involved in the BRB breakdown are the polyol pathway, the AGEs pathway, the PKC pathway and the hexosamine pathway.…”

Section: Diabetic Retinopathymentioning

confidence: 99%

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EndMT Regulation by Small RNAs in Diabetes-Associated Fibrotic Conditions: Potential Link With Oxidative Stress

Giordo

Ahmed

Allam

et al. 2021

Front. Cell Dev. Biol.

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Diabetes-associated complications, such as retinopathy, nephropathy, cardiomyopathy, and atherosclerosis, the main consequences of long-term hyperglycemia, often lead to organ dysfunction, disability, and increased mortality. A common denominator of these complications is the myofibroblast-driven excessive deposition of extracellular matrix proteins. Although fibroblast appears to be the primary source of myofibroblasts, other cells, including endothelial cells, can generate myofibroblasts through a process known as endothelial to mesenchymal transition (EndMT). During EndMT, endothelial cells lose their typical phenotype to acquire mesenchymal features, characterized by the development of invasive and migratory abilities as well as the expression of typical mesenchymal products such as α-smooth muscle actin and type I collagen. EndMT is involved in many chronic and fibrotic diseases and appears to be regulated by complex molecular mechanisms and different signaling pathways. Recent evidence suggests that small RNAs, in particular microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are crucial mediators of EndMT. Furthermore, EndMT and miRNAs are both affected by oxidative stress, another key player in the pathophysiology of diabetic fibrotic complications. In this review, we provide an overview of the primary redox signals underpinning the diabetic-associated fibrotic process. Then, we discuss the current knowledge on the role of small RNAs in the regulation of EndMT in diabetic retinopathy, nephropathy, cardiomyopathy, and atherosclerosis and highlight potential links between oxidative stress and the dyad small RNAs-EndMT in driving these pathological states.

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Section: Diabetic Retinopathymentioning

confidence: 99%

Section: Diabetic Retinopathymentioning

confidence: 99%

EndMT Regulation by Small RNAs in Diabetes-Associated Fibrotic Conditions: Potential Link With Oxidative Stress

Giordo

Ahmed

Allam

et al. 2021

Front. Cell Dev. Biol.

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“…Transendothelial electrical resistance measurements were performed once endothelial cultures of 3 models reached 95%-100% confluent. In Transwell (0.4 μ m pore size) cultures, TEER was conducted by a Millicell device (Millicell-ERS-2, MA, USA) and chopstick-like electrodes as described elsewhere [ 28 ]. One electrode was immersed in the upper chamber of Transwell and the other electrode in the lower chamber of a 24-well plate.…”

Section: Methodsmentioning

confidence: 99%

Pericytes of Indirect Contact Coculture Decrease Integrity of Inner Blood-Retina Barrier Model In Vitro by Upgrading MMP-2/9 Activity

et al. 2021

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Inner blood-retina barrier (iBRB) is primarily formed of retinal microvascular endothelial cells (ECs) with tight junctions, which are surrounded and supported by retinal microvascular pericytes (RMPs) and basement membrane. Pericytes are believed to be critically involved in the physiology and pathology of iBRB. However, the underlying mechanism remains to be fully elucidated. We developed a novel in vitro iBRB model which was composed of primary cultures of rat retinal ECs and RMPs based on Transwell system. We tested the involvement of pericytes in the migration and invasion of ECs, examined the expression and activity of matrix metalloproteinase- (MMP-) 2/MMP-9 in the culture, evaluated the TEER and permeability of iBRB, and assessed the expression of ZO-1, occludin, claudin-5, and VE-cadherin of endothelial junctions. We found that RMPs with indirect contact of ECs can increase the expression of MMP-2 and upgrade the activity of MMP-2/9 in the coculture, which subsequently decreased TJ protein abundance of ZO-1 and occludin in ECs, promoted the migration of ECs, and finally reduced the integrity of iBRB. Taken together, our data show that RMP relative location with ECs is involved in the integrity of iBRB via MMP-2/9 and has important implications for treating diabetic retinopathy and other retinal disorders involving iBRB dysfunction.

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“…For this reason, numerous in vitro models were validated to mimic the in vivo conditions, which represent valuable tools to study the impact of high glucose at the BRB level as well as the trafficking between barrier sides or to develop novel molecules with beneficial effects against the BRB injury. An in vitro model of human BRB uses retinal pericytes, retinal astrocytes, and endothelial cells applicating the same in vivo layer order and the numerical ratio to mimic the physiological conditions [ 88 ]. After the assessment of the barrier, it was shown that glucose exposure induced BRB breakdown, increased barrier permeability, and reduced the expression of junctional proteins [ 88 ].…”

Section: Alternative 2d In Vitro Modelsmentioning

confidence: 99%

Looking for In Vitro Models for Retinal Diseases

Alfonsetti

Castelli

Benedetti

et al. 2021

IJMS

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Retina is a layered structure of the eye, composed of different cellular components working together to produce a complex visual output. Because of its important role in visual function, retinal pathologies commonly represent the main causes of visual injury and blindness in the industrialized world. It is important to develop in vitro models of retinal diseases to use them in first screenings before translating in in vivo experiments and clinics. For this reason, it is important to develop bidimensional (2D) models that are more suitable for drug screening and toxicological studies and tridimensional (3D) models, which can replicate physiological conditions, for investigating pathological mechanisms leading to visual loss. This review provides an overview of the most common retinal diseases, relating to in vivo models, with a specific focus on alternative 2D and 3D in vitro models that can replicate the different cellular and matrix components of retinal layers, as well as injury insults that induce retinal disease and loss of the visual function.

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A New Human Blood–Retinal Barrier Model Based on Endothelial Cells, Pericytes, and Astrocytes

Cited by 60 publications

References 75 publications

EndMT Regulation by Small RNAs in Diabetes-Associated Fibrotic Conditions: Potential Link With Oxidative Stress

EndMT Regulation by Small RNAs in Diabetes-Associated Fibrotic Conditions: Potential Link With Oxidative Stress

Pericytes of Indirect Contact Coculture Decrease Integrity of Inner Blood-Retina Barrier Model In Vitro by Upgrading MMP-2/9 Activity

Looking for In Vitro Models for Retinal Diseases

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