Muller glial cells span the entire thickness of the tissue, and ensheath all retinal neurons, in vertebrate retinae of all species. This morphological relationship is reflected by a multitude of functional interactions between neurons and Muller cells, including a 'metabolic symbiosis' and the processing of visual information. Muller cells are also responsible for the maintenance of the homeostasis of the retinal extracellular milieu (ions, water, neurotransmitter molecules, and pH). In vascularized retinae, Muller cells may also be involved in the control of angiogenesis, and the regulation of retinal blood flow. Virtually every disease of the retina is associated with a reactive Muller cell gliosis which, on the one hand, supports the survival of retinal neurons but, on the other hand, may accelerate the progress of neuronal degeneration: Muller cells protect neurons via a release of neurotrophic factors, the uptake and degradation of the excitotoxin, glutamate, and the secretion of the antioxidant, glutathione. However, gliotic Muller cells display a dysregulation of various neuron-supportive functions. This contributes to a disturbance of retinal glutamate metabolism and ion homeostasis, and causes the development of retinal edema and neuronal cell death. Moreover, there are diseases evoking a primary Muller cell insufficiency, such as hepatic retinopathy and certain forms of glaucoma. Any impairment of supportive functions of Muller cells, primary or secondary, must cause and/or aggravate a dysfunction and loss of neurons, by increasing the susceptibility of neurons to stressful stimuli in the diseased retina. On the contrary, Muller cells may be used in the future for novel therapeutic strategies to protect neurons against apoptosis (somatic gene therapy), or to differentiate retinal neurons from Muller/stem cells. Meanwhile, a proper understanding of the gliotic responses of Muller cells in the diseased retina, and of their protective vs. detrimental effects, is essential for the development of efficient therapeutic strategies that use and stimulate the neuron-supportive/protective-and prevent the destructive-mechanisms of gliosis.

https://www.springer.com/cda/content/document/productFlyer/productFlyer_978-1-4419-1671-6.pdf?SGWID=0-0-1297-173938007-0

Müller Cells in the Healthy and Diseased Retina

Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema.

Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of blindness in the working-age population of most developed countries. The increasing number of individuals with diabetes worldwide suggests that DR and DME will continue to be major contributors to vision loss and associated functional impairment for years to come. Early detection of retinopathy in individuals with diabetes is critical in preventing visual loss, but current methods of screening fail to identify a sizable number of high-risk patients. The control of diabetes-associated metabolic abnormalities (i.e., hyperglycemia, hyperlipidemia, and hypertension) is also important in preserving visual function because these conditions have been identified as risk factors for both the development and progression of DR/DME. The currently available interventions for DR/DME, laser photocoagulation and vitrectomy, only target advanced stages of disease. Several biochemical mechanisms, including protein kinase C-beta activation, increased vascular endothelial growth factor production, oxidative stress, and accumulation of intracellular sorbitol and advanced glycosylation end products, may contribute to the vascular disruptions that characterize DR/DME. The inhibition of these pathways holds the promise of intervention for DR at earlier non-sight-threatening stages. To implement new therapies effectively, more individuals will need to be screened for DR/DME at earlier stages-a process requiring both improved technology and interdisciplinary cooperation among physicians caring for patients with diabetes.

https://care.diabetesjournals.org/content/diacare/26/9/2653.full.pdf

Diabetic Retinopathy and Diabetic Macular Edema: Pathophysiology, screening, and novel therapies

Intravitreal aflibercept for diabetic macular edema.

Diabetic macular edema: pathogenesis and treatment.

Diabetic maculopathy is characterized by the accumulation of extracellular fluid in Henle's layer and the inner nuclear layer of the retina. The localization of the edema is likely to be due, in part, to the relative barrier properties of the inner and outer plexiform layers. The origin of the extracellular fluid is from the intravascular compartment. Although changes to retinal blood flow may partly explain the extravasation of fluid, the most important mechanism is breakdown of the blood retinal barriers. Both the inner blood retinal barrier formed by the retinal capillary endothelial cell tight junctions and the outer barrier formed by the retinal pigment epithelial cell tight junctions can be affected. The mechanism of breakdown of the blood retinal barriers is likely to be changes to the tight junction proteins including occludin and ZO-1. The biochemical messenger inducing these changes may be vascular endothelial growth factor. The origin of this or other cofactors may be the retinal glial cells. The underlying biochemical stimulus to the production of vascular endothelial growth factor is chronic hyperglycaemia, but it is uncertain by what pathway this is effected.

R. J. Antcliff

Papers

The Pathogenesis of Edema in Diabetic Maculopathy