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Glia Jul 2022Microglia are known for important phagocytic functions in the vertebrate retina. Reports also suggest that Müller glia have phagocytic capacity, though the relative...
Microglia are known for important phagocytic functions in the vertebrate retina. Reports also suggest that Müller glia have phagocytic capacity, though the relative levels and contexts in which this occurs remain to be thoroughly examined. Here, we investigate Müller glial engulfment of dying cells in the developing zebrafish retina in the presence and absence of microglia, using a genetic mutant in which microglia do not develop. We show that in normal conditions clearance of dying cells is dominated by microglia; however, Müller glia do have a limited clearance role. In retinas lacking intact microglial populations, we found a striking increase in the engulfment load assumed by the Müller glia, which displayed prominent cellular compartments containing apoptotic cells, several of which localized with the early phagosome/endosome marker Rab5. Consistent with increased engulfment, lysosomal staining was also increased in Müller glia in the absence of microglia. Increased engulfment load led to evidence of Müller glia reactivity including upregulation of gfap but did not trigger cell cycle re-entry by differentiated Müller glia. Our work provides important insight into the phagocytic capacity of Müller glia and the ability for compensatory functions and downstream effects. Therefore, effects of microglial deficiency or depletion on other glial cell types should be well-considered in experimental manipulations, in neurodegenerative disease, and in therapeutic approaches that target microglia. Our findings further justify future work to understand differential mechanisms and contexts of phagocytosis by glial cells in the central nervous system, and the significance of these mechanisms in health and disease.
Topics: Animals; Ependymoglial Cells; Microglia; Neurodegenerative Diseases; Neuroglia; Retina; Zebrafish
PubMed: 35451181
DOI: 10.1002/glia.24182 -
The European Journal of Neuroscience Jun 2018Müller glial cells (MGCs) are known to participate actively in retinal development and to contribute to homoeostasis through many intracellular mechanisms. As there are... (Review)
Review
Müller glial cells (MGCs) are known to participate actively in retinal development and to contribute to homoeostasis through many intracellular mechanisms. As there are no homologous cells in other neuronal tissues, it is certain that retinal health depends on MGCs. These macroglial cells are located at the centre of the columnar subunit and have a great ability to interact with neurons, astrocytes, microglia and endothelial cells in order to modulate different events. Several investigations have focused their attention on the role of MGCs in diabetic retinopathy, a progressive pathology where several insults coexist. As expected, data suggest that MGCs display different responses according to the severity of the stimulus, and therefore trigger distinct events throughout the course of the disease. Here, we describe physiological functions of MGCs and their participation in inflammation, gliosis, synthesis and secretion of trophic and antioxidant factors in the diabetic retina. We invite the reader to consider the protective/deleterious role of MGCs in the early and late stages of the disease. In the light of the results, we open up the discussion around and ask the question: Is it possible that the modulation of a single cell type could improve or even re-establish retinal function after an injury?
Topics: Animals; Diabetic Retinopathy; Ependymoglial Cells; Gliosis; Humans; Inflammation; Nerve Growth Factors; Oxidative Stress
PubMed: 29790615
DOI: 10.1111/ejn.13965 -
Biomedical Materials (Bristol, England) Nov 2022Müller cells are the principal glial cells for the maintenance of structural stability and metabolic homeostasis in the human retina. Although variousexperiments using...
Müller cells are the principal glial cells for the maintenance of structural stability and metabolic homeostasis in the human retina. Although variousexperiments using two-dimensional (2D) monolayer cell cultures have been performed, the results provided only limited results because of the lack of 3D structural environment and different cellular morphology. We studied a Müller cell-based 3D biomimetic model for use in experiments on the-like functions of Müller cells within the sensory retina. Isolated primary Müller cells were bioprinted and a 3D-aligned architecture was induced, which aligned Müller cell structure in retinal tissue. The stereographic and functional characteristics of the biomimetic model were investigated and compared to those of the conventional 2D cultured group. The results showed the potential to generate Müller cell-based biomimetic models with characteristic morphological features such as endfeet, soma, and microvilli. Especially, the 3D Müller cell model under hyperglycemic conditions showed similar responses as observed in thediabetic model with retinal changes, whereas the conventional 2D cultured group showed different cytokine and growth factor secretions. These results show that our study is a first step toward providing advanced tools to investigate thefunction of Müller cells and to develop complete 3D models of the vertebrate retina.
Topics: Humans; Bioprinting; Ependymoglial Cells; Biomimetics; Retina; Neuroglia
PubMed: 36343367
DOI: 10.1088/1748-605X/aca0d5 -
Microvascular Research Jul 2024Exosomes are nanosized vesicles that have been reported as cargo-delivering vehicles between cells. Müller cells play a crucial role in the pathogenesis of diabetic...
Exosomes are nanosized vesicles that have been reported as cargo-delivering vehicles between cells. Müller cells play a crucial role in the pathogenesis of diabetic retinopathy (DR). Activated Müller cells in the diabetic retina mediate disruption of barrier integrity and neovascularization. Endothelial cells constitute the inner blood-retinal barrier (BRB). Herein, we aim to evaluate the effect of Müller cell-derived exosomes on endothelial cell viability and barrier function under normal and hyperglycemic conditions. Müller cell-derived exosomes were isolated and characterized using Western blotting, nanoparticle tracking, and electron microscopy. The uptake of Müller cells-derived exosomes by the human retinal endothelial cells (HRECs) was monitored by labeling exosomes with PKH67. Endothelial cell vitality after treatment by exosomes under normo- and hypoglycemic conditions was checked by MTT assay and Western blot for apoptotic proteins. The barrier function of HRECs was evaluated by analysis of ZO-1 and transcellular electrical resistance (TER) using ECIS. Additionally, intracellular Ca in HRECs was assessed by spectrofluorimetry. Analysis of the isolated exosomes showed a non-significant change in the number of exosomes isolated from both normal and hyperglycemic condition media, however, the average size of exosomes isolated from the hyperglycemic group showed a significant rise when compared to that of the normoglycemic group. Müller cells derived exosomes from hyperglycemic condition media markedly reduced HRECs cell count, increased caspase-3 and Annexin V, decreased ZO-1 levels and TER, and increased intracellular Ca when compared to other groups. However, treatment of HRECs under hyperglycemia with normo-glycemic Müller cells-derived exosomes significantly decreased cell death, preserved cellular integrity and barrier function, and reduced intracellular Ca. Collectively, Müller cell-derived exosomes play a remarkable role in the pathological changes associated with hyperglycemia-induced inner barrier dysfunction in DR. Further in vivo research will help in understanding the role of exosomes as therapeutic targets and/or delivery systems for DR.
Topics: Exosomes; Diabetic Retinopathy; Ependymoglial Cells; Humans; Endothelial Cells; Blood-Retinal Barrier; Cell Survival; Cells, Cultured; Apoptosis; Zonula Occludens-1 Protein; Capillary Permeability; Calcium Signaling; Cell Line; Retinal Vessels
PubMed: 38723843
DOI: 10.1016/j.mvr.2024.104695 -
Annual Review of Vision Science Sep 2020Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and... (Review)
Review
Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and cells of the retinal pigment epithelium (RPE), which provide essential metabolites, phagocytose waste, and control the composition of the surrounding microenvironment. A third vital supporting cell type, the retinal microglia, can provide photoreceptors with neurotrophic support or exacerbate neuroinflammation and hasten neuronal cell death. Understanding the physiological requirements for photoreceptor homeostasis and the factors that drive microglia to best promote photoreceptor survival has important implications for the treatment and prevention of blinding degenerative diseases like retinitis pigmentosa and age-related macular degeneration.
Topics: Animals; Apoptosis; Ependymoglial Cells; Humans; Macrophage Activation; Phagocytosis; Photoreceptor Cells; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinal Pigment Epithelium; Signal Transduction
PubMed: 32936734
DOI: 10.1146/annurev-vision-121219-081730 -
Neuroendocrinology 2020Tanycytes are peculiar ependymoglial cells lining the bottom and the lateral wall of the third ventricle. For a decade, the utilization of molecular genetic approaches... (Review)
Review
Tanycytes are peculiar ependymoglial cells lining the bottom and the lateral wall of the third ventricle. For a decade, the utilization of molecular genetic approaches allowed us to make important discoveries about their diverse physiological functions. Here, I review the current methods used to target tanycytes, focusing on their specificity, their efficiency, their limitations, as well as their potential future improvements.
Topics: Animals; Drug Delivery Systems; Ependymoglial Cells; Gene Expression Regulation; Gene Targeting; Humans; Sensitivity and Specificity; Third Ventricle
PubMed: 31986518
DOI: 10.1159/000505549 -
Biochemistry. Biokhimiia Sep 2018Age is the major risk factor in the age-related macular degeneration (AMD) which is a complex multifactor neurodegenerative disease of the retina and the main cause of... (Review)
Review
Age is the major risk factor in the age-related macular degeneration (AMD) which is a complex multifactor neurodegenerative disease of the retina and the main cause of irreversible vision loss in people over 60 years old. The major role in AMD pathogenesis belongs to structure-functional changes in the retinal pigment epithelium cells, while the onset and progression of AMD are commonly believed to be caused by the immune system dysfunctions. The role of retinal glial cells (Muller cells, astrocytes, and microglia) in AMD pathogenesis is studied much less. These cells maintain neurons and retinal vessels through the synthesis of neurotrophic and angiogenic factors, as well as perform supporting, separating, trophic, secretory, and immune functions. It is known that retinal glia experiences morphological and functional changes with age. Age-related impairments in the functional activity of glial cells are closely related to the changes in the expression of trophic factors that affect the status of all cell types in the retina. In this review, we summarized available literature data on the role of retinal macro- and microglia and on the contribution of these cells to AMD pathogenesis.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Astrocytes; Ependymoglial Cells; Gliosis; Humans; Intercellular Signaling Peptides and Proteins; Macular Degeneration; Neuroglia; Retina
PubMed: 30472939
DOI: 10.1134/S000629791809002X -
Aging and Disease May 2024Age-related macular degeneration (AMD) is a progressive neurodegeneration disease that causes photoreceptor demise and vision impairments. In AMD pathogenesis, the... (Review)
Review
Age-related macular degeneration (AMD) is a progressive neurodegeneration disease that causes photoreceptor demise and vision impairments. In AMD pathogenesis, the primary death of retinal neurons always leads to the activation of resident microglia. The migration of activated microglia to the ongoing retinal lesion and their morphological transformation from branching to ameboid-like are recognized as hallmarks of AMD pathogenesis. Activated microglia send signals to Müller cells and promote them to react correspondingly to damaging stimulus. Müller cells are a type of neuroglia cells that maintain the normal function of retinal neurons, modulating innate inflammatory responses, and stabilize retinal structure. Activated Müller cells can accelerate the progression of AMD by damaging neurons and blood vessels. Therefore, the crosstalk between microglia and Müller cells plays a homeostatic role in maintaining the retinal environment, and this interaction is complicatedly modulated. In particular, the mechanism of mutual regulation between the two glia populations is complex under pathological conditions. This paper reviews recent findings on the crosstalk between microglia and Müller glia during AMD pathology process, with special emphasis on its therapeutic potentials.
Topics: Humans; Macular Degeneration; Ependymoglial Cells; Microglia; Neuroinflammatory Diseases; Animals
PubMed: 37728589
DOI: 10.14336/AD.2023.0823-3 -
Graefe's Archive For Clinical and... Feb 2020Diabetic retinopathy (DR) is a sight-threatening complication associated with the highly prevalent diabetes disorder. Both the microvascular damage and neurodegeneration... (Review)
Review
Diabetic retinopathy (DR) is a sight-threatening complication associated with the highly prevalent diabetes disorder. Both the microvascular damage and neurodegeneration detected in the retina caused by chronic hyperglycemia have brought special attention to Müller cells, the major macroglia of the retina that are responsible for retinal homeostasis. Given the role of glucocorticoid signaling in anti-inflammatory responses and the almost exclusive expression of glucocorticoid receptors (GRs) in retinal Müller cells, administration of corticosteroid agonists as a potential treatment option has been widely studied. Although these approaches have been moderately efficacious in treating or de-escalating DR pathomechanisms, there are various side effects and gaps of knowledge with regard to introducing exogenous glucocorticoids to the diseased retina. In this paper, we provide a review of the literature concerning the available evidence for the role of Müller cell glucocorticoid signaling in DR and we discuss previously investigated approaches in modulating this system as possible treatment options. Furthermore, we propose a novel alternative to the available choices of treatment by using gene therapy as a tool to regulate the expression of GR in retinal Müller cells. Upregulating GR expression allows for induced glucocorticoid signaling with more enduring effects compared to injection of agonists. Hence, repetitive injections would no longer be required. Lastly, side effects of glucocorticoid therapy such as glucocorticoid resistance of GR following chronic exposure to excess ligands or agonists can be avoided.
Topics: Animals; Diabetic Retinopathy; Ependymoglial Cells; Humans; Receptors, Glucocorticoid; Retina; Signal Transduction
PubMed: 31734719
DOI: 10.1007/s00417-019-04521-w -
ASN Neuro 2022Müller glial cells exert multiple essential functions in retinal physiology and retinopathies reflecting perhaps the existence of distinct Müller cellular...
Müller glial cells exert multiple essential functions in retinal physiology and retinopathies reflecting perhaps the existence of distinct Müller cellular subpopulations. Harnessing Müller cell heterogeneity may serve to enhance new therapeutic approaches for retinal disease.
Topics: Ependymoglial Cells; Neuroglia; Retina
PubMed: 35673270
DOI: 10.1177/17590914221106903