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Trends in Endocrinology and Metabolism:... Apr 2020Müller cells are glia that play important regulatory roles in retinal metabolism. These roles have been evolutionarily conserved across at least 300 million years.... (Review)
Review
Müller cells are glia that play important regulatory roles in retinal metabolism. These roles have been evolutionarily conserved across at least 300 million years. Müller cells have a tightly locked metabolic signature in the healthy retina, which rapidly degrades in response to insult and disease. This variation in metabolic signature occurs in a chaotic fashion, involving some central metabolic pathways. The cause of this divergence of Müller cells, from a single class with a unique metabolic signature to numerous separable metabolic classes, is currently unknown and illuminates potential alternative metabolic pathways that may be revealed in disease. Understanding the impacts of this heterogeneity on degenerate retinas and the implications for the metabolic support of surrounding neurons will be critical to long-term integration of retinal therapeutics for the restoration of visual perception following photoreceptor degeneration.
Topics: Ependymoglial Cells; Glutamate-Ammonia Ligase; Humans; Metabolome; Retinal Degeneration
PubMed: 32187524
DOI: 10.1016/j.tem.2020.01.005 -
Cells Jul 2021Müller glia, the major glial cell types in the retina, maintain retinal homeostasis and provide structural support to retinal photoreceptors. They also possess... (Review)
Review
Müller glia, the major glial cell types in the retina, maintain retinal homeostasis and provide structural support to retinal photoreceptors. They also possess regenerative potential that might be used for retinal repair in response to injury or disease. In teleost fish (such as zebrafish), the Müller glia response to injury involves reprogramming events that result in a population of proliferative neural progenitors that can regenerate the injured retina. Recent studies have revealed several important mechanisms for the regenerative capacity of Müller glia in fish, which may shed more light on the mechanisms of Müller glia reprogramming and regeneration in mammals. Mammalian Müller glia can adopt stem cell characteristics, and in response to special conditions, be persuaded to proliferate and regenerate, although their native regeneration potential is limited. In this review, we consider the work to date revealing the regenerative potential of the mammalian Müller glia and discuss whether they are a potential source for cell regeneration therapy in humans.
Topics: Animals; Cell Differentiation; Cell Proliferation; Ependymoglial Cells; Humans; Regeneration; Retina; Retinal Diseases; Signal Transduction; Stem Cells
PubMed: 34440726
DOI: 10.3390/cells10081957 -
Translational Vision Science &... Sep 2021The purpose of this study was to image and investigate the foveal microstructure of human cone and Müller cells using adaptive optics-optical coherence tomography.
PURPOSE
The purpose of this study was to image and investigate the foveal microstructure of human cone and Müller cells using adaptive optics-optical coherence tomography.
METHODS
Six healthy subjects underwent the prototype adaptive optics-optical coherence tomography imaging, which allowed an axial resolution of 3.4 µm and a transverse resolution of approximately 3 µm. The morphological features of the individual retinal cells observed in the foveola were qualitatively and quantitatively evaluated.
RESULTS
In the six healthy subjects, the image B-scans showed hyper-reflective dots that were densely packed in the outer nuclear layer. The mean number, diameter, and density of hyper-reflective dots in the foveola were 250.8 ± 59.6, 12.7 ± 59.6 µm, and 6966 ± 1833/mm2, respectively. These qualitative and quantitative findings regarding the hyper-reflective dots were markedly consistent with the morphological features of the foveal cone cell nuclei. Additionally, the images showed the funnel-shaped hyporeflective bodies running vertically and obliquely between the inner and external limiting membranes, illustrating the cell morphology of the foveal Müller cells.
CONCLUSIONS
Using adaptive optics, we succeeded in visualizing cross-sectional images of the individual cone and Müller cells of the human retina in vivo.
TRANSLATIONAL RELEVANCE
Adaptive optics-optical coherence tomography would help to improve our understanding of the pathogenesis of macular diseases.
Topics: Ependymoglial Cells; Fovea Centralis; Humans; Retinal Cone Photoreceptor Cells; Tomography, Optical Coherence; Visual Acuity
PubMed: 34559184
DOI: 10.1167/tvst.10.11.17 -
Frontiers in Endocrinology 2022The median eminence (ME) is part of the neuroendocrine system (NES) that functions as a crucial interface between the hypothalamus and pituitary gland. The ME contains... (Review)
Review
The median eminence (ME) is part of the neuroendocrine system (NES) that functions as a crucial interface between the hypothalamus and pituitary gland. The ME contains many non-neuronal cell types, including oligodendrocytes, oligodendrocyte precursor cells (OPCs), tanycytes, astrocytes, pericytes, microglia and other immune cells, which may be involved in the regulation of NES function. For example, in mice, ablation of tanycytes (a special class of ependymal glia with stem cell-like functions) results in weight gain, feeding, insulin insensitivity and increased visceral adipose, consistent with the demonstrated ability of these cells to sense and transport both glucose and leptin, and to differentiate into neurons that control feeding and metabolism in the hypothalamus. To give a further example, OPCs in the ME of mice have been shown to rapidly respond to dietary signals, in turn controlling composition of the extracellular matrix in the ME, derived from oligodendrocyte-lineage cells, which may contribute to the previously described role of these cells in actively maintaining leptin-receptor-expressing dendrites in the ME. In this review, we explore and discuss recent advances such as these, that have developed our understanding of how the various cell types of the ME contribute to its function in the NES as the interface between the hypothalamus and pituitary gland. We also highlight avenues of future research which promise to uncover additional functions of the ME and the glia, stem and progenitor cells it contains.
Topics: Animals; Ependymoglial Cells; Hypothalamus; Leptin; Median Eminence; Mice; Neuroglia
PubMed: 35966104
DOI: 10.3389/fendo.2022.953995 -
Diabetologia Dec 2022CD40 expressed in Müller cells is a central driver of diabetic retinopathy. CD40 causes phospholipase Cγ1 (PLCγ1)-dependent ATP release in Müller cells followed by...
AIMS/HYPOTHESIS
CD40 expressed in Müller cells is a central driver of diabetic retinopathy. CD40 causes phospholipase Cγ1 (PLCγ1)-dependent ATP release in Müller cells followed by purinergic receptor (P2X)-dependent production of proinflammatory cytokines in myeloid cells. In the diabetic retina, CD40 and P2X upregulate a broad range of inflammatory molecules that promote development of diabetic retinopathy. The molecular event downstream of CD40 that activates the PLCγ1-ATP-P2X-proinflammatory cytokine cascade and promotes development of diabetic retinopathy is unknown. We hypothesise that disruption of the CD40-driven molecular events that trigger this cascade prevents/treats diabetic retinopathy in mice.
METHODS
B6 and transgenic mice with Müller cell-restricted expression of wild-type (WT) CD40 or CD40 with mutations in TNF receptor-associated factor (TRAF) binding sites were made diabetic using streptozotocin. Leucostasis was assessed using FITC-conjugated concanavalin A. Histopathology was examined in the retinal vasculature. Expression of inflammatory molecules and phospho-Tyr783 PLCγ1 (p-PLCγ1) were assessed using real-time PCR, immunoblot and/or immunohistochemistry. Release of ATP and cytokines were measured by ATP bioluminescence and ELISA, respectively.
RESULTS
Human Müller cells with CD40 ΔT2,3 (lacks TRAF2,3 binding sites) were unable to phosphorylate PLCγ1 and release ATP in response to CD40 ligation, and could not induce TNF-α/IL-1β secretion in bystander myeloid cells. CD40-TRAF signalling acted via Src to induce PLCγ1 phosphorylation. Diabetic mice in which WT CD40 in Müller cells was replaced by CD40 ΔT2,3 failed to exhibit phosphorylation of PLCγ1 in these cells and upregulate P2X and TNF-α in microglia/macrophages. P2x (also known as P2rx7), Tnf-α (also known as Tnf), Il-1β (also known as Il1b), Nos2, Icam-1 (also known as Icam1) and Ccl2 mRNA were not increased in these mice and the mice did not develop retinal leucostasis and capillary degeneration. Diabetic B6 mice treated intravitreally with a cell-permeable peptide that disrupts CD40-TRAF2,3 signalling did not exhibit either upregulation of P2X and inflammatory molecules in the retina or leucostasis.
CONCLUSIONS/INTERPRETATION
CD40-TRAF2,3 signalling activated the CD40-PLCγ1-ATP-P2X-proinflammatory cytokine pathway. Src functioned as a link between CD40-TRAF2,3 and PLCγ1. Replacing WT CD40 with CD40 ΔT2,3 impaired activation of PLCγ1 in Müller cells, upregulation of P2X in microglia/macrophages, upregulation of a broad range of inflammatory molecules in the diabetic retina and the development of diabetic retinopathy. Administration of a peptide that disrupts CD40-TRAF2,3 signalling reduced retinal expression of inflammatory molecules and reduced leucostasis in diabetic mice, supporting the therapeutic potential of pharmacological inhibition of CD40-TRAF2,3 in diabetic retinopathy.
Topics: Mice; Humans; Animals; Ependymoglial Cells; Diabetic Retinopathy; Diabetes Mellitus, Experimental; Tumor Necrosis Factor-alpha; TNF Receptor-Associated Factor 2; CD40 Antigens; Retina; Inflammation; Cytokines; Peptides; Adenosine Triphosphate; Mutation
PubMed: 35920844
DOI: 10.1007/s00125-022-05775-6 -
Experimental Eye Research Jan 2016In response to injury, reparative processes are triggered to restore the damaged tissue; however, such processes are not always successful in rebuilding the original... (Review)
Review
In response to injury, reparative processes are triggered to restore the damaged tissue; however, such processes are not always successful in rebuilding the original state. The formation of fibrous connective tissue is known as fibrosis, a hallmark of the reparative process. For fibrosis to be successful, delicately balanced cellular events involving cell proliferation, cell migration, and extracellular matrix (ECM) remodeling must occur in a highly orchestrated manner. While successful repair may result in a fibrous scar, this often restores structural stability and functionality to the injured tissue. However, depending on the functionality of the injured tissue, a fibrotic scar can have a devastating effect. For example, in the retina, fibrotic scarring may compromise vision and ultimately lead to blindness. In this review, we discuss some of the retinal fibrotic complications and highlight mechanisms underlying the development of retinal fibrosis in diabetic retinopathy.
Topics: Angiogenesis Inhibitors; Diabetic Retinopathy; Ependymoglial Cells; Fibrosis; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Light Coagulation; Neuroglia
PubMed: 26675403
DOI: 10.1016/j.exer.2015.04.004 -
Investigative Ophthalmology & Visual... Mar 2020To analyze the role of microglial and Müller cells in the formation of rings of photoreceptor degeneration caused by phototoxicity.
PURPOSE
To analyze the role of microglial and Müller cells in the formation of rings of photoreceptor degeneration caused by phototoxicity.
METHODS
Two-month-old Sprague-Dawley rats were exposed to light and processed 1, 2, or 3 months later. Retinas were dissected as whole-mounts, immunodetected for microglial cells, Müller cells, and S- and L/M-cones and analyzed using fluorescence, thunder imaging, and confocal microscopy. Cone populations were automatically counted and isodensity maps constructed to document cone topography.
RESULTS
Phototoxicity causes a significant progressive loss of S- and L/M-cones of up to 68% and 44%, respectively, at 3 months after light exposure (ALE). One month ALE, we observed rings of cone degeneration in the photosensitive area of the superior retina. Two and 3 months ALE, these rings had extended to the central and inferior retina. Within the rings of cone degeneration, there were degenerating cones, often activated microglial cells, and numerous radially oriented processes of Müller cells that showed increased expression of intermediate filaments. Between 1 and 3 months ALE, the rings coalesced, and at the same time the microglial cells resumed a mosaic-like distribution, and there was a decrease of Müller cell gliosis at the areas devoid of cones.
CONCLUSIONS
Light-induced photoreceptor degeneration proceeds with rings of cone degeneration, as observed in inherited retinal degenerations in which cone death is secondary to rod degeneration. The spatiotemporal relationship of cone death microglial cell activation and Müller cell gliosis within the rings of cone degeneration suggests that, although both glial cells are involved in the formation of the rings, they may have coordinated actions and, while microglial cells may be more involved in photoreceptor phagocytosis, Müller cells may be more involved in cone and microglial cell migration, retinal remodeling and glial seal formation.
Topics: Animals; Cone Opsins; Ependymoglial Cells; Gliosis; Light; Microglia; Microscopy, Confocal; Microscopy, Fluorescence; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Retina; Retinal Cone Photoreceptor Cells; Retinal Degeneration
PubMed: 32232352
DOI: 10.1167/iovs.61.3.47 -
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 -
ASN Neuro 2022Müller glial cells (MGCs), the main glial component of the retina, play an active role in retinal homeostasis during development and pathological processes. They... (Review)
Review
Müller glial cells (MGCs), the main glial component of the retina, play an active role in retinal homeostasis during development and pathological processes. They strongly monitor retinal environment and, in response to retinal imbalance, activate neuroprotective mechanisms mainly characterized by the increase of glial fibrillary acidic protein (GFAP). Under these circumstances, if homeostasis is not reestablished, the retina can be severely injured and GFAP contributes to neuronal degeneration, as they occur in several proliferative retinopathies such as diabetic retinopathy, sickle cell retinopathy and retinopathy of prematurity. In addition, MGCs have an active participation in inflammatory responses releasing proinflammatory mediators and metalloproteinases to the extracellular space and vitreous cavity. MGCs are also involved in the retinal neovascularization and matrix extracellular remodeling during the proliferative stage of retinopathies. Interestingly, low-density lipoprotein receptor-related protein 1 (LRP1) and its ligand α-macroglobulin (αM) are highly expressed in MGCs and they have been established to participate in multiple cellular and molecular activities with relevance in retinopathies. However, the exact mechanism of regulation of retinal LRP1 in MGCs is still unclear. Thus, the active participation of MGCs and LRP1 in these diseases, strongly supports the potential interest of them for the design of novel therapeutic approaches. In this review, we discuss the role of LRP1 in the multiple MGCs activities involved in the development and progression of proliferative retinopathies, identifying opportunities in the field that beg further research in this topic area.MGCs and LRP1 are active players in injured retinas, participating in key features such as gliosis and neurotoxicity, neovascularization, inflammation, and glucose control homeostasis during the progression of ischemic diseases, such as proliferative retinopathies.
Topics: Humans; Ependymoglial Cells; Glial Fibrillary Acidic Protein; Low Density Lipoprotein Receptor-Related Protein-1; Retina; Retinal Neovascularization
PubMed: 36317314
DOI: 10.1177/17590914221136365 -
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