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Progress in Retinal and Eye Research Sep 2018A fovea is a pitted invagination in the inner retinal tissue (fovea interna) that overlies an area of photoreceptors specialized for high acuity vision (fovea externa).... (Review)
Review
A fovea is a pitted invagination in the inner retinal tissue (fovea interna) that overlies an area of photoreceptors specialized for high acuity vision (fovea externa). Although the shape of the vertebrate fovea varies considerably among the species, there are two basic types. The retina of many predatory fish, reptilians, and birds possess one (or two) convexiclivate fovea(s), while the retina of higher primates contains a concaviclivate fovea. By refraction of the incoming light, the convexiclivate fovea may function as image enlarger, focus indicator, and movement detector. By centrifugal displacement of the inner retinal layers, which increases the transparency of the central foveal tissue (the foveola), the primate fovea interna improves the quality of the image received by the central photoreceptors. In this review, we summarize ‒ with the focus on Müller cells of the human and macaque fovea ‒ data regarding the structure of the primate fovea, discuss various aspects of the optical function of the fovea, and propose a model of foveal development. The "Müller cell cone" of the foveola comprises specialized Müller cells which do not support neuronal activity but may serve optical and structural functions. In addition to the "Müller cell cone", structural stabilization of the foveal morphology may be provided by the 'z-shaped' Müller cells of the fovea walls, via exerting tractional forces onto Henle fibers. The spatial distribution of glial fibrillary acidic protein may suggest that the foveola and the Henle fiber layer are subjects to mechanical stress. During development, the foveal pit is proposed to be formed by a vertical contraction of the centralmost Müller cells. After widening of the foveal pit likely mediated by retracting astrocytes, Henle fibers are formed by horizontal contraction of Müller cell processes in the outer plexiform layer and the centripetal displacement of photoreceptors. A better understanding of the molecular, cellular, and mechanical factors involved in the developmental morphogenesis and the structural stabilization of the fovea may help to explain the (patho-) genesis of foveal hypoplasia and macular holes.
Topics: Animals; Astrocytes; Ependymoglial Cells; Fovea Centralis; Glial Fibrillary Acidic Protein; Humans; Macaca; Retinal Diseases
PubMed: 29609042
DOI: 10.1016/j.preteyeres.2018.03.006 -
Translational Vision Science &... Apr 2022Müller glia (MG) in the retina of Xenopus laevis (African clawed frog) reprogram to a transiently amplifying retinal progenitor state after an injury. These progenitors...
PURPOSE
Müller glia (MG) in the retina of Xenopus laevis (African clawed frog) reprogram to a transiently amplifying retinal progenitor state after an injury. These progenitors then give rise to new retinal neurons. In contrast, mammalian MG have a restricted neurogenic capacity and undergo reactive gliosis after injury. This study sought to establish MG cell lines from the regeneration-competent frog and the regeneration-deficient mouse.
METHODS
MG were isolated from postnatal day 5 GLAST-CreERT; Rbfl/fl mice and from adult (3-5 years post-metamorphic) X laevis. Serial adherent subculture resulted in spontaneously immortalized cells and the establishment of two MG cell lines: murine retinal glia 17 (RG17) and Xenopus glia 69 (XG69). They were characterized for MG gene and protein expression by qPCR, immunostaining, and Western blot. Purinergic signaling was assessed with calcium imaging. Pharmacological perturbations with 2'-3'-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (BzATP) and KN-62 were performed on RG17 cells.
RESULTS
RG17 and XG69 cells express several MG markers and retain purinergic signaling. Pharmacological perturbations of intracellular calcium responses with BzATP and KN-62 suggest that the ionotropic purinergic receptor P2X7 is present and functional in RG17 cells. Stimulation of XG69 cells with adenosine triphosphate-induced calcium responses in a dose-dependent manner.
CONCLUSIONS
We report the characterization of RG17 and XG69, two novel MG cell lines from species with significantly disparate retinal regenerative capabilities.
TRANSLATIONAL RELEVANCE
RG17 and XG69 cell line models will aid comparative studies between species endowed with varied regenerative capacity and will facilitate the development of new cell-based strategies for treating retinal degenerative diseases.
Topics: Animals; Ependymoglial Cells; Mammals; Mice; Neuroglia; Retina; Retinal Neurons; Xenopus laevis
PubMed: 35377941
DOI: 10.1167/tvst.11.4.4 -
Molecular Neurobiology Jun 2018The Müller cells represent the predominant macroglial cell in the retina. In recent decades, Müller cells have been acknowledged to be far more influential on neuronal... (Review)
Review
The Müller cells represent the predominant macroglial cell in the retina. In recent decades, Müller cells have been acknowledged to be far more influential on neuronal homeostasis in the retina than previously assumed. With its unique localization, spanning the entire retina being interposed between the vessels and neurons, Müller cells are responsible for the functional and metabolic support of the surrounding neurons. As a consequence of major energy demands in the retina, high levels of glucose are consumed and processed by Müller cells. The present review provides a perspective on the symbiotic relationship between Müller cells and inner retinal neurons on a cellular level by emphasizing the essential role of energy metabolism within Müller cells in relation to retinal neuron survival.
Topics: Animals; Energy Metabolism; Ependymoglial Cells; Humans; Metabolomics; Neurons; Neurovascular Coupling; Retina
PubMed: 28929338
DOI: 10.1007/s12035-017-0760-7 -
Current Opinion in Neurobiology Dec 2017Müller Glia (MG), the radial glia cells of the retina, have spectacular morphologies subserving their enormous functional complexity. As early as 1892, the great... (Review)
Review
Müller Glia (MG), the radial glia cells of the retina, have spectacular morphologies subserving their enormous functional complexity. As early as 1892, the great neuroanatomist Santiago Ramon y Cajal studied the morphological development of MG, defining several steps in their morphogenesis [1,2]. However, the molecular cues controlling these developmental steps remain poorly understood. As MG have roles to play in every cellular and plexiform layer, this review discusses our current understanding on how MG morphology may be linked to their function, including the developmental mechanisms involved in MG patterning and morphogenesis. Uncovering the mechanisms governing glial morphogenesis, using transcriptomics and imaging, may provide shed new light on the pathophysiology and treatment of human neurological disorders.
Topics: Animals; Cell Differentiation; Ependymoglial Cells; Humans; Morphogenesis; Retina
PubMed: 28850820
DOI: 10.1016/j.conb.2017.08.005 -
Life Sciences Dec 2023Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus and one of the major causes of visual impairment and blindness in industrialized...
AIMS
Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus and one of the major causes of visual impairment and blindness in industrialized countries. The early neuro-glial perturbations, especially retinal Müller cells (rMC) activation, intimately associated with the vascular alterations. MicroRNAs (miRNAs) have been reported to play critical roles in the progression of DR. Here, we aimed to further explore the role and underlying mechanism of miR-423-5p in Müller cell activation in streptozotocin (STZ)-induced diabetic mice and oxygen-induced retinopathy (OIR) model.
MATERIALS AND METHODS
Retinal histology, optical coherence tomography (OCT) and biochemical markers were assessed.
KEY FINDINGS
Our data revealed that the expression of miR-423-5p was significantly increased under high-glucose environment. We also demonstrated that miR-423-5p overexpression markedly accelerated retinal vascular leakage, leukocytosis, and rMC activation. This response was ameliorated in animals pre-treated with the inhibition of miR-423-5p. Specifically, miR-423-5p bound to the nerve growth factor (NGF) 3' UTR region to induce its silencing. NGF inhibition significantly promoted retinal microvascular dysfunction.
SIGNIFICANCE
These findings demonstrate that miR-423-5p is a critical miRNA that promotes microvascular dysfunction in DR.
Topics: Mice; Animals; Diabetic Retinopathy; Ependymoglial Cells; Nerve Growth Factor; Diabetes Mellitus, Experimental; MicroRNAs
PubMed: 37925140
DOI: 10.1016/j.lfs.2023.122217 -
Cells Jun 2023Retinal detachment (RD) is a neurodegenerative blinding disease caused by plethora of clinical conditions. RD is characterized by the physical separation of retina from...
Retinal detachment (RD) is a neurodegenerative blinding disease caused by plethora of clinical conditions. RD is characterized by the physical separation of retina from the underlying retinal pigment epithelium (RPE), eventually leading to photoreceptor cell death, inflammation, and vision loss. Albeit the activation of complement plays a critical role in the pathogenesis of RD, the retinal cellular source for complement production remains elusive. Here, using C3 tdTomato reporter mice we show that retinal injury upregulates C3 expression, specifically in Müller cells. Activation of the complement cascade results in the generation of proinflammatory cleaved products, C3a and C5a, that bind C3aR and C5aR1, respectively. Our flow cytometry data show that retinal injury significantly upregulated C3aR and C5aR1 in microglia and resulted in the infiltration of peripheral immune cells. Loss of C3, C5, C3aR or C5aR1 reduced photoreceptor cell death and infiltration of microglia and peripheral immune cells into the sub-retinal space. These results indicate that C3/C3aR and C5/C5aR1 play a crucial role in eliciting photoreceptor degeneration and inflammatory responses in RD.
Topics: Mice; Animals; Ependymoglial Cells; Neuroinflammatory Diseases; Photoreceptor Cells; Cell Death; Retina; Retinal Detachment; Complement System Proteins
PubMed: 37443787
DOI: 10.3390/cells12131754 -
Mitochondrion Sep 2017Growing evidence suggests that mitochondrial dysfunction might play a key role in the pathogenesis of age-related neurodegenerative inner retinal diseases such as... (Review)
Review
Growing evidence suggests that mitochondrial dysfunction might play a key role in the pathogenesis of age-related neurodegenerative inner retinal diseases such as diabetic retinopathy and glaucoma. Therefore, the present review provides a perspective on the impact of functional mitochondria in the most predominant glial cells of the retina, the Müller cells. Müller cells span the entire thickness of the neuroretina and are in close proximity to retinal cells including the retinal neurons that provides visual signaling to the brain. Among multiple functions, Müller cells are responsible for the removal of neurotransmitters, buffering potassium, and providing neurons with essential metabolites. Thus, Müller cells are responsible for a stable metabolic dialogue in the inner retina and their crucial role in supporting retinal neurons is indisputable. Müller cell functions require considerable energy production and previous literature has primarily emphasized glycolysis as the main energy provider. However, recent studies highlight the need of mitochondrial ATP production to upheld Müller cell functions. Therefore, the present review aims to provide an overview of the current evidence on the impact of mitochondrial functions in Müller cells.
Topics: Adenosine Triphosphate; Diabetic Retinopathy; Ependymoglial Cells; Glaucoma; Humans; Mitochondria
PubMed: 28179130
DOI: 10.1016/j.mito.2017.02.002 -
CNS & Neurological Disorders Drug... 2018Müller cell is the major type of glial cell in the vertebrate retina. Müller cells express various types of K+ channels, such as inwardly rectifying K+ (Kir) channels,... (Review)
Review
BACKGROUND & OBJECTIVE
Müller cell is the major type of glial cell in the vertebrate retina. Müller cells express various types of K+ channels, such as inwardly rectifying K+ (Kir) channels, big conductance Ca2+-activated K+ (BKCa) channels, delayed rectifier K+ channels (KDR), and transient A-type K+ channels. These K+ channels play important roles in maintaining physiological functions of Müller cells. Under some retinal pathological conditions, the changed expression and functions of K+ channels may contribute to retinal pathogenesis.
CONCLUSION
In this article, we reviewed the physiological properties of K+ channels in retinal Müller cells and the functional changes of these channels in retinal disorders.
Topics: Animals; Cell Membrane; Ependymoglial Cells; Humans; Neuroglia; Potassium Channels, Voltage-Gated; Retina; Retinal Diseases
PubMed: 29422007
DOI: 10.2174/1871527317666180202114233 -
International Ophthalmology Dec 2023This study investigated the protective effect of probucol on Müller cells exposed to high glucose conditions and examined potential mechanisms of action.
PURPOSE
This study investigated the protective effect of probucol on Müller cells exposed to high glucose conditions and examined potential mechanisms of action.
METHODS
Primary human retinal Müller cells were incubated with high glucose (HG, 35 mM) in the present or absence of different concentrations of probucol for 24 h. Cell viability was determined using the CCK-8 method. Mitochondrial membrane potential (MMP) was measured using JC-1 staining and cell cycle by flow cytometry. The expression of nuclear factor E2-related factor 2 (Nrf2), glutamate-cysteine ligase catalytic subunit, and p62 was quantified using quantitative polymerase chain reaction and western blot.
RESULTS
We found that HG inhibited cell proliferation, arrested cell cycle, and increased MMP in human Müller cells. Probucol activated the Nrf2/p62 pathway and upregulated the anti-apoptotic protein, Bcl2, and attenuated HG-mediated damage in Müller cells.
CONCLUSIONS
Our results suggest that probucol may protect Müller cells from HG-induced damage through enhancing the Nrf2/p62 signaling pathway.
Topics: Humans; Ependymoglial Cells; Glucose; NF-E2-Related Factor 2; Probucol; Signal Transduction
PubMed: 37688651
DOI: 10.1007/s10792-023-02859-z -
Bio Systems Nov 2022Presently a detailed biophysical model describing reversible and irreversible swelling dynamics of Müller cells (MC) is reported. The model includes a biophysical block...
Presently a detailed biophysical model describing reversible and irreversible swelling dynamics of Müller cells (MC) is reported. The model includes a biophysical block of ionic and neutral species transport via MC membrane, water transport induced by osmotic pressure and pressure generated by membrane deformations, MC membrane potential and membrane mechanical properties. The model describes reversible and irreversible MC swelling (MCS) using the same set of parameters. The model was used in fitting available experimental data, and produced numerical values of previously unknown model parameters, including those describing mechanical properties of Müller cell membrane (MCM) with respect to bending and stretching. Numerical experiments simulating MC swelling showed complex oscillation dynamics of the relevant parameters in physiological initial conditions. In particular, MC membrane potential (ΔΨ) demonstrated complex oscillation dynamics, which may be described by a superposition of several oscillations with their periods in the milliseconds, 100-ms and seconds time ranges. Dynamics of reversible and irreversible MCS, and the transition criteria from reversible to irreversible MCS modes were determined in model simulations.
Topics: Ependymoglial Cells; Membrane Potentials; Neuroglia; Osmotic Pressure; Water
PubMed: 36113739
DOI: 10.1016/j.biosystems.2022.104772