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Investigative Ophthalmology & Visual... Feb 2024Müller glia, the main glial cell of the retina, are critical for neuronal and vascular homeostasis in the retina. During age-related macular degeneration (AMD)... (Review)
Review
Müller glia, the main glial cell of the retina, are critical for neuronal and vascular homeostasis in the retina. During age-related macular degeneration (AMD) pathogenesis, Müller glial activation, remodeling, and migrations are reported in the areas of retinal pigment epithelial (RPE) degeneration, photoreceptor loss, and choroidal neovascularization (CNV) lesions. Despite this evidence indicating glial activation localized to the regions of AMD pathogenesis, it is unclear whether these glial responses contribute to AMD pathology or occur merely as a bystander effect. In this review, we summarize how Müller glia are affected in AMD retinas and share a prospect on how Müller glial stress might directly contribute to the pathogenesis of AMD. The goal of this review is to highlight the need for future studies investigating the Müller cell's role in AMD. This may lead to a better understanding of AMD pathology, including the conversion from dry to wet AMD, which has no effective therapy currently and may shed light on drug intolerance and resistance to current treatments.
Topics: Humans; Ependymoglial Cells; Macula Lutea; Retina; Cell Communication; Wet Macular Degeneration; Geographic Atrophy
PubMed: 38416457
DOI: 10.1167/iovs.65.2.42 -
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 -
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 -
BioMed Research International 2016Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes and Müller cells (retinal... (Review)
Review
Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes and Müller cells (retinal macroglia) provide physical support to neurons and supplement them with several metabolites and growth factors. Macroglia are involved in maintaining the homeostasis of extracellular ions and neurotransmitters, are essential for information processing in neural circuits, participate in retinal glucose metabolism and in removing metabolic waste products, regulate local blood flow, induce the blood-retinal barrier (BRB), play fundamental roles in local immune response, and protect neurons from oxidative damage. In response to polyetiological insults, glia cells react with a process called reactive gliosis, seeking to maintain retinal homeostasis. When malfunctioning, macroglial cells can become primary pathogenic elements. A reactive gliosis has been described in different retinal pathologies, including age-related macular degeneration (AMD), diabetes, glaucoma, retinal detachment, or retinitis pigmentosa. A better understanding of the dual, neuroprotective, or cytotoxic effect of macroglial involvement in retinal pathologies would help in treating the physiopathology of these diseases. The extensive participation of the macroglia in retinal diseases points to these cells as innovative targets for new drug therapies.
Topics: Astrocytes; Blood-Retinal Barrier; Ependymoglial Cells; Gliosis; Glucose; Homeostasis; Humans; Immunity, Cellular; Neurons; Oxidative Stress; Retina
PubMed: 27294114
DOI: 10.1155/2016/2954721 -
Development (Cambridge, England) Dec 2019As with all glial cells, the major role of retinal Müller glia (MG) is to provide essential neuronal support. However, the MG of some non-mammalian species have the... (Review)
Review
As with all glial cells, the major role of retinal Müller glia (MG) is to provide essential neuronal support. However, the MG of some non-mammalian species have the additional ability to generate new retinal neurons capable of sight restoration. Unfortunately, mammalian MG do not possess this ability. However, if we could understand the reasons why, we may be able to devise strategies to confer regenerative potential. The recent discovery that the Hippo signaling pathway acts as an intrinsic block to mammalian MG proliferation, along with reports of adeno-associated virus (AAV)-based MG reprogramming and functional photoreceptor differentiation, may indicate a watershed moment in the field of mammalian retinal regeneration. However, as researchers delve deeper into the cellular and molecular mechanisms, and further refine MG reprogramming strategies, we should recall past misinterpretations of data in this field and proceed with caution. Here, we provide a summary of these emerging data and a discussion of technical concerns specific to AAV-mediated reprogramming experiments that must be addressed in order for the field to move forward.
Topics: Animals; Cell Proliferation; Cellular Reprogramming; Cellular Reprogramming Techniques; Dependovirus; Ependymoglial Cells; Genetic Vectors; Humans; Photoreceptor Cells, Vertebrate; Regeneration
PubMed: 31792065
DOI: 10.1242/dev.182642 -
Cellular Physiology and Biochemistry :... 2019Hypoxia of the retina is a common pathogenic drive leading to vision loss as a result of tissue ischemia, increased vascular permeability and ultimately retinal...
BACKGROUND/AIMS
Hypoxia of the retina is a common pathogenic drive leading to vision loss as a result of tissue ischemia, increased vascular permeability and ultimately retinal neovascularisation. Here we tested the hypothesis that Müller cells stabilize the neurovascular unit, microvasculature by suppression of HIF-1α activation as a result of hypoxic preconditioning.
METHODS
Tube Formation Assay and In vitro Vascular Permeability Image Assay were used to analyze angiogenesis and vascular integrity. Seahorse XF Cell Mito Stress Test was used to measure mitochondrial respiration. Gene and protein expression were examined by qRTPCR, ELISA and western blot.
RESULTS
Hypoxic insult induces a significant induction of proangiogenic factors including vascular endothelial growth factor (VEGF) and angiopoietinlike 4 (ANGPTL-4) resulting in angiogenesis and increased vascular permeability of vascular endothelial cells. Hypoxic preconditioning of a human retinal Müller glia cell line significantly attenuates HIF-1α activation through the inhibition of mTOR and concomitant induction of aerobic glycolysis, stabilizing endothelial cells.
CONCLUSION
Hypoxic preconditioning of Müller cells confers a robust protection to endothelial cells, through the suppression of HIF1α activation and its downstream regulation of VEGF and ANGPTL-4.
Topics: Angiopoietin-Like Protein 4; Cell Hypoxia; Cell Line; Cell Proliferation; Cell Survival; Culture Media, Conditioned; Ependymoglial Cells; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Microvessels; Mitochondria; Neovascularization, Physiologic; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A
PubMed: 30921506
DOI: 10.33594/000000047 -
Translational Vision Science &... Nov 2022The cone-dominant, 13-lined ground squirrel (13-LGS) retina mimics the human central retina, but a thorough examination of retinal development in this species has not...
PURPOSE
The cone-dominant, 13-lined ground squirrel (13-LGS) retina mimics the human central retina, but a thorough examination of retinal development in this species has not been reported. Here, the embryonic and postnatal development of the 13-LGS retina was studied to further characterize 13-LGS as a practical alternative animal model for investigating cone-based vision in health and disease.
METHODS
The spatiotemporal expression of key progenitor and cell type markers was examined in retinas from defined embryonic and postnatal stages using immunohistochemistry. Postnatal gene expression changes were validated by quantitative PCR.
RESULTS
The 13-LGS neuroblastic layer expressed key progenitor markers (Sox2, Vsx2, Pax6, and Lhx2) at E18. Sequential cell fate determination evidenced by the first appearance of cell-type-specific marker labeling was at embryonic stage 18 (E18) with ganglion cells (Brn-3A, HuC/D) and microglia (Iba1); at E22.5 with photoreceptor progenitors (Otx2, recoverin) followed shortly by horizontal and amacrine cells (Lhx1, Oc1) at E24 to E25.5; and at postnatal stage 15 (P15) with bipolar cells (Vsx1, CaBP5) and Müller glia cells (GS, Rlbp1). Photoreceptor maturation indicated by opsin-positive outer segments and peanut agglutinin (PNA) labeling of cone sheaths was completed at the time of eye opening (P21-P24).
CONCLUSIONS
The timeline and order of retinal cell development in the 13-LGS generally matches that recorded from other mammalian models but with a stark variation in the proportion of various cell types due to cone-dense photoreceptors.
TRANSLATIONAL RELEVANCE
This thorough examination of an emerging translationally relevant cone-dominant specie provides a baseline for future disease modeling and stem cell approach studies of human vision.
Topics: Animals; Humans; Retinal Cone Photoreceptor Cells; Sciuridae; Retina; Amacrine Cells; Ependymoglial Cells
PubMed: 36409292
DOI: 10.1167/tvst.11.11.17 -
Development (Cambridge, England) May 2020Neurovascular pathologies of the central nervous system (CNS), which are associated with barrier dysfunction, are leading causes of death and disability. The roles that... (Review)
Review
Neurovascular pathologies of the central nervous system (CNS), which are associated with barrier dysfunction, are leading causes of death and disability. The roles that neuronal and glial progenitors and mature cells play in CNS angiogenesis and neurovascular barrier maturation have been elucidated in recent years. Yet how neuronal activity influences these processes remains largely unexplored. Here, we discuss our current understanding of how neuronal and glial development affects CNS angiogenesis and barriergenesis, and outline future directions to elucidate how neuronal activity might influence these processes. An understanding of these mechanisms is crucial for developing new interventions to treat neurovascular pathologies.
Topics: Animals; Astrocytes; Blood-Brain Barrier; Central Nervous System; Ependymoglial Cells; Female; Humans; Male; Models, Biological; Neovascularization, Physiologic
PubMed: 32358096
DOI: 10.1242/dev.182279 -
International Journal of Molecular... Aug 2016The main water channel of the brain, aquaporin-4 (AQP4), is one of the classical water-specific aquaporins. It is expressed in many epithelial tissues in the basolateral... (Review)
Review
The main water channel of the brain, aquaporin-4 (AQP4), is one of the classical water-specific aquaporins. It is expressed in many epithelial tissues in the basolateral membrane domain. It is present in the membranes of supporting cells in most sensory organs in a specifically adapted pattern: in the supporting cells of the olfactory mucosa, AQP4 occurs along the basolateral aspects, in mammalian retinal Müller cells it is highly polarized. In the cochlear epithelium of the inner ear, it is expressed basolaterally in some cells but strictly basally in others. Within the central nervous system, aquaporin-4 (AQP4) is expressed by cells of the astroglial family, more specifically, by astrocytes and ependymal cells. In the mammalian brain, AQP4 is located in high density in the membranes of astrocytic endfeet facing the pial surface and surrounding blood vessels. At these locations, AQP4 plays a role in the maintenance of ionic homeostasis and volume regulation. This highly polarized expression has not been observed in the brain of fish where astroglial cells have long processes and occur mostly as radial glial cells. In the brain of the zebrafish, AQP4 immunoreactivity is found along the radial extent of astroglial cells. This suggests that the polarized expression of AQP4 was not present at all stages of evolution. Thus, a polarized expression of AQP4 as part of a control mechanism for a stable ionic environment and water balanced occurred at several locations in supporting and glial cells during evolution. This initially basolateral membrane localization of AQP4 is shifted to highly polarized expression in astrocytic endfeet in the mammalian brain and serves as a part of the neurovascular unit to efficiently maintain homeostasis.
Topics: Animals; Aquaporin 4; Astrocytes; Brain; Ependymoglial Cells; Humans; Olfactory Mucosa; Water
PubMed: 27571065
DOI: 10.3390/ijms17091411