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International Journal of Molecular... Mar 2018Diabetic retinopathy is a common complication of diabetes and remains the leading cause of blindness among the working-age population. For decades, diabetic retinopathy... (Review)
Review
Diabetic retinopathy is a common complication of diabetes and remains the leading cause of blindness among the working-age population. For decades, diabetic retinopathy was considered only a microvascular complication, but the retinal microvasculature is intimately associated with and governed by neurons and glia, which are affected even prior to clinically detectable vascular lesions. While progress has been made to improve the vascular alterations, there is still no treatment to counteract the early neuro-glial perturbations in diabetic retinopathy. Diabetes is a complex metabolic disorder, characterized by chronic hyperglycemia along with dyslipidemia, hypoinsulinemia and hypertension. Increasing evidence points to inflammation as one key player in diabetes-associated retinal perturbations, however, the exact underlying molecular mechanisms are not yet fully understood. Interlinked molecular pathways, such as oxidative stress, formation of advanced glycation end-products and increased expression of vascular endothelial growth factor have received a lot of attention as they all contribute to the inflammatory response. In the current review, we focus on the involvement of inflammation in the pathophysiology of diabetic retinopathy with special emphasis on the functional relationships between glial cells and neurons. Finally, we summarize recent advances using novel targets to inhibit inflammation in diabetic retinopathy.
Topics: Animals; Astrocytes; Diabetic Retinopathy; Ependymoglial Cells; Humans; Inflammation; Neurodegenerative Diseases
PubMed: 29565290
DOI: 10.3390/ijms19040942 -
Nature Communications May 2021Hippo signaling is an evolutionarily conserved pathway that restricts growth and regeneration predominantly by suppressing the activity of the transcriptional...
Hippo signaling is an evolutionarily conserved pathway that restricts growth and regeneration predominantly by suppressing the activity of the transcriptional coactivator Yap. Using a high-throughput phenotypic screen, we identified a potent and non-toxic activator of Yap. In vitro kinase assays show that the compound acts as an ATP-competitive inhibitor of Lats kinases-the core enzymes in Hippo signaling. The substance prevents Yap phosphorylation and induces proliferation of supporting cells in the murine inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the inhibitor reversibly activates the expression of transcriptional Yap targets: upon withdrawal, a subset of supporting-cell progeny exits the cell cycle and upregulates genes characteristic of sensory hair cells. Our results suggest that the pharmacological inhibition of Lats kinases may promote initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Line; Cell Line, Tumor; Cell Proliferation; Ependymoglial Cells; HEK293 Cells; Hair Cells, Auditory, Inner; Humans; Mice, Knockout; Mice, Transgenic; Myocytes, Cardiac; Protein Serine-Threonine Kinases; Signal Transduction; Small Molecule Libraries; Tumor Suppressor Proteins; YAP-Signaling Proteins; Mice
PubMed: 34035288
DOI: 10.1038/s41467-021-23395-3 -
Seminars in Cell & Developmental Biology Mar 2021Neurological disorders are challenging to study given the complexity and species-specific features of the organ system. Brain organoids are three dimensional structured... (Review)
Review
Neurological disorders are challenging to study given the complexity and species-specific features of the organ system. Brain organoids are three dimensional structured aggregates of neural tissue that are generated by self-organization and differentiation from pluripotent stem cells under optimized culture conditions. These brain organoids exhibit similar features of structural organization and cell type diversity as the developing human brain, creating opportunities to recapitulate disease phenotypes that are not otherwise accessible. Here we review the initial attempt in the field to apply brain organoid models for the study of many different types of human neurological disorders across a wide range of etiologies and pathophysiologies. Forthcoming advancements in both brain organoid technology as well as analytical methods have significant potentials to advance the understanding of neurological disorders and to uncover opportunities for meaningful therapeutic intervention.
Topics: Brain; Cell Differentiation; Ependymoglial Cells; Gene Expression Regulation; Humans; Models, Biological; Mutation; Neoplasms; Nerve Tissue Proteins; Nervous System Diseases; Neurodegenerative Diseases; Neurons; Organoids; Pluripotent Stem Cells; Primary Cell Culture; Virus Diseases
PubMed: 32561297
DOI: 10.1016/j.semcdb.2020.05.026 -
Annual Review of Vision Science Sep 2020In humans, various genetic defects or age-related diseases, such as diabetic retinopathies, glaucoma, and macular degeneration, cause the death of retinal neurons and... (Review)
Review
In humans, various genetic defects or age-related diseases, such as diabetic retinopathies, glaucoma, and macular degeneration, cause the death of retinal neurons and profound vision loss. One approach to treating these diseases is to utilize stem and progenitor cells to replace neurons in situ, with the expectation that new neurons will create new synaptic circuits or integrate into existing ones. Reprogramming non-neuronal cells in vivo into stem or progenitor cells is one strategy for replacing lost neurons. Zebrafish have become a valuable model for investigating cellular reprogramming and retinal regeneration. This review summarizes our current knowledge regarding spontaneous reprogramming of Müller glia in zebrafish and compares this knowledge to research efforts directed toward reprogramming Müller glia in mammals. Intensive research using these animal models has revealed shared molecular mechanisms that make Müller glia attractive targets for cellular reprogramming and highlighted the potential for curing degenerative retinal diseases from intrinsic cellular sources.
Topics: Animals; Animals, Genetically Modified; Cell Differentiation; DNA Methylation; Ependymoglial Cells; Epigenomics; Humans; Nerve Regeneration; Receptors, Notch; Retinal Neurons; Signal Transduction; Stem Cells; Zebrafish
PubMed: 32343929
DOI: 10.1146/annurev-vision-121219-081808 -
ELife Oct 2023Mononuclear cells are involved in the pathogenesis of retinal diseases, including age-related macular degeneration (AMD). Here, we examined the mechanisms that underlie...
Mononuclear cells are involved in the pathogenesis of retinal diseases, including age-related macular degeneration (AMD). Here, we examined the mechanisms that underlie macrophage-driven retinal cell death. Monocytes were extracted from patients with AMD and differentiated into macrophages (hMdɸs), which were characterized based on proteomics, gene expression, and ex vivo and in vivo properties. Using bioinformatics, we identified the signaling pathway involved in macrophage-driven retinal cell death, and we assessed the therapeutic potential of targeting this pathway. We found that M2a hMdɸs were associated with retinal cell death in retinal explants and following adoptive transfer in a photic injury model. Moreover, M2a hMdɸs express several CCRI (C-C chemokine receptor type 1) ligands. Importantly, CCR1 was upregulated in Müller cells in models of retinal injury and aging, and CCR1 expression was correlated with retinal damage. Lastly, inhibiting CCR1 reduced photic-induced retinal damage, photoreceptor cell apoptosis, and retinal inflammation. These data suggest that hMdɸs, CCR1, and Müller cells work together to drive retinal and macular degeneration, suggesting that CCR1 may serve as a target for treating these sight-threatening conditions.
Topics: Humans; Animals; Retinal Degeneration; Ependymoglial Cells; Photoreceptor Cells; Retina; Macular Degeneration; Cell Death; Disease Models, Animal; Receptors, CCR1
PubMed: 37903056
DOI: 10.7554/eLife.81208 -
Journal of Extracellular Vesicles Sep 2022Cell-cell interactions in the central nervous system are based on the release of molecules mediating signal exchange and providing structural and trophic support through...
Cell-cell interactions in the central nervous system are based on the release of molecules mediating signal exchange and providing structural and trophic support through vesicular exocytosis and the formation of extracellular vesicles. The specific mechanisms employed by each cell type in the brain are incompletely understood. Here, we explored the means of communication used by Müller cells, a type of radial glial cells in the retina, which forms part of the central nervous system. Using immunohistochemical, electron microscopic, and molecular analyses, we provide evidence for the release of distinct extracellular vesicles from endfeet and microvilli of retinal Müller cells in adult mice in vivo. We identify VAMP5 as a Müller cell-specific SNARE component that is part of extracellular vesicles and responsive to ischemia, and we reveal differences between the secretomes of immunoaffinity-purified Müller cells and neurons in vitro. Our findings suggest extracellular vesicle-based communication as an important mediator of cellular interactions in the retina.
Topics: Animals; Ependymoglial Cells; Extracellular Vesicles; Mice; Neuroglia; Neurons; Retina
PubMed: 36043482
DOI: 10.1002/jev2.12254 -
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 -
Ophthalmic Research 2019Lamellar macular hole (LMH) is a vitreoretinal disorder characterized by an irregular foveal contour, a break in the inner fovea, dehiscence of the inner foveal retina... (Review)
Review
Lamellar macular hole (LMH) is a vitreoretinal disorder characterized by an irregular foveal contour, a break in the inner fovea, dehiscence of the inner foveal retina from the outer retina, and the absence of a full-thickness foveal defect with intact foveal photoreceptors. The pathogenesis is only partially known. The advent of high-resolution optical coherence tomography has allowed distinguishing between two types of epiretinal membrane (ERM) associated with LMH: a conventional ERM (commonly found in macular pucker) and an atypical ERM (known by varied names: dense, epiretinal proliferation, or degenerative). These two types of ERM not only influence LMH morphology but also differ in cell and collagen composition. It remains unclear if these two types are indeed two distinct clinical entities or rather two stages of the same macular disorder. Studies of the natural evolution of LMH have not fully resolved this issue and also offered variable results. Surgical treatment leads to excellent anatomical and functional outcomes, but not without risks. This review provides a critical summary of the available data on LMH including some new insights.
Topics: Ependymoglial Cells; Epiretinal Membrane; Fovea Centralis; Humans; Retinal Perforations; Retrospective Studies; Tomography, Optical Coherence; Visual Acuity
PubMed: 30625477
DOI: 10.1159/000494687 -
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 -
Nature Communications Dec 2023Following acute retinal damage, zebrafish possess the ability to regenerate all neuronal subtypes through Müller glia (MG) reprogramming and asymmetric cell division...
Following acute retinal damage, zebrafish possess the ability to regenerate all neuronal subtypes through Müller glia (MG) reprogramming and asymmetric cell division that produces a multipotent Müller glia-derived neuronal progenitor cell (MGPC). This raises three key questions. First, do MG reprogram to a developmental retinal progenitor cell (RPC) state? Second, to what extent does regeneration recapitulate retinal development? And finally, does loss of different retinal cell subtypes induce unique MG regeneration responses? We examined these questions by performing single-nuclear and single-cell RNA-Seq and ATAC-Seq in both developing and regenerating retinas. Here we show that injury induces MG to reprogram to a state similar to late-stage RPCs. However, there are major transcriptional differences between MGPCs and RPCs, as well as major transcriptional differences between activated MG and MGPCs when different retinal cell subtypes are damaged. Validation of candidate genes confirmed that loss of different subtypes induces differences in transcription factor gene expression and regeneration outcomes.
Topics: Animals; Zebrafish; Gene Regulatory Networks; Retina; Neurogenesis; Neuroglia; Cell Proliferation; Ependymoglial Cells
PubMed: 38123561
DOI: 10.1038/s41467-023-44142-w