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Progress in Retinal and Eye Research Mar 2016The mammalian retina provides an excellent opportunity to study glia-neuron interactions and the interactions of glia with blood vessels. Three main types of glial cells... (Review)
Review
The mammalian retina provides an excellent opportunity to study glia-neuron interactions and the interactions of glia with blood vessels. Three main types of glial cells are found in the mammalian retina that serve to maintain retinal homeostasis: astrocytes, Müller cells and resident microglia. Müller cells, astrocytes and microglia not only provide structural support but they are also involved in metabolism, the phagocytosis of neuronal debris, the release of certain transmitters and trophic factors and K(+) uptake. Astrocytes are mostly located in the nerve fibre layer and they accompany the blood vessels in the inner nuclear layer. Indeed, like Müller cells, astrocytic processes cover the blood vessels forming the retinal blood barrier and they fulfil a significant role in ion homeostasis. Among other activities, microglia can be stimulated to fulfil a macrophage function, as well as to interact with other glial cells and neurons by secreting growth factors. This review summarizes the main functional relationships between retinal glial cells and neurons, presenting a general picture of the retina recently modified based on experimental observations. The preferential involvement of the distinct glia cells in terms of the activity in the retina is discussed, for example, while Müller cells may serve as progenitors of retinal neurons, astrocytes and microglia are responsible for synaptic pruning. Since different types of glia participate together in certain activities in the retina, it is imperative to explore the order of redundancy and to explore the heterogeneity among these cells. Recent studies revealed the association of glia cell heterogeneity with specific functions. Finally, the neuroprotective effects of glia on photoreceptors and ganglion cells under normal and adverse conditions will also be explored.
Topics: Animals; Astrocytes; Blood Vessels; Cell Communication; Cell Differentiation; Ependymoglial Cells; Humans; Macrophages; Microglia; Retinal Ganglion Cells
PubMed: 26113209
DOI: 10.1016/j.preteyeres.2015.06.003 -
Nature Reviews. Neuroscience Jul 2014Müller glia are the major glial component of the retina. They are one of the last retinal cell types to be born during development, and they function to maintain... (Review)
Review
Müller glia are the major glial component of the retina. They are one of the last retinal cell types to be born during development, and they function to maintain retinal homeostasis and integrity. In mammals, Müller glia respond to retinal injury in various ways that can be either protective or detrimental to retinal function. Although these cells can be coaxed to proliferate and generate neurons under special circumstances, these responses are meagre and insufficient for repairing a damaged retina. By contrast, in teleost fish (such as zebrafish), the response of Müller glia to retinal injury involves a reprogramming event that imparts retinal stem cell characteristics and enables them to produce a proliferating population of progenitors that can regenerate all major retinal cell types and restore vision. Recent studies have revealed several important mechanisms underlying Müller glial cell reprogramming and retina regeneration in fish that may lead to new strategies for stimulating retina regeneration in mammals.
Topics: Animals; Ependymoglial Cells; Humans; Nerve Net; Nerve Regeneration; Neuroglia; Retina; Signal Transduction
PubMed: 24894585
DOI: 10.1038/nrn3723 -
Cell Reports Mar 2017The hypothalamus is one of the most complex brain structures involved in homeostatic regulation. Defining cell composition and identifying cell-type-specific...
The hypothalamus is one of the most complex brain structures involved in homeostatic regulation. Defining cell composition and identifying cell-type-specific transcriptional features of the hypothalamus is essential for understanding its functions and related disorders. Here, we report single-cell RNA sequencing results of adult mouse hypothalamus, which defines 11 non-neuronal and 34 neuronal cell clusters with distinct transcriptional signatures. Analyses of cell-type-specific transcriptomes reveal gene expression dynamics underlying oligodendrocyte differentiation and tanycyte subtypes. Additionally, data analysis provides a comprehensive view of neuropeptide expression across hypothalamic neuronal subtypes and uncover Crabp1 and Pax6 neuronal populations in specific hypothalamic sub-regions. Furthermore, we found food deprivation exhibited differential transcriptional effects among the different neuronal subtypes, suggesting functional specification of various neuronal subtypes. Thus, the work provides a comprehensive transcriptional perspective of adult hypothalamus, which serves as a valuable resource for dissecting cell-type-specific functions of this complex brain region.
Topics: Aging; Animals; Cell Differentiation; Ependymoglial Cells; Female; Food Deprivation; Gene Expression Regulation; Hypothalamus; Male; Mice, Inbred C57BL; Neurons; Neuropeptides; Oligodendroglia; Sequence Analysis, RNA; Single-Cell Analysis; Transcription, Genetic; Transcriptome
PubMed: 28355573
DOI: 10.1016/j.celrep.2017.03.004 -
Journal of Neuroinflammation Dec 2021Glaucoma, the leading cause of irreversible blindness, is a retinal neurodegenerative disease, which results from progressive apoptotic death of retinal ganglion cells...
BACKGROUND
Glaucoma, the leading cause of irreversible blindness, is a retinal neurodegenerative disease, which results from progressive apoptotic death of retinal ganglion cells (RGCs). Although the mechanisms underlying RGC apoptosis in glaucoma are extremely complicated, an abnormal cross-talk between retinal glial cells and RGCs is generally thought to be involved. However, how interaction of Müller cells and microglia, two types of glial cells, contributes to RGC injury is largely unknown.
METHODS
A mouse chronic ocular hypertension (COH) experimental glaucoma model was produced. Western blotting, immunofluorescence, quantitative real-time polymerase chain reaction (q-PCR), transwell co-culture of glial cells, flow cytometry assay, ELISA, Ca image, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) techniques were employed to investigate the interaction of Müller cells and microglia, and its underlying mechanisms in COH retina.
RESULTS
We first showed that Müller cell activation in mice with COH induced microglia activation through the ATP/P2X7 receptor pathway. The activation of microglia resulted in a significant increase in mRNA and protein levels of pro-inflammatory factors, such as tumor necrosis factor-α and interleukin-6. These inflammatory factors in turn caused the up-regulation of mRNA expression of pro-inflammatory factors in Müller cells through a positive feedback manner.
CONCLUSIONS
These findings provide robust evidence, for the first time, that retinal inflammatory response may be aggravated by an interplay between activated two types of glial cells. These results also suggest that to reduce the interplay between Müller cells and microglia could be a potential effective strategy for preventing the loss of RGCs in glaucoma.
Topics: Adenosine Triphosphate; Animals; Coculture Techniques; Cytokines; Ependymoglial Cells; Glaucoma; Macrophage Activation; Mice; Mice, Inbred C57BL; Microglia; Ocular Hypertension; Receptors, Purinergic P2X7; Retinal Ganglion Cells; Retinitis; Signal Transduction
PubMed: 34952606
DOI: 10.1186/s12974-021-02366-x -
Notoginsenoside R1 Ameliorates Diabetic Retinopathy through PINK1-Dependent Activation of Mitophagy.Cells Mar 2019Accumulating evidence has indicated that inflammation, oxidative stress, apoptosis, and autophagy in retinal Müller cells are involved in diabetic retinopathy (DR)....
Accumulating evidence has indicated that inflammation, oxidative stress, apoptosis, and autophagy in retinal Müller cells are involved in diabetic retinopathy (DR). Notoginsenoside R1 (NGR1), a novel saponin extracted from , posesses pharmacological properties, including treating diabetic encephalopathy and improving microcirculatory disorders. Nevertheless, its beneficial effects on DR and the potential mechanism remain to be elucidated. In this study, we found retinal vascular degeneration, reduced retinal thickness, and impaired retinal function in db/db mice were all dramatically attenuated by oral treatment with NGR1 (30 mg/kg) for 12 weeks. NGR1 pretreatment also significantly inhibited apoptosis, markedly suppressed the VEGF expression, markedly increased PEDF expression and markedly inhibited oxidative stress and inflammation in rat retinal Müller cells (rMC-1) subjected to high glucose (HG) and in the retinas of db/db mice. Furthermore, NGR1 pre-treatment upregulated the level of PINK1 and Parkin, increased the LC3-II/LC3-I ratio, and downregulated the level of p62/SQSTM1 in rMC-1 cells induced by HG and in the retinas of db/db mice. Moreover, NGR1 administration enhanced the co-localization of GFP-LC3 puncta and MitoTracker in rMC-1 cells. Importantly, knockdown of PINK1 abolished the protective effects of NGR1. In conclusion, these phenomena suggested that NGR1 prevented DR via PINK1-dependent enhancement of mitophagy.
Topics: Animals; Cell Death; Diabetic Retinopathy; Ependymoglial Cells; Eye Proteins; Ginsenosides; Glucose; Inflammation; Mice; Mitochondria; Mitophagy; Nerve Growth Factors; Oxidative Stress; Protein Kinases; Rats; Serpins; Vascular Endothelial Growth Factor A
PubMed: 30832367
DOI: 10.3390/cells8030213 -
Science (New York, N.Y.) Nov 2020Injury induces retinal Müller glia of certain cold-blooded vertebrates, but not those of mammals, to regenerate neurons. To identify gene regulatory networks that...
Injury induces retinal Müller glia of certain cold-blooded vertebrates, but not those of mammals, to regenerate neurons. To identify gene regulatory networks that reprogram Müller glia into progenitor cells, we profiled changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick, and mice in response to different stimuli. We identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, reactivity, and neurogenesis. In zebrafish and chick, the transition from quiescence to reactivity is essential for retinal regeneration, whereas in mice, a dedicated network suppresses neurogenic competence and restores quiescence. Disruption of nuclear factor I transcription factors, which maintain and restore quiescence, induces Müller glia to proliferate and generate neurons in adult mice after injury. These findings may aid in designing therapies to restore retinal neurons lost to degenerative diseases.
Topics: Animals; Cellular Reprogramming; Chickens; Ependymoglial Cells; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Mice; Nerve Regeneration; Neurogenesis; RNA-Seq; Zebrafish
PubMed: 33004674
DOI: 10.1126/science.abb8598 -
Glia Jul 2022Müller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons....
Müller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons. Identification of cell signaling pathways and gene regulatory networks that regulate MG-mediated regeneration is key to harnessing the regenerative potential of MG. Here, we study how NFkB-signaling influences glial responses to damage and reprogramming of MG into neurons in the rodent retina. We find activation of NFkB and dynamic expression of NFkB-associated genes in MG after damage, however damage-induced NFkB activation is inhibited by microglia ablation. Knockout of NFkB in MG suppressed the accumulation of immune cells after damage. Inhibition of NFkB following NMDA-damage significantly enhanced the reprogramming of Ascl1-overexpressing MG into neuron-like cells. scRNA-seq of retinal glia following inhibition of NFkB reveals coordination with signaling via TGFβ2 and suppression of NFI and Id transcription factors. Inhibition of Smad3 signal transducer or Id transcription factors increased numbers of neuron-like cells produced by Ascl1-overexpressing MG. We conclude that NFkB is a key signaling hub that is activated in MG after damage, mediates the accumulation of immune cells, and suppresses the neurogenic potential of MG.
Topics: Animals; Cell Proliferation; Ependymoglial Cells; Mammals; NF-kappa B; Neuroglia; Neurons; Regeneration; Retina; Signal Transduction; Transcription Factors
PubMed: 35388544
DOI: 10.1002/glia.24181 -
Neuron Jun 2020The habenula complex is appreciated as a critical regulator of motivated and pathological behavioral states via its output to midbrain nuclei. Despite this,...
The habenula complex is appreciated as a critical regulator of motivated and pathological behavioral states via its output to midbrain nuclei. Despite this, transcriptional definition of cell populations that comprise both the medial habenular (MHb) and lateral habenular (LHb) subregions in mammals remain undefined. To resolve this, we performed single-cell transcriptional profiling and highly multiplexed in situ hybridization experiments of the mouse habenula complex in naive mice and those exposed to an acute aversive stimulus. Transcriptionally distinct neuronal cell types identified within the MHb and LHb, were spatially defined, differentially engaged by aversive stimuli, and had distinct electrophysiological properties. Cell types identified in mice also displayed a high degree of transcriptional similarity to those previously described in zebrafish, highlighting the well-conserved nature of habenular cell types across the phylum. These data identify key molecular targets within habenular cell types and provide a critical resource for future studies.
Topics: Animals; Astrocytes; Endothelial Cells; Ependymoglial Cells; Gene Expression Profiling; Gene Ontology; Habenula; Mice; Microglia; Neuroglia; Neurons; Oligodendroglia; RNA-Seq; Single-Cell Analysis; Zebrafish
PubMed: 32272058
DOI: 10.1016/j.neuron.2020.03.011 -
Stem Cell Reports Aug 2023Human gliogenesis remains poorly understood, and derivation of astrocytes from human pluripotent stem cells (hPSCs) is inefficient and cumbersome. Here, we report...
Human gliogenesis remains poorly understood, and derivation of astrocytes from human pluripotent stem cells (hPSCs) is inefficient and cumbersome. Here, we report controlled glial differentiation from hPSCs that bypasses neurogenesis, which otherwise precedes astrogliogenesis during brain development and in vitro differentiation. hPSCs were first differentiated into radial glial cells (RGCs) resembling resident RGCs of the fetal telencephalon, and modulation of specific cell signaling pathways resulted in direct and stepwise induction of key astroglial markers (NFIA, NFIB, SOX9, CD44, S100B, glial fibrillary acidic protein [GFAP]). Transcriptomic and genome-wide epigenetic mapping and single-cell analysis confirmed RGC-to-astrocyte differentiation, obviating neurogenesis and the gliogenic switch. Detailed molecular and cellular characterization experiments uncovered new mechanisms and markers for human RGCs and astrocytes. In summary, establishment of a glia-exclusive neural lineage progression model serves as a unique serum-free platform of manufacturing large numbers of RGCs and astrocytes for neuroscience, disease modeling (e.g., Alexander disease), and regenerative medicine.
Topics: Humans; Astrocytes; Ependymoglial Cells; Pluripotent Stem Cells; Neurogenesis; Cell Differentiation; Glial Fibrillary Acidic Protein
PubMed: 37451260
DOI: 10.1016/j.stemcr.2023.06.007 -
Development (Cambridge, England) Jan 2019Numerous protocols have been described for producing neural retina from human pluripotent stem cells (hPSCs), many of which are based on the culture of 3D organoids....
Numerous protocols have been described for producing neural retina from human pluripotent stem cells (hPSCs), many of which are based on the culture of 3D organoids. Although nearly all such methods yield at least partial segments of retinal structure with a mature appearance, variabilities exist within and between organoids that can change over a protracted time course of differentiation. Adding to this complexity are potential differences in the composition and configuration of retinal organoids when viewed across multiple differentiations and hPSC lines. In an effort to understand better the current capabilities and limitations of these cultures, we generated retinal organoids from 16 hPSC lines and monitored their appearance and structural organization over time by light microscopy, immunocytochemistry, metabolic imaging and electron microscopy. We also employed optical coherence tomography and 3D imaging techniques to assess and compare whole or broad regions of organoids to avoid selection bias. Results from this study led to the development of a practical staging system to reduce inconsistencies in retinal organoid cultures and increase rigor when utilizing them in developmental studies, disease modeling and transplantation.
Topics: Cell Differentiation; Cell Line; Cell Proliferation; Cell Shape; Ependymoglial Cells; Humans; Interneurons; Models, Biological; Neural Stem Cells; Organoids; Pluripotent Stem Cells; Reproducibility of Results; Retina; Retinal Ganglion Cells; Synapses; Tomography, Optical Coherence
PubMed: 30567931
DOI: 10.1242/dev.171686