scholarly journals In vivo Regeneration of Ganglion Cells for Vision Restoration in Mammalian Retinas

2021 ◽  
Vol 9 ◽  
Author(s):  
Dongchang Xiao ◽  
Kangxin Jin ◽  
Suo Qiu ◽  
Qiannan Lei ◽  
Wanjing Huang ◽  
...  
Keyword(s):  
Ganglion Cells ◽  
Visual Pathway ◽  
Retinal Ganglion ◽  
Visual Responses ◽  
Promising Alternative ◽  
Electrophysiological Properties ◽  
Alternative Approach ◽  
Mature Mouse ◽  
Vision Restoration

Glaucoma and other optic neuropathies affect millions of people worldwide, ultimately causing progressive and irreversible degeneration of retinal ganglion cells (RGCs) and blindness. Previous research into cell replacement therapy of these neurodegenerative diseases has been stalled due to the incapability for grafted RGCs to integrate into the retina and project properly along the long visual pathway. In vivo RGC regeneration would be a promising alternative approach but mammalian retinas lack regenerative capacity. It therefore has long been a great challenge to regenerate functional and properly projecting RGCs for vision restoration in mammals. Here we show that the transcription factors (TFs) Math5 and Brn3b together are able to reprogram mature mouse Müller glia (MG) into RGCs. The reprogrammed RGCs extend long axons that make appropriate intra-retinal and extra-retinal projections through the entire visual pathway to innervate both image-forming and non-image-forming brain targets. They exhibit typical neuronal electrophysiological properties and improve visual responses in RGC loss mouse models. Together, our data provide evidence that mammalian MG can be reprogrammed by defined TFs to achieve in vivo regeneration of functional RGCs as well as a promising new therapeutic approach to restore vision to patients with glaucoma and other optic neuropathies.

scholarly journals Directed robust generation of functional retinal ganglion cells from Müller glia

2019 ◽  
Author(s):  
Dongchang Xiao ◽  
Suo Qiu ◽  
Xiuting Huang ◽  
Rong Zhang ◽  
Qiannan Lei ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Visual Pathway ◽  
Retinal Ganglion ◽  
Muller Glia ◽  
Müller Glia ◽  
Visual Responses ◽  
Promising Alternative

AbstractGlaucoma and optic neuropathies cause progressive and irreversible degeneration of retinal ganglion cells (RGCs) and the optic nerve and are currently without any effective treatment. Previous research into cell replacement therapy of these neurodegenerative diseases has been stalled due to the limited capability for grafted RGCs to integrate into the retina and project properly along the long visual pathway to reach their brain targets. In vivo RGC regeneration would be a promising alternative approach but mammalian retinas lack regenerative capacity even though cold-blood vertebrates such as zebrafish have the full capacity to regenerate a damaged retina using Müller glia (MG) as retinal stem cells. Nevertheless, mammalian MG undergo limited neurogenesis when stimulated by retinal injury. Therefore, a fundamental question that remains to be answered is whether MG can be induced to efficiently regenerate functional RGCs for vision restoration in mammals. Here we show that without stimulating proliferation, the transcription factor (TF) Math5 together with a Brn3 TF family member are able to reprogram mature mouse MG into RGCs with exceedingly high efficiency while either alone has no or limited capacity. The reprogrammed RGCs extend long axons that make appropriate intra-retinal and extra-retinal projections through the entire visual pathway including the optic nerve, optic chiasm and optic tract to innervate both image-forming and non-image-forming brain targets. They exhibit typical neuronal electrophysiological properties and improve visual responses in two glaucoma mouse models: Brn3b null mutant mice and mice with the optic nerve crushed (ONC). Together, our data provide evidence that mammalian MG can be reprogrammed by defined TFs to achieve robust in vivo regeneration of functional RGCs as well as a promising new therapeutic approach to restore vision to patients with glaucoma and other optic neuropathies.

scholarly journals An alternative approach to produce versatile retinal organoids with accelerated ganglion cell development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Philip E. Wagstaff ◽  
Anneloor L. M. A. ten Asbroek ◽  
Jacoline B. ten Brink ◽  
Nomdo M. Jansonius ◽  
Arthur A. B. Bergen
Keyword(s):  
Ganglion Cells ◽  
Cell Types ◽  
Retinal Cell ◽  
Specific Cell ◽  
Retinal Ganglion ◽  
In Vivo Models ◽  
Alternative Approach

AbstractGenetically complex ocular neuropathies, such as glaucoma, are a major cause of visual impairment worldwide. There is a growing need to generate suitable human representative in vitro and in vivo models, as there is no effective treatment available once damage has occured. Retinal organoids are increasingly being used for experimental gene therapy, stem cell replacement therapy and small molecule therapy. There are multiple protocols for the development of retinal organoids available, however, one potential drawback of the current methods is that the organoids can take between 6 weeks and 12 months on average to develop and mature, depending on the specific cell type wanted. Here, we describe and characterise a protocol focused on the generation of retinal ganglion cells within an accelerated four week timeframe without any external small molecules or growth factors. Subsequent long term cultures yield fully differentiated organoids displaying all major retinal cell types. RPE, Horizontal, Amacrine and Photoreceptors cells were generated using external factors to maintain lamination.

Stimulus size and intensity alter fundamental receptive-field properties of mouse retinal ganglion cellsin vivo

2005 ◽  
Vol 22 (5) ◽  
pp. 649-659 ◽  
Author(s):  
BOTIR T. SAGDULLAEV ◽  
MAUREEN A. MCCALL
Keyword(s):  
Receptive Field ◽  
Ganglion Cells ◽  
General Interest ◽  
Visual Response ◽  
Field Stimulation ◽  
Retinal Ganglion ◽  
Visual Responses ◽  
Full Field ◽  
Response Properties

The receptive field (RF) of most retinal ganglion cells (RGCs) is comprised of an excitatory center and an antagonistic surround. Interactions between these RF elements shape most of the visual responses of RGCs. To begin to investigate center-surround interactions of mouse RGCs quantitatively, we characterized their responses in anin vivopreparation to a variety of spot and full-field stimuli. When RGCs were stimulated with a spot that matched the cell's RF center diameter (optimal spot), all RGCs could be categorized as either ON- or OFF-center. In all RGCs, full-field stimulation significantly reduced both the peak and the mean firing rates evoked with an optimal spot stimulus. Full-field stimulation revealed differences in other response properties between ON- and OFF-center RGCs. With a full-field stimulus, the duration of the OFF-center RGCs response was reduced making them more transient, while the duration of the ON-center RGCs increased making them more sustained. Of most interest, full-field stimulation altered the RF center response sign in approximately half of the OFF-center RGCs, which became either OFF/ON or ON only. In contrast, all ON-center and the other OFF-center cells conserved their RF response sign in the presence of the full-field stimulus. We propose that sign-altering OFF-center RGCs possess an additional RF surround mechanism that underlies this alteration in their response. Of general interest these results suggest that the sole use of full-field stimulation to categorize visual response properties of RGCs does not adequately reflect their RF organization and, therefore, is not an optimal strategy for their classification.

scholarly journals Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Olivia J. Marola ◽  
Stephanie B. Syc-Mazurek ◽  
Gareth R. Howell ◽  
Richard T. Libby
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Retinal Vessel ◽  
Vessel Diameter ◽  
Retinal Ganglion ◽  
Retinal Ganglion Cell Death ◽  
Ganglion Cell Death

Abstract Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun−/−), Ddit3 null (Ddit3−/−), and Ddit3−/−Jun−/− mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation.

scholarly journals Spatial receptive field properties of rat retinal ganglion cells

2011 ◽  
Vol 28 (5) ◽  
pp. 403-417 ◽  
Author(s):  
WALTER F. HEINE ◽  
CHRISTOPHER L. PASSAGLIA
Keyword(s):  
Receptive Field ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Cell Types ◽  
Quantitative Information ◽  
Retinal Ganglion ◽  
X And Y Cells ◽  
Y Cells

AbstractThe rat is a popular animal model for vision research, yet there is little quantitative information about the physiological properties of the cells that provide its brain with visual input, the retinal ganglion cells. It is not clear whether rats even possess the full complement of ganglion cell types found in other mammals. Since such information is important for evaluating rodent models of visual disease and elucidating the function of homologous and heterologous cells in different animals, we recorded from rat ganglion cells in vivo and systematically measured their spatial receptive field (RF) properties using spot, annulus, and grating patterns. Most of the recorded cells bore likeness to cat X and Y cells, exhibiting brisk responses, center-surround RFs, and linear or nonlinear spatial summation. The others resembled various types of mammalian W cell, including local-edge-detector cells, suppressed-by-contrast cells, and an unusual type with an ON–OFF surround. They generally exhibited sluggish responses, larger RFs, and lower responsiveness. The peak responsivity of brisk-nonlinear (Y-type) cells was around twice that of brisk-linear (X-type) cells and several fold that of sluggish cells. The RF size of brisk-linear and brisk-nonlinear cells was indistinguishable, with average center and surround diameters of 5.6 ± 1.3 and 26.4 ± 11.3 deg, respectively. In contrast, the center diameter of recorded sluggish cells averaged 12.8 ± 7.9 deg. The homogeneous RF size of rat brisk cells is unlike that of cat X and Y cells, and its implication regarding the putative roles of these two ganglion cell types in visual signaling is discussed.

scholarly journals Otx2 Promotes the Survival of Damaged Adult Retinal Ganglion Cells and Protects against Excitotoxic Loss of Visual Acuity In Vivo

2011 ◽  
Vol 31 (14) ◽  
pp. 5495-5503 ◽  
Author(s):  
R. T. Ibad ◽  
J. Rheey ◽  
S. Mrejen ◽  
V. Forster ◽  
S. Picaud ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Loss Of Visual Acuity

scholarly journals Photoreceptive retinal ganglion cells control the information rate of the optic nerve

2018 ◽  
Vol 115 (50) ◽  
pp. E11817-E11826 ◽  
Author(s):  
Nina Milosavljevic ◽  
Riccardo Storchi ◽  
Cyril G. Eleftheriou ◽  
Andrea Colins ◽  
Rasmus S. Petersen ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Information Flow ◽  
Information Transfer ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Ambient Light ◽  
Visual Responses ◽  
Light Irradiance ◽  
The Brain

Information transfer in the brain relies upon energetically expensive spiking activity of neurons. Rates of information flow should therefore be carefully optimized, but mechanisms to control this parameter are poorly understood. We address this deficit in the visual system, where ambient light (irradiance) is predictive of the amount of information reaching the eye and ask whether a neural measure of irradiance can therefore be used to proactively control information flow along the optic nerve. We first show that firing rates for the retina’s output neurons [retinal ganglion cells (RGCs)] scale with irradiance and are positively correlated with rates of information and the gain of visual responses. Irradiance modulates firing in the absence of any other visual signal confirming that this is a genuine response to changing ambient light. Irradiance-driven changes in firing are observed across the population of RGCs (including in both ON and OFF units) but are disrupted in mice lacking melanopsin [the photopigment of irradiance-coding intrinsically photosensitive RGCs (ipRGCs)] and can be induced under steady light exposure by chemogenetic activation of ipRGCs. Artificially elevating firing by chemogenetic excitation of ipRGCs is sufficient to increase information flow by increasing the gain of visual responses, indicating that enhanced firing is a cause of increased information transfer at higher irradiance. Our results establish a retinal circuitry driving changes in RGC firing as an active response to alterations in ambient light to adjust the amount of visual information transmitted to the brain.

Imaging Mouse Retinal Ganglion Cells and Their Loss In Vivo by a Fundus Camera in the Normal and Ischemia-Reperfusion Model

2008 ◽  
Vol 49 (12) ◽  
pp. 5546 ◽  
Author(s):  
Hiroshi Murata ◽  
Makoto Aihara ◽  
Yi-Ning Chen ◽  
Takashi Ota ◽  
Jiro Numaga ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Ischemia Reperfusion ◽  
Retinal Ganglion ◽  
Fundus Camera
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