Retinal Ganglion Cells With a Glaucoma OPTN(E50K) Mutation Exhibit Neurodegenerative Phenotypes when Derived from Three-Dimensional Retinal Organoids

Inherited optic neuropathies share visual impairment due to the degeneration of retinal ganglion cells (RGCs) as the hallmark of the disease. This group of genetic disorders are caused by mutations in nuclear genes or in the mitochondrial DNA (mtDNA). An impaired mitochondrial function is the underlying mechanism of these diseases. Currently, optic neuropathies lack an effective treatment, and the implementation of induced pluripotent stem cell (iPSC) technology would entail a huge step forward. The generation of iPSC-derived RGCs would allow faithfully modeling these disorders, and these RGCs would represent an appealing platform for drug screening as well, paving the way for a proper therapy. Here, we review the ongoing two-dimensional (2D) and three-dimensional (3D) approaches based on iPSCs and their applications, taking into account the more innovative technologies, which include tissue engineering or microfluidics.

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Retinal Image Formation and Sampling in a Three-Dimensional World

Annual Review of Vision Science ◽

10.1146/annurev-vision-121219-081840 ◽

2020 ◽

Vol 6 (1) ◽

pp. 469-489

Author(s):

Larry N. Thibos

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Three Dimensional ◽

Visual Space ◽

Image Formation ◽

Field Size ◽

Retinal Ganglion ◽

Visual Objects ◽

Psychophysical Studies ◽

The Brain

In this review, I develop an empirically based model of optical image formation by the human eye, followed by neural sampling by retinal ganglion cells, to demonstrate the perceptual effects of blur, aliasing, and distortion of visual space in the brain. The optical model takes account of ocular aberrations and their variation across the visual field, in addition to variations of defocus due to variation of target vergence in three-dimensional scenes. Neural sampling by retinal ganglion cells with receptive field size and spacing that increases with eccentricity is used to visualize the neural image carried by the optic nerve to the brain. Anatomical parameters are derived from psychophysical studies of sampling-limited visual resolution of sinusoidal interference fringes. Retinotopic projection of the neural image onto brainstem nuclei reveals features of the neural image in a perceptually uniform brain space where location and size of visual objects may be measured by counting neurons.

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Optimized Culture System to Induce Neurite Outgrowth From Retinal Ganglion Cells in Three-Dimensional Retinal Aggregates Differentiated From Mouse and Human Embryonic Stem Cells

Current Eye Research ◽

10.3109/02713683.2015.1038359 ◽

2015 ◽

pp. 1-11 ◽

Cited By ~ 14

Author(s):

Yuki Maekawa ◽

Akishi Onishi ◽

Keizo Matsushita ◽

Naoshi Koide ◽

Michiko Mandai ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Neurite Outgrowth ◽

Retinal Ganglion Cells ◽

Human Embryonic Stem Cells ◽

Culture System ◽

Ganglion Cells ◽

Three Dimensional ◽

Embryonic Stem ◽

Retinal Ganglion

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1640 Three dimensional dendritic structure of the long survived axotomized retinal ganglion cells in the mammalian retina

Neuroscience Research Supplements ◽

10.1016/s0921-8696(05)81209-5 ◽

1993 ◽

Vol 18 ◽

pp. S188

Author(s):

Masaki Tauchi

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Three Dimensional ◽

Dendritic Structure ◽

Retinal Ganglion ◽

Mammalian Retina

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Beyond colour gamuts: Novel metrics for the reproduction of photoreceptor signals

10.1101/2021.02.27.433203 ◽

2021 ◽

Author(s):

Allie C. Hexley ◽

Takuma Morimoto ◽

Hannah E. Smithson ◽

Manuel Spitschan

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Three Dimensional ◽

Retinal Ganglion ◽

Chromaticity Diagram ◽

Colour Space ◽

Light Responses ◽

Light Levels ◽

Primary Display ◽

Visual Light

AbstractColour gamuts describe the chromaticity reproduction capabilities of a display, i.e. its ability to reproduce the relative cone excitations from real-world radiance spectra. While the cones dominate “canonical” visual function (i.e. perception of colour, space, and motion) under photopic light levels, they are not the only photoreceptors in the human retina. Rods and melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) also respond to light and contribute to both visual and non-visual light responses, including circadian rhythms, sleep-wake control, mood, pupil size, and alertness. Three-primary display technologies, with their focus on reproducing colour, are not designed to reproduce the rod and melanopsin excitations. Moreover, conventional display metrics used to characterize three-primary displays fail to describe the display’s ability (or inability) to reproduce rod and melanopsin excitations, and thus do not capture the display’s ability to reproduce the full human physiological response to light. In this paper, three novel physiologically relevant metrics are proposed for quantifying the reproduction and distortion of the photoreceptor signals by visual displays. A novel equal-luminance photoreceptor excitation diagram is proposed, extending the well-known MacLeod-Boynton chromaticity diagram, to allow visualizations of the five-dimensional photoreceptor signal space in a three-dimensional projection.

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Retinal ganglion cells harboring the OPTN(E50K) mutation exhibit neurodegenerative phenotypes when derived from hPSC-derived three dimensional retinal organoids

10.1101/820159 ◽

2019 ◽

Author(s):

KB VanderWall ◽

KC Huang ◽

Y Pan ◽

SS Lavekar ◽

CM Fligor ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Gene Editing ◽

Ganglion Cells ◽

Three Dimensional ◽

Retinal Ganglion ◽

Cellular Mechanisms ◽

Novel Treatments ◽

Neurite Retraction ◽

Precise Analysis ◽

The Brain

SummaryRetinal ganglion cells (RGCs) serve as the primary connection between the eye and the brain, with this connection disrupted in glaucoma. Numerous cellular mechanisms have been associated with glaucomatous neurodegeneration, and useful models of glaucoma allow for the precise analysis of degenerative phenotypes. Human pluripotent stem cells (hPSCs) serve as powerful tools for studying human neurodegenerative diseases, particularly cellular mechanisms underlying degeneration. Thus, efforts were initially focused upon the use of hPSCs with an E50K mutation in the Optineurin (OPTN) gene. CRISPR/Cas9 gene editing was used to introduce the OPTN(E50K) mutation into existing lines of hPSCs, as well as the generation of isogenic control lines from OPTN(E50K) patient-derived hPSC lines. OPTN(E50K) RGCs exhibited numerous neurodegenerative deficits, including neurite retraction, autophagy dysfunction, apoptosis, and increased excitability. The results of this study provide an extensive analysis of the OPTN(E50K) mutation in hPSC-derived RGCs, with the opportunity to develop novel treatments for glaucoma.

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