Abstract
Retinal organoids are three-dimensional structures derived from human pluripotent stem cells (hPSCs) which recapitulate the spatial and temporal differentiation of the retina, serving as effective in vitro models of retinal development. However, a lack of emphasis has been placed upon the development and organization of retinal ganglion cells (RGCs) within retinal organoids. Thus, initial efforts were made to characterize RGC differentiation throughout early stages of organoid development, with a clearly defined RGC layer developing in a temporally-appropriate manner expressing a complement of RGC-associated markers. Beyond studies of RGC development, retinal organoids may also prove useful for cellular replacement in which extensive axonal outgrowth is necessary to reach post-synaptic targets. Organoid-derived RGCs could help to elucidate factors promoting axonal outgrowth, thereby identifying approaches to circumvent a formidable obstacle to RGC replacement. As such, additional efforts demonstrated significant enhancement of neurite outgrowth through modulation of both substrate composition and growth factor signaling. Additionally, organoid-derived RGCs exhibited diverse phenotypes, extending elaborate growth cones and expressing numerous guidance receptors. Collectively, these results establish retinal organoids as a valuable tool for studies of RGC development, and demonstrate the utility of organoid-derived RGCs as an effective platform to study factors influencing neurite outgrowth from organoid-derived RGCs.
Highlights
Retinal organoids are three-dimensional structures derived from human pluripotent stem cells which recapitulate the spatial and temporal differentiation of the retina, serving as effective in vitro models of retinal development
Retinal ganglion cells develop within a defined set of spatial and temporal parameters within the retina, with retinal ganglion cells (RGCs) appearing as the first cell type to be specified within the innermost layers and identified by the expression of a variety of unique markers[32,33]
RGCs self-organized within the basal layers of retinal organoids as identified by the expression of BRN3, with photoreceptors differentiating toward more peripheral regions, corresponding to the native location and stratification of layers within the retina (Fig. 1c,d)
Summary
Retinal organoids are three-dimensional structures derived from human pluripotent stem cells (hPSCs) which recapitulate the spatial and temporal differentiation of the retina, serving as effective in vitro models of retinal development. Organoid-derived RGCs exhibited diverse phenotypes, extending elaborate growth cones and expressing numerous guidance receptors These results establish retinal organoids as a valuable tool for studies of RGC development, and demonstrate the utility of organoid-derived RGCs as an effective platform to study factors influencing neurite outgrowth from organoid-derived RGCs. Retinal ganglion cells (RGCs) play a critical role in the transmission of visual information between the eye and the brain, with many retinal degenerative diseases leading to the damage and loss of RGC axons[1,2,3]. Recent studies have demonstrated the ability to differentiate hPSCs into RGCs17–21, resulting in cells possessing appropriate morphological and functional properties These RGCs were often derived in a stochastic manner, with cells lacking the organization typical of the retina, including the cell-to-cell interactions associated with retinogenesis. The differentiation of retinal organoids from hPSCs provides a population of RGCs that more faithfully recapitulates their spatial and temporal development within the retina and may serve as a more effective in vitro model of RGC axonal outgrowth
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