Human Pluripotent Stem Cells as In Vitro Models for Retinal Development and Disease

Sridhar, Akshayalakshmi; Langer, Kirstin B.; Fligor, Clarisse M.; Steinhart, Matthew R.; Miller, Casey A.; Ho-A-Lim, Kimberly T.; Ohlemacher, Sarah K.; Meyer, Jason S.

doi:10.1007/978-3-319-98080-5_2

Cited by 4 publications

(3 citation statements)

References 148 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…hPSCs have been used as a reliable model system for studying both the development of many retinal cell types ( Lamba et al., 2006 , Lu and Barnstable, 2019 , Meyer et al., 2011 , Sridhar et al., 2020 , Zhong et al., 2014 ) as well as diseases which result in the degeneration of these cells ( Ohlemacher et al., 2016 , Sridhar et al., 2018 , Teotia et al., 2017b ). The current understanding of glaucomatous neurodegeneration has been established in part by the use of animal models mimicking RGC degeneration and injury ( Agostinone et al., 2018 , Kalesnykas et al., 2012 , Tseng et al., 2015 , Williams et al., 2013 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

Summary Retinal ganglion cells (RGCs) serve as the connection between the eye and the brain, with this connection disrupted in glaucoma. Numerous cellular mechanisms have been associated with glaucomatous neurodegeneration, and useful cellular models of glaucoma allow for the precise analysis of degenerative phenotypes. Human pluripotent stem cells (hPSCs) serve as powerful tools for studying human disease, particularly cellular mechanisms underlying neurodegeneration. Thus, efforts focused upon hPSCs with an E50K mutation in the Optineurin (OPTN) gene, a leading cause of inherited forms of glaucoma. CRISPR/Cas9 gene editing introduced the OPTN(E50K) mutation into existing lines of hPSCs, as well as generating isogenic controls from patient-derived lines. RGCs differentiated from OPTN(E50K) hPSCs exhibited numerous neurodegenerative deficits, including neurite retraction, autophagy dysfunction, apoptosis, and increased excitability. These results demonstrate the utility of OPTN(E50K) RGCs as an in vitro model of neurodegeneration, with the opportunity to develop novel therapeutic approaches for glaucoma.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Three-dimensional organoids derived from human pluripotent stem cells (hPSCs) have revolutionized the ability to model the development of human tissues, closely recapitulating both the spatial and the temporal differentiation of cell types ( Ader and Tanaka, 2014 ; Brown et al., 2018 ; Lancaster and Knoblich, 2014 ; Quadrato and Arlotta, 2017 ). Among the tissues to be modeled with organoids, retinal organoids closely model the stratification of all of the major cell types of the retina ( Lu and Barnstable, 2019 ; Sridhar et al., 2018 ), including the organization of photoreceptors in apical layers and retinal ganglion cells (RGCs) found within basal layers. This spatiotemporal organization of retinal organoids has resulted in their use for studies related to human retinogenesis ( Capowski et al., 2019 ; Cowan et al., 2020 ; Eldred et al., 2018 ; Fligor et al., 2018 ; Kallman et al., 2020 ; Sridhar et al., 2020 ; Wahlin et al., 2017 ; Zhong et al., 2014 ), as well as diseases resulting in the degeneration of retinal neurons ( Huang et al., 2019 ; Lane et al., 2020 ; Parfitt et al., 2016 ; VanderWall et al., 2020a ).…”

Section: Introductionmentioning

confidence: 99%

Extension of retinofugal projections in an assembled model of human pluripotent stem cell-derived organoids

et al. 2021

Self Cite

View full text Add to dashboard Cite

The development of the visual system involves the coordination of spatial and temporal events to specify the organization of varied cell types, including the elongation of axons from retinal ganglion cells (RGCs) to post-synaptic targets in the brain. Retinal organoids recapitulate many features of retinal development, yet have lacked downstream targets into which RGC axons extend, limiting the ability to model projections of the human visual system. To address these issues, retinal organoids were generated and organized into an in vitro assembloid model of the visual system with cortical and thalamic organoids. RGCs responded to environmental cues and extended axons deep into assembloids, modeling the projections of the visual system. In addition, RGC survival was enhanced in long-term assembloids, overcoming prior limitations of retinal organoids in which RGCs are lost. Overall, these approaches will facilitate studies of human visual system development, as well as diseases or injuries to this critical pathway.

show abstract

“…hPSCs have been used as a reliable model system for studying both the development of many retinal cell types (Lamba et al, 2006; Meyer et al, 2011) as well as diseases which result in the degeneration of these cells (Sridhar, 2018). The current understanding of glaucomatous neurodegeneration has been established in part by the use of animal models mimicking RGC degeneration and injury (Agostinone et al, 2018; Kalesnykas et al, 2012; Tseng et al, 2015; Williams et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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

VanderWall

Huang

Pan

et al. 2019

Preprint

View full text Add to dashboard Cite

Retinal 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.

show abstract

Human Pluripotent Stem Cells as In Vitro Models for Retinal Development and Disease

Cited by 4 publications

References 148 publications

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

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

Extension of retinofugal projections in an assembled model of human pluripotent stem cell-derived organoids

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

Contact Info

Product

Resources

About