Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

Huang, Kang-Chieh; Wang, Mong‐Lien; Chen, Shih‐Jen; Kuo, Jean Cheng; Wang, Won Jing; Nguyen, Phan Nguyen Nhi; Wahlin, Karl; Lu, Jyh-Feng; Tran, Ashley; Shi, Michael A.; Chien, Yueh; Yarmishyn, Aliaksandr A.; Tsai, Ping-Hsing; Yang, Tien Chun; Jane, Wann Neng; Chang, Chia-Ching; Peng, Chi Hsien; Schlaeger, Thorsten M.; Chiou, Shih Hwa

doi:10.1016/j.stemcr.2019.09.010

Cited by 75 publications

(78 citation statements)

References 44 publications

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“…Here, we have analyzed the disease phenotype and expression profile within a staging system, which is largely consistent with their findings. Based on the staging system, the RO disease models established to date have all been early-or mid-stage (Parfitt David et al, 2016;Shimada et al, 2017;Teotia et al, 2017;Buskin et al, 2018;Deng et al, 2018;Guo et al, 2019;Huang et al, 2019;Li et al, 2019;Quinn et al, 2019). For example, in a previous RPGR-RP model established in our lab (Deng et al, 2018), impaired gene expression was found as early as D90, and impaired photoreceptor morphology was observed at approximately D150.…”

Section: Discussionmentioning

confidence: 99%

Patient-Specific Retinal Organoids Recapitulate Disease Features of Late-Onset Retinitis Pigmentosa

Gao

Lei

Han

et al. 2020

Front. Cell Dev. Biol.

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Although an increasing number of disease genes have been identified, the exact cellular mechanisms of retinitis pigmentosa (RP) remain largely unclear. Retinal organoids (ROs) derived from the induced pluripotent stem cells (iPSCs) of patients provide a potential but unvalidated platform for deciphering disease mechanisms and an advantageous tool for preclinical testing of new treatments. Notably, early-onset RP has been extensively recapitulated by patient-iPSC-derived ROs. However, it remains a challenge to model late-onset disease in a dish due to its chronicity, complexity, and instability. Here, we generated ROs from late-onset RP proband-derived iPSCs harboring a PDE6B mutation. Transcriptome analysis revealed a remarkably distinct gene expression profile in the patient ROs at differentiation day (D) 230. Changes in the expression genes regulating cGMP hydrolysis prompted the elevation of cGMP levels, which was verified by a cGMP enzyme-linked immunosorbent assay (ELISA) in patient ROs. Furthermore, significantly higher cGMP levels in patient ROs than in control ROs at D193 and D230 might lead to impaired formation of synaptic connections and the connecting cilium in photoreceptor cells. In this study, we established the first late-onset RP model with a consistent phenotype using an in vitro cell culture system and provided new insights into the PDE6B-related mechanism of RP.

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Section: Discussionmentioning

confidence: 99%

Patient-Specific Retinal Organoids Recapitulate Disease Features of Late-Onset Retinitis Pigmentosa

Gao

Lei

Han

et al. 2020

Front. Cell Dev. Biol.

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“…In addition to genes encoding ciliary proteins, mutations in two genes related to structural integrity of the retina have been studied in organoid cultures. Organoids derived from iPSCs of a X‐linked retinoschisis patient with RS1 mutation recapitulated the retinal phenotype 48 . In organoids derived from patient with mutations in the CRB1 gene, the outer limiting membrane was disrupted with ectopic photoreceptor cell bodies detected beyond the apical limit of the neural retina 49 .…”

Section: Retinal Organoids As Disease Modelsmentioning

confidence: 94%

“…Most studies to date have used gene editing in iPSCs to rescue disease phenotypes 41,47,48 . However, such a strategy is not yet applicable for patient treatment.…”

Section: Evaluation Of Therapeutic Strategies In Human Retinal Organoidsmentioning

confidence: 99%

Pluripotent stem cell-derived retinal organoids for disease modeling and development of therapies

Kruczek

Swaroop

2020

Stem Cells

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Retinal diseases constitute a genetically and phenotypically diverse group of clinical conditions leading to vision impairment or blindness with limited treatment options. Advances in reprogramming of somatic cells to induced pluripotent stem cells and generation of three-dimensional organoids resembling the native retina offer promising tools to interrogate disease mechanisms and evaluate potential therapies for currently incurable retinal neurodegeneration. Next-generation sequencing, singlecell analysis, advanced electrophysiology, and high-throughput screening approaches are expected to greatly expand the utility of stem cell-derived retinal cells and organoids for developing personalized treatments. In this review, we discuss the current status and future potential of combining retinal organoids as human models with recent technologies to advance the development of gene, cell, and drug therapies for retinopathies.

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“…CRISPR-Cas-9 gene correction in retinal organoids has been tested successfully in several human RD models ( Deng et al, 2018 ; Huang et al, 2019 ; Lane et al, 2020 ) as well as in vivo in mice (with up to 45% efficiency of repair of dominant-negative Rho mutation to wild type allele in photoreceptors) ( Li et al, 2018 ). CRISPR-Cas-9-based repair may be especially productive and needed for RP diseases, which are caused by dominant-negative mutations, and may potentially work together with retinal tissue replacement (discussed above).…”

Section: D Retinal Tissue Models For Elucidating Disease Mechanisms mentioning

confidence: 99%

Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness

Singh

Nasonkin

2020

Front. Cell. Neurosci.

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The self-formation of retinal tissue from pluripotent stem cells generated a tremendous promise for developing new therapies of retinal degenerative diseases, which previously seemed unattainable. Together with use of induced pluripotent stem cells or/and CRISPR-based recombineering the retinal organoid technology provided an avenue for developing models of human retinal degenerative diseases “in a dish” for studying the pathology, delineating the mechanisms and also establishing a platform for large-scale drug screening. At the same time, retinal organoids, highly resembling developing human fetal retinal tissue, are viewed as source of multipotential retinal progenitors, young photoreceptors and just the whole retinal tissue, which may be transplanted into the subretinal space with a goal of replacing patient’s degenerated retina with a new retinal “patch.” Both approaches (transplantation and modeling/drug screening) were projected when Yoshiki Sasai demonstrated the feasibility of deriving mammalian retinal tissue from pluripotent stem cells, and generated a lot of excitement. With further work and testing of both approaches in vitro and in vivo , a major implicit limitation has become apparent pretty quickly: the absence of the uniform layer of Retinal Pigment Epithelium (RPE) cells, which is normally present in mammalian retina, surrounds photoreceptor layer and develops and matures first. The RPE layer polarize into apical and basal sides during development and establish microvilli on the apical side, interacting with photoreceptors, nurturing photoreceptor outer segments and participating in the visual cycle by recycling 11-trans retinal (bleached pigment) back to 11-cis retinal. Retinal organoids, however, either do not have RPE layer or carry patches of RPE mostly on one side, thus directly exposing most photoreceptors in the developing organoids to neural medium. Recreation of the critical retinal niche between the apical RPE and photoreceptors, where many retinal disease mechanisms originate, is so far unattainable, imposes clear limitations on both modeling/drug screening and transplantation approaches and is a focus of investigation in many labs. Here we dissect different retinal degenerative diseases and analyze how and where retinal organoid technology can contribute the most to developing therapies even with a current limitation and absence of long and functional outer segments, supported by RPE.

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Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

Cited by 75 publications

References 44 publications

Patient-Specific Retinal Organoids Recapitulate Disease Features of Late-Onset Retinitis Pigmentosa

Patient-Specific Retinal Organoids Recapitulate Disease Features of Late-Onset Retinitis Pigmentosa

Pluripotent stem cell-derived retinal organoids for disease modeling and development of therapies

Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness

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