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Retinal organoids provide a suitable tool for toxicological drug screening – a comprehensive study validating well-known drug effects on retinal organoids

ABSTRACT: Retinal organoids provide a suitable tool for toxicological drug screening – a comprehensive study validating well-known drug effects on retinal organoids

PROVIDER: PRJNA722233 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14243500.fastq.gz	Fastqsanger.gz
	SRR14243501.fastq.gz	Fastqsanger.gz
	SRR14243502.fastq.gz	Fastqsanger.gz
	SRR14243503.fastq.gz	Fastqsanger.gz
	SRR14243504.fastq.gz	Fastqsanger.gz

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Retinal organoids provide a suitable tool for toxicological drug screening – a comprehensive study validating well-known drug effects on retinal organoids

Project description:Drug toxicity screening on retina is essential for the development of safe therapies for a large number of diseases, whilst preserving visual acuity and function. To this end, retinal organoids derived from human pluripotent stem cells (hPSCs) provide a suitable screening platform due to their similarity to human retina and the ease of generation in large-scale formats, offering almost unlimited excess of tissue. Two hPSC cell lines were differrentiated to retinal organoids which comprised all key retinal cell types in multiple nuclear and synaptic layers, enabling the maintenance of retinal ganglion and bipolar cells and moreover allowed the development of subtypes as revealed by the single cell RNA-Seq analysis. Ketorolac, Digoxin, Thioridazine, Sildenafil, Ethanol and Methanol were used to screen drug effects on retinal organoids. Exposure of the hPSC-derived retinal organoids to Diogxin, Thioridazine and Sildenafil exposure resulted in photoreceptor cell death, while Digoxin and Thioridazine additionally affected all other cell types, including Müller glia cells. Ethanol and Methanol caused an upregulation in retinal ganglion cell related geneexpression. All drug treatments activated astrocytes, indicated by dendrites sprouting into neuroepithelium and upregulation of astrocyte related genes. The ability to resond to light was presereved in organoids although the number of active retinal ganglion cells decreased after drug expsoure. These data indicate comparable drug effects in organoids to those reported in in vitro models and/or in humans, thus providing first robust experimental evidence of their suitability for toxicological studies.

2023-03-03 | GSE172138 | GEO

Microarray analysis of mouse retinal organoids

Project description:ES/iPS-retinal sheet transplantation, which supplies photoreceptors as well as other retinal cells, has been shown able to restore visual function in mice with end-stage retinal degeneration. Here, we introduce a novel type of genetically engineered mouse ES/iPS-retinal sheet with reduced numbers of secondary retinal neurons but intact photoreceptor cell layer structure (Bhlhb4 knockout and Islet1 knockout). We show that this KO grafts can differentiate into retinal organoids with similar potency as wildtype retinal organoids. The data set contains data from 3 cell lines: wildtype (WT, specified as ‘NCT’), B4KO (Bhlhb4 knock-out), and Isl1KO(Islet-1 knockout) across 3 differential days (DDs, DD10, DD16, and DD23) along the early differentiation of retinal tissue.

2021-06-23 | GSE178653 | GEO

Molecular pathology of Usher 1B patient-derived retinal organoids at single cell resolution

Project description:Compare single cell transcriptomes of control and USH1B patient iPSC-derived retinal organoids to elucidate disease mechanisms of Usher syndrome type IB (USH1B). USH1B patient fibroblasts were collected at Great Ormond Street Hospital (GOSH) and reprogrammed to iPSCs. Control and patient iPSCs differentiated in vitro to generate retinal organoids and collected at 35wks. Sequencing was performed at GENEWIZ (Azenta life sciences) on a Illumina NovaSeq system. Data aligned to the human genome UCSC hg38 using cellranger package.

2023-03-27 | E-MTAB-11990 | biostudies-arrayexpress

Transcriptomics of CD29+/CD44+ cells isolated from hPSC retinal organoids reveals a cell population with retinal progenitor and Müller glia characteristics.

Project description:Müller glia play very important and diverse roles in retinal homeostasis and disease, bur very little is known of their development during human retinal embryogenesis. Since they share several markers with retinal progenitors, they are often considered as a different cell population. In this study we isolated CD29+/CD44+cells from retinal organoids formed by hEPSC cells in vitro, and examined their transcriptome profile at various stages of organoid development to identify their transcriptomic profile.

2023-02-21 | E-MTAB-12467 | biostudies-arrayexpress

Single cell transcriptomic comparison of human fetal retina, hPSC-derived retinal organoids, and long-term retinal cultures.

Project description:To study the development of human retina, we used single cell RNAseq at key fetal stages and followed the development of the major cell types, as well as populations of transitional cells. We also analyzed stem cell (hPSC)-derived retinal organoids; although organoids have a very similar cellular composition at equivalent ages to the fetal retina, there are some differences in gene expression of particular cell types. Moreover, the inner retinal lamination is disrupted in more advanced stages of organoids when compared with fetal retina. To determine whether the disorganization in the inner retina was due to the culture conditions, we analyzed retinal development in fetal retina maintained under similar conditions. These retinospheres develop for at least 6 months, displaying better inner retinal lamination than retinal organoids. Our scRNAseq comparisons between fetal retina, retinal organoids and retinospheres provide a new resource for developing better in vitro models for retinal disease.

2020-01-10 | GSE142526 | GEO

Single-Cell RNA Sequencing of Retinal Organoids Derived by CSC14 hESCs

Project description:Retinal organoids samples that derived from human embryonic stem cells were analyzed by single-cell RNA sequencing. Two samples at different differentiation stages (day57 and day 171) were included in this study for cell type comparison.

2022-01-01 | E-MTAB-11121 | biostudies-arrayexpress

RNA-seq of retinal organoids differentiated from hESCs carrying mutations in the RB1 gene

Project description:hESC lines carrying deleterious mutations in the RB1 gene in heterozygous and homozygous state were generated by genome-editing based on CRISPR/Cas9. Parental cell line and genome-edited cell lines were differentiated into retinal organoids for 152 days based on the Protocol published by Döpper et al., Current protocols, PMID: 32956559. Briefly, single cells were reaggregated in presence of dual SMAD and WNT-inhibition; retinal tissue became visible from day 12 onward. BMP4-induction and addition of small molecules CHIR99021 and SU5402 directed differentiation towards retina and retinal pigment epithelium. Long-term differentiation was carried out in the presence of 10% FBS, taurine and retinoic acids. Organoids were collected at indicated time points and either embedded for cryosectioning and immunostaining or frozen at -80°C for RNA preparation.

2022-05-10 | E-MTAB-10331 | biostudies-arrayexpress

Generation, transcriptome profiling, and functional validation of cone-enriched human retinal organoids

Project description:The macula of the retina has a high ratio of cones to rods and is critical for central vision and visual acuity. Macula degenerations affect vision the most and are incurable. Here we report the generation, transcriptome profiling, and functional validation of cone-enriched human retinal organoids differentiated from hESCs. Transcriptome profiling using bulk RNA-seq demonstrated that retinal differentiation in vitro recapitulated retinogenesis in vivo in the temporal expression of cell differentiation markers and retinal disease genes, as well as in mRNA alternative splicing. Single-cell RNA-seq of 8-month retinal organoids identified clusters of cone and rod photoreceptors and confirmed the cone enrichment initially revealed by immunostaining. Notably, comparisons of single-cell transcriptomes demonstrated the similarity between retinal organoids and human macula in cones and rods. Cones in retinal organoids exhibited electrophysiological functions. Collectively, we have established cone-enriched retinal organoids and a reference of transcriptomes that are rich resources for retinal studies.

2019-04-25 | GSE119274 | GEO

SARS-CoV-2 infects and replicates in photoreceptor and retinal ganglion cells of human retinal organoids

Project description:Recent data suggests that COVID-19 is a systemic disease affecting multiple organs including the central nervous system. Retinal involvement in COVID-19 has been indicated by several studies, yet many questions remain regarding the ability of SARS-CoV-2 to infect and replicate retinal cells and its effect on the retina. Here we have used human stem cell derived retinal organoids to study retinal infection by SARS-CoV-2. Indeed, SARS-CoV-2 can infect and replicate in retinal organoids, as it is shown to be able to infect different retinal lineages, including retinal ganglion cells and photoreceptors which are the targets of many retinal diseases leading to blindness. SARS-CoV-2 infection of retinal organoids also induces the expression of several inflammatory genes, including Interleukin 33, which is known to be associated with acute COVID-19 disease and with retinal degeneration. Finally, we show that blocking the ACE2 receptor using antibody treatment significantly reduces retinal organoid infection, indicating that SARS-CoV-2 infects retinal cells in an ACE2 dependent manner. These results suggest a direct retinal involvement in COVID-19, and emphasize the need to monitor retinal pathologies as a possible element of “long COVID”.

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Untreated vs. QR-110 treated retinal organoids

Project description:CEP290 c.2991+1655 homozygous retinal organoids were treated with 1 µM QR-110 for 28 days

2018-10-01 | GSE116797 | GEO