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Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy

ABSTRACT: Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy

PROVIDER: PRJNA910547 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22589200_1.fastq.gz	Fastqsanger.gz
	SRR22589200_2.fastq.gz	Fastqsanger.gz
	SRR22589201_1.fastq.gz	Fastqsanger.gz
	SRR22589201_2.fastq.gz	Fastqsanger.gz
	SRR22592450_1.fastq.gz	Fastqsanger.gz

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Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy [human_retinal_organoid]

Project description:Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy [human_retinal_organoid]

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Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy [mouse_choroid_scRNAseq]

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Integration of human stem cell-derived <i>in vitro</i> systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy.

Project description:Rare DRAM2 coding variants cause retinal dystrophy with early macular involvement via unknown mechanisms. We found that DRAM2 is ubiquitously expressed in the human eye and expression changes were observed in eyes with more common maculopathy such as Age-related Macular Degeneration (AMD). To gain insights into pathogenicity of DRAM2-related retinopathy, we used a combination of in vitro and in vivo models. We found that DRAM2 loss in human pluripotent stem cell (hPSC)-derived retinal organoids caused the presence of additional mesenchymal cells. Interestingly, Dram2 loss in mice also caused increased proliferation of cells from the choroid in vitro and exacerbated choroidal neovascular lesions in vivo. Furthermore, we observed that DRAM2 loss in human retinal pigment epithelial (RPE) cells resulted in increased susceptibility to stress-induced cell death in vitro and that Dram2 loss in mice caused age-related photoreceptor degeneration. This highlights the complexity of DRAM2 function, as its loss in choroidal cells provided a proliferative advantage, whereas its loss in post-mitotic cells, such as photoreceptor and RPE cells, increased degeneration susceptibility. Different models such as human pluripotent stem cell-derived systems and mice can be leveraged to study and model human retinal dystrophies; however, cell type and species-specific expression must be taken into account when selecting relevant systems.

| S-EPMC10483287 | biostudies-literature

Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-15 | GSE220627 | GEO

Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy [human_retinal_organoid]

Project description:We have optimized CRISPR/Cas genome editing in human Embryonic Stem Cells (hESCs) and developed a method to generate hESC-derived eye organoids to investigate the cell type composition of these eye organoids using single cell RNA sequencing. We also investigate the consequences of the loss of a new AMD-associated gene, DRAM2, on the cell composition of the eye organoids.

2023-09-15 | GSE220624 | GEO

Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy [mouse_retina_scRNAseq]

Project description:We investigated the cell type composition of mouse retinas and identified which cell type(s) express genes we identified as being AMD-associated in human patients. We generated Dram2 KO mice to investigate how DRAM2 loss affects the mouse retina. Our in vitro data showed that DRAM2 loss affects human stem cell-derived eye organoids, we investigate if it is the case in mice.

2023-09-15 | GSE220626 | GEO

Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy [mouse_choroid_scRNAseq]

Project description:We are investigating the AMD-associated gene DRAM2. Our in vitro data showed that DRAM2 loss in human embryonic stem cell derived eye organoids generates a distinct fibroblast-like population secreting proteins related to connective tissue extracellular matrix. We generated Dram2 KO mice and did scRNA-seq on cells from the retina, and did not find any significant difference between DRAM2 KO and WT. However, our data from human organoids indicates that the difference should be in the choroid, and not in the retina of the eye. Indeed, we find that DRAM2 KO cells from mouse choroid have a growth advantage compared with WT. Here we investigate the cell type composition of mouse choroid and identify putative genes responsible for the growth advantage in DRAM2 KO choroid cells.

2023-09-15 | GSE220625 | GEO

Non-steroidal mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy

Project description:The objective of this study was to test the novel non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone as a monotherapy in a preclinical Duchenne muscular dystrophy (DMD) model. Microarray was used to detail gene expression differences in ventricular heart tissue from finerenone-treated dystrophin-deficient, utrophin-haploinsufficient Het (utrn+/−; mdx) mice versus untreated Het mice.

2020-08-10 | GSE150302 | GEO

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Project description:Preclinical characterization of antagomiR-218 as a potential treatment for Myotonic Dystrophy

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Project description:Large animal models for Duchenne muscular dystrophy (DMD) are indispensible for preclinical evaluation of novel diagnostic procedures and treatment strategies. To evaluate functional consequences of Duchenne muscular dystrophy (DMD) in skeletal muscle and myocardium, we used a new genetically engineered dystrophin KO pig model displaying hallmarks of human DMD. Heart and skeletal muscle tissue samples of DMD pigs and wild-type (WT) controls at three different ages were analyzed by label-free proteomics.

2021-12-01 | PXD027772 | Pride

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