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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: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE220627 | GEO | 2023/09/15

REPOSITORIES: GEO

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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 [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

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 [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

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

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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]

Project description: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 in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy [human_retinal_organoid]

| PRJNA910552 | ENA

Retinal Dystrophy analysis

Project description:Inherited retinal dystrophies (IRD) are a group of diseases characterized by the loss or dysfunction of photoreceptors and a high genetic and clinical heterogeneity. Currently, over 270 genes have been associated with IRD which makes genetic diagnosis very difficult. The recent advent of next generation sequencing has greatly facilitated the diagnosis process, making possible to provide the patients with accurate genetic counseling in some cases. We studied 92 patients clinically diagnosed with IRD with two different custom -panels.

| EGAS00001005369 | EGA

Improved DEMATEL-ISM integration approach for complex systems.

Project description:PurposeDecision Making Trial and Evaluation Laboratory (DEMATEL) and Interpretive Structural Modeling (ISM) are commonly used separately, but also may be combined per their common characteristics to identify causal relationships and hierarchical structure among factors in complex systems with a relatively small computational burden. The purpose of this study is to establish an improved DEMATEL-ISM integration approach to remedy the disadvantages of the traditional DEMATEL-ISM integration method. A case study was conducted to compare the proposed improved integration approach against the traditional integration method, and to validate its feasibility and effectiveness.MethodsThe proposed improved DEMATEL-ISM integration approach has two main parts: a threshold determination via maximum mean de-entropy (MMDE) method and an additional transitivity check process. The factors influencing China's rural-urban floating population's willingness to participate in social insurance was analyzed as a case study.ResultsThe traditional and improved methods show notable differences in the hierarchical factor structure and the inner influence relationship among factors that they respectively reveal. The traditional integration approach results in some irrationality, while the improved approach does not.OriginalityThis study confirms the importance of proper threshold determination and reachability matrix transitivity checking during DEMATEL-ISM integration. The improved approach includes a scientific threshold determination method based on the MMDE method, plus a transitivity check of the reachability matrix with necessary corrections to ensure its soundness. It can be straightforwardly operated at a relatively low computational burden while providing accurate analysis results.

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Cells of Matter-In Vitro Models for Myotonic Dystrophy.

Project description:Myotonic dystrophy type 1 (DM1 also known as Steinert disease) is a multisystemic disorder mainly characterized by myotonia, progressive muscle weakness and wasting, cognitive impairments, and cardiac defects. This autosomal dominant disease is caused by the expression of nuclear retained RNAs containing pathologic expanded CUG repeats that alter the function of RNA-binding proteins in a tissue-specific manner, leading ultimately to neuromuscular dysfunction and clinical symptoms. Although considerable knowledge has been gathered on myotonic dystrophy since its first description, the development of novel relevant disease models remains of high importance to investigate pathophysiologic mechanisms and to assess new therapeutic approaches. In addition to animal models, in vitro cell cultures provide a unique resource for both fundamental and translational research. This review discusses how cellular models broke ground to decipher molecular basis of DM1 and describes currently available cell models, ranging from exogenous expression of the CTG tracts to variable patients' derived cells.

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