Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis
| Autor: | Ping Hsing Tsai, Audrey A. Tran, Wann-Neng Jane, Aliaksandr A. Yarmishyn, Yueh Chien, Shih Hwa Chiou, Chi Hsien Peng, Tien Chun Yang, Kang Chieh Huang, Chia-Ching Chang, Thorsten M. Schlaeger, Shih Jen Chen, Won Jing Wang, Jean Cheng Kuo, Karl J. Wahlin, Phan Nguyen Nhi Nguyen, Jyh Feng Lu, Michael Shi, Mong Lien Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Retinal degeneration Male RS1 induced pluripotent stem cells Retinoschisis retinogenesis retinoschisin Biology medicine.disease_cause Biochemistry Article Retina 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genetics Organoid medicine Humans Point Mutation Induced pluripotent stem cell Eye Proteins lcsh:QH301-705.5 Cells Cultured Gene Editing Mutation lcsh:R5-920 retinal organoid Cilium X-linked juvenile retinoschisis Retinal Cell Biology medicine.disease Phenotype Cell biology Organoids 030104 developmental biology chemistry lcsh:Biology (General) retinal degeneration CRISPR/Cas9 gene editing RETINOSCHISIN lcsh:Medicine (General) 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 13, Iss 5, Pp 906-923 (2019) |
| ISSN: | 2213-6711 |
| Popis: | Summary X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model. Highlights • hiPSC-derived retinal organoid model recapitulates key features of XLRS • CRISPR/Cas9 correction normalizes RS1 secretion and retinal development • Transcriptome analysis links XLRS to other hereditary retinopathies Chiou, Schlaeger, and colleagues use hiPSC-derived retinal organoids to model X-linked juvenile retinoschisis. They show that patient hiPSC-derived retinal organoids replicate key pathologies observed in patients, including retinal splitting and photoreceptor deficit. The observed abnormalities were normalized in organoids derived from isogenic CRISPR/Cas9 gene-corrected hiPSCs. This validated XLRS in vitro model could be used to test and optimize therapeutic approaches. |
| Databáze: | OpenAIRE |
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