Details

Autor(en) / Beteiligte

• Huang, Kang-Chieh
• Wang, Mong-Lien
• Chen, Shih-Jen
• Kuo, Jean-Cheng
• Wang, Won-Jing
• Nhi Nguyen, Phan Nguyen
• Wahlin, Karl J.
• Lu, Jyh-Feng
• Tran, Audrey A.
• Shi, Michael
• 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

Titel

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

Ist Teil von

• Stem cell reports, 2019-11, Vol.13 (5), p.906-923

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •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.