Identifying Multiomic Signatures of X‐Linked Retinoschisis‐Derived Retinal Organoids and Mice Harboring Patient‐Specific Mutation Using Spatiotemporal Single‐Cell Transcriptomics
Abstract X‐linked retinoschisis (XLRS) is an inherited retinal disorder with severe retinoschisis and visual impairments. Multiomics approaches integrate single‐cell RNA‐sequencing (scRNA‐seq) and spatiotemporal transcriptomics (ST) offering potential for dissecting transcriptional networks and reve...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202405818 |
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| author | Yueh Chien You‐Ren Wu Chih‐Ying Chen Yi‐Ping Yang Lo‐Jei Ching Bo‐Xuan Wang Wei‐Chao Chang I‐Hsun Chiang Pong Su Shih‐Yu Chen Wen‐Chang Lin I‐Chieh Wang Tai‐Chi Lin Shih‐Jen Chen Shih‐Hwa Chiou |
| author_facet | Yueh Chien You‐Ren Wu Chih‐Ying Chen Yi‐Ping Yang Lo‐Jei Ching Bo‐Xuan Wang Wei‐Chao Chang I‐Hsun Chiang Pong Su Shih‐Yu Chen Wen‐Chang Lin I‐Chieh Wang Tai‐Chi Lin Shih‐Jen Chen Shih‐Hwa Chiou |
| author_sort | Yueh Chien |
| collection | DOAJ |
| description | Abstract X‐linked retinoschisis (XLRS) is an inherited retinal disorder with severe retinoschisis and visual impairments. Multiomics approaches integrate single‐cell RNA‐sequencing (scRNA‐seq) and spatiotemporal transcriptomics (ST) offering potential for dissecting transcriptional networks and revealing cell‐cell interactions involved in biomolecular pathomechanisms. Herein, a multimodal approach is demonstrated combining high‐throughput scRNA‐seq and ST to elucidate XLRS‐specific transcriptomic signatures in two XLRS‐like models with retinal splitting phenotypes, including genetically engineered (Rs1emR209C) mice and patient‐derived retinal organoids harboring the same patient‐specific p.R209C mutation. Through multiomics transcriptomic analysis, the endoplasmic reticulum (ER) stress/eukryotic initiation factor 2 (eIF2) signaling, mTOR pathway, and the regulation of eIF4 and p70S6K pathways are identified as chronically enriched and highly conserved disease pathways between two XLRS‐like models. Western blots and proteomics analysis validate the occurrence of unfolded protein responses, chronic eIF2α signaling activation, and chronic ER stress‐induced apoptosis. Furthermore, therapeutic targeting of the chronic ER stress/eIF2α pathway activation synergistically enhances the efficacy of AAV‐mediated RS1 gene delivery, ultimately improving bipolar cell integrity, postsynaptic transmission, disorganized retinal architecture, and electrophysiological responses. Collectively, the complex transcriptomic signatures obtained from Rs1emR209C mice and patient‐derived retinal organoids using the multiomics approach provide opportunities to unravel potential therapeutic targets for incurable retinal diseases, such as XLRS. |
| format | Article |
| id | doaj-art-0f320ead8a3f411d8476882cca194be4 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-0f320ead8a3f411d8476882cca194be42025-01-09T11:44:45ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202405818Identifying Multiomic Signatures of X‐Linked Retinoschisis‐Derived Retinal Organoids and Mice Harboring Patient‐Specific Mutation Using Spatiotemporal Single‐Cell TranscriptomicsYueh Chien0You‐Ren Wu1Chih‐Ying Chen2Yi‐Ping Yang3Lo‐Jei Ching4Bo‐Xuan Wang5Wei‐Chao Chang6I‐Hsun Chiang7Pong Su8Shih‐Yu Chen9Wen‐Chang Lin10I‐Chieh Wang11Tai‐Chi Lin12Shih‐Jen Chen13Shih‐Hwa Chiou14Department of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanCenter for Molecular Medicine China Medical University Hospital Taichung 40447 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanInstitute of Biomedical Sciences Academia Sinica Taipei 11529 TaiwanInstitute of Biomedical Sciences Academia Sinica Taipei 11529 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanDepartment of Ophthalmology Taipei Veterans General Hospital Taipei 112201 TaiwanDepartment of Medical Research Taipei Veterans General Hospital Taipei 11217 TaiwanAbstract X‐linked retinoschisis (XLRS) is an inherited retinal disorder with severe retinoschisis and visual impairments. Multiomics approaches integrate single‐cell RNA‐sequencing (scRNA‐seq) and spatiotemporal transcriptomics (ST) offering potential for dissecting transcriptional networks and revealing cell‐cell interactions involved in biomolecular pathomechanisms. Herein, a multimodal approach is demonstrated combining high‐throughput scRNA‐seq and ST to elucidate XLRS‐specific transcriptomic signatures in two XLRS‐like models with retinal splitting phenotypes, including genetically engineered (Rs1emR209C) mice and patient‐derived retinal organoids harboring the same patient‐specific p.R209C mutation. Through multiomics transcriptomic analysis, the endoplasmic reticulum (ER) stress/eukryotic initiation factor 2 (eIF2) signaling, mTOR pathway, and the regulation of eIF4 and p70S6K pathways are identified as chronically enriched and highly conserved disease pathways between two XLRS‐like models. Western blots and proteomics analysis validate the occurrence of unfolded protein responses, chronic eIF2α signaling activation, and chronic ER stress‐induced apoptosis. Furthermore, therapeutic targeting of the chronic ER stress/eIF2α pathway activation synergistically enhances the efficacy of AAV‐mediated RS1 gene delivery, ultimately improving bipolar cell integrity, postsynaptic transmission, disorganized retinal architecture, and electrophysiological responses. Collectively, the complex transcriptomic signatures obtained from Rs1emR209C mice and patient‐derived retinal organoids using the multiomics approach provide opportunities to unravel potential therapeutic targets for incurable retinal diseases, such as XLRS.https://doi.org/10.1002/advs.202405818chronic ER stress‐associated apoptosiseIF2α signalinggenetically engineered miceretinoschisin 1 (RS1)single‐cell RNA‐sequencingspatiotemporal transcriptomics |
| spellingShingle | Yueh Chien You‐Ren Wu Chih‐Ying Chen Yi‐Ping Yang Lo‐Jei Ching Bo‐Xuan Wang Wei‐Chao Chang I‐Hsun Chiang Pong Su Shih‐Yu Chen Wen‐Chang Lin I‐Chieh Wang Tai‐Chi Lin Shih‐Jen Chen Shih‐Hwa Chiou Identifying Multiomic Signatures of X‐Linked Retinoschisis‐Derived Retinal Organoids and Mice Harboring Patient‐Specific Mutation Using Spatiotemporal Single‐Cell Transcriptomics Advanced Science chronic ER stress‐associated apoptosis eIF2α signaling genetically engineered mice retinoschisin 1 (RS1) single‐cell RNA‐sequencing spatiotemporal transcriptomics |
| title | Identifying Multiomic Signatures of X‐Linked Retinoschisis‐Derived Retinal Organoids and Mice Harboring Patient‐Specific Mutation Using Spatiotemporal Single‐Cell Transcriptomics |
| title_full | Identifying Multiomic Signatures of X‐Linked Retinoschisis‐Derived Retinal Organoids and Mice Harboring Patient‐Specific Mutation Using Spatiotemporal Single‐Cell Transcriptomics |
| title_fullStr | Identifying Multiomic Signatures of X‐Linked Retinoschisis‐Derived Retinal Organoids and Mice Harboring Patient‐Specific Mutation Using Spatiotemporal Single‐Cell Transcriptomics |
| title_full_unstemmed | Identifying Multiomic Signatures of X‐Linked Retinoschisis‐Derived Retinal Organoids and Mice Harboring Patient‐Specific Mutation Using Spatiotemporal Single‐Cell Transcriptomics |
| title_short | Identifying Multiomic Signatures of X‐Linked Retinoschisis‐Derived Retinal Organoids and Mice Harboring Patient‐Specific Mutation Using Spatiotemporal Single‐Cell Transcriptomics |
| title_sort | identifying multiomic signatures of x linked retinoschisis derived retinal organoids and mice harboring patient specific mutation using spatiotemporal single cell transcriptomics |
| topic | chronic ER stress‐associated apoptosis eIF2α signaling genetically engineered mice retinoschisin 1 (RS1) single‐cell RNA‐sequencing spatiotemporal transcriptomics |
| url | https://doi.org/10.1002/advs.202405818 |
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