Identifying Multiomic Signatures of X-Linked Retinoschisis-Derived Retinal Organoids and Mice Harboring Patient-Specific Mutation Using Spatiotemporal Single-Cell Transcriptomics.

Autor: Chien Y; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Wu YR; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Chen CY; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Yang YP; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.; Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Ching LJ; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.; Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Wang BX; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Chang WC; Center for Molecular Medicine, China Medical University Hospital, Taichung, 40447, Taiwan., Chiang IH; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan., Su P; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan., Chen SY; Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan.; Genome and Systems Biology Degree Program, Academia Sinica and National Taiwan University, Taipei, 10617, Taiwan., Lin WC; Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan.; Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Wang IC; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan., Lin TC; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan., Chen SJ; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan., Chiou SH; Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan.; Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Nov 06, pp. e2405818. Date of Electronic Publication: 2024 Nov 06.
DOI: 10.1002/advs.202405818
Abstrakt: 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 (Rs1 emR209C ) 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 Rs1 emR209C mice and patient-derived retinal organoids using the multiomics approach provide opportunities to unravel potential therapeutic targets for incurable retinal diseases, such as XLRS.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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