{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T02:57:35Z","timestamp":1791428255144,"version":"4.3.3"},"reference-count":79,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Augusta University","award":["P30EY031631"],"award-info":[{"award-number":["P30EY031631"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The retina is highly sensitive to oxygen and blood supply, and hypoxia plays a key role in retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). M\u00fcller glial cells, which are essential for retinal homeostasis, respond to injury and hypoxia with reactive gliosis, characterized by the upregulation of the glial fibrillary acidic protein (GFAP) and vimentin, cellular hypertrophy, and extracellular matrix changes, which can impair retinal function and repair. The retinal pigment epithelium (RPE) supports photoreceptors, forms part of the blood\u2013retinal barrier, and protects against oxidative stress; its dysfunction contributes to retinal degenerative diseases such as AMD, retinitis pigmentosa (RP), and Stargardt disease (SD). Extracellular vesicles (EVs) play a crucial role in intercellular communication, protein homeostasis, and immune modulation, and have emerged as promising diagnostic and therapeutic tools. Understanding the role of extracellular vesicles\u2019 (EVs\u2019) signaling machinery of glial cells and the retinal pigment epithelium (RPE) is critical for developing effective treatments for retinal degeneration. In this study, we investigated the bidirectional EV-mediated crosstalk between RPE and M\u00fcller cells under hypoxic conditions and its impact on cellular metabolism and retinal cell integrity. Our findings demonstrate that RPE-derived extracellular vesicles (RPE EVs) induce time-dependent metabolic reprogramming in M\u00fcller cells. Short-term exposure (24 h) promotes pathways supporting neurotransmitter cycling, calcium and mineral absorption, and glutamate metabolism, while prolonged exposure (72 h) shifts M\u00fcller cell metabolism toward enhanced mitochondrial function and ATP production. Conversely, M\u00fcller cell-derived EVs under hypoxia influenced RPE metabolic pathways, enhancing fatty acid metabolism, intracellular vesicular trafficking, and the biosynthesis of mitochondrial co-factors such as ubiquinone. Proteomic analysis revealed significant modulation of key regulatory proteins. In M\u00fcller cells, hypoxic RPE-EV exposure led to reduced expression of Dyskerin Pseudouridine Synthase 1 (DKc1), Eukaryotic Translation Termination Factor 1 (ETF1), and Protein Ser\/Thr phosphatases (PPP2R1B), suggesting alterations in RNA processing, translational fidelity, and signaling. RPE cells exposed to hypoxic M\u00fcller cell EVs exhibited elevated Ribosome-binding protein 1 (RRBP1), RAC1\/2, and Guanine Nucleotide-Binding Protein G(i) Subunit Alpha-1 (GNAI1), supporting enhanced endoplasmic reticulum (ER) function and cytoskeletal remodeling. Functional assays also revealed the compromised barrier integrity of the outer blood\u2013retinal barrier (oBRB) under hypoxic co-culture conditions. These results underscore the adaptive but time-sensitive nature of retinal cell communication via EVs in response to hypoxia. Targeting this crosstalk may offer novel therapeutic strategies to preserve retinal structure and function in ischemic retinopathies.<\/jats:p>","DOI":"10.3390\/biology14081014","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T10:58:26Z","timestamp":1754564306000},"page":"1014","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Bidirectional Hypoxic Extracellular Vesicle Signaling Between M\u00fcller Glia and Retinal Pigment Epithelium Regulates Retinal Metabolism and Barrier Function"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8595-6949","authenticated-orcid":false,"given":"Alaa M.","family":"Mansour","sequence":"first","affiliation":[{"name":"Department of Oral Biology, The Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"DCG Center for Excellence in Research, Scholarship, and Innovation (CERSI), Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3473-7062","authenticated-orcid":false,"given":"Mohamed S.","family":"Gad","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, The Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"DCG Center for Excellence in Research, Scholarship, and Innovation (CERSI), Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0690-8277","authenticated-orcid":false,"given":"Samar","family":"Habib","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, The Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"DCG Center for Excellence in Research, Scholarship, and Innovation (CERSI), Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Medical Parasitology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3529-8962","authenticated-orcid":false,"given":"Khaled","family":"Elmasry","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, The Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"DCG Center for Excellence in Research, Scholarship, and Innovation (CERSI), Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Cellular Biology and Anatomy, The Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Human Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.exer.2006.01.016","article-title":"Oxygen-dependent diseases in the retina: Role of hypoxia-inducible factors","volume":"83","author":"Arjamaa","year":"2006","journal-title":"Exp. 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