Generic placeholder image

Current Molecular Medicine


ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Review Article

Intraocular Exosomes in Eye Diseases

Author(s): Hui Zhang, Xiaomin Zhang* and Xiaorong Li

Volume 22, Issue 6, 2022

Published on: 01 September, 2021

Page: [540 - 548] Pages: 9

DOI: 10.2174/1566524021666210901122948

Price: $65


Exosomes, nanosized extracellular vesicles with a size of 30–150nm, contain many biological materials, such as messenger RNA (mRNA), microRNA (miRNA), proteins, and transcription factors. It has been identified in all biological fluids and recognized as an important part of intercellular communication. While the role of exosomes in cancer has been studied in-depth, our understanding of their relevance for ocular tissues has just begun to evolve. Intraocular fluids, including aqueous humor and vitreous humor, play a role in nourishing eye tissues and in expelling metabolites. In the pathological state, intraocular exosomes can mediate pathological processes such as ECM remodeling, retinal inflammation, and blood-retinal barrier dysfunction. Herein, we reviewed the latest advances of intraocular exosomes in the research of several eye diseases, including glaucoma, age-related macular degeneration, myopia, and ocular tumors, and discuss how intraocular exosomes contribute to the pathogenesis and progression of multiple eye diseases.

Keywords: Exosomes, aqueous humor, vitreous humor, glaucoma, age-related macular degeneration, extracellular vesicles.

Mead B, Tomarev S. Extracellular vesicle therapy for retinal diseases. Prog Retin Eye Res 2020; 79: 100849.
[] [PMID: 32169632]
Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020; 367(6478): eaau6977.
[] [PMID: 32029601]
Guo S, Perets N, Betzer O, et al. Intranasal delivery of mesenchymal stem cell derived exosomes loaded with phosphatase and tensin homolog sirna repairs complete spinal cord injury. ACS Nano 2019; 13(9): 10015-28.
[] [PMID: 31454225]
Elliott RO, He M. Unlocking the power of exosomes for crossing biological barriers in drug delivery. Pharmaceutics 2021; 13(1): 122.
[] [PMID: 33477972]
Xu L, Wu LF, Deng FY. Exosome: An emerging source of biomarkers for human diseases. Curr Mol Med 2019; 19(6): 387-94.
[] [PMID: 31288712]
Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523(7559): 177-82.
[] [PMID: 26106858]
Shi M, Liu C, Cook TJ, et al. Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease. Acta Neuropathol 2014; 128(5): 639-50.
[] [PMID: 24997849]
Garcia-Contreras M, Brooks RW, Boccuzzi L, Robbins PD, Ricordi C. Exosomes as biomarkers and therapeutic tools for type 1 diabetes mellitus. Eur Rev Med Pharmacol Sci 2017; 21(12): 2940-56.
[PMID: 28682421]
Barbosa Breda J, Croitor Sava A, Himmelreich U, et al. Metabolomic profiling of aqueous humor from glaucoma patients - The metabolomics in surgical ophthalmological patients (MISO) study. Exp Eye Res 2020; 201: 108268.
[] [PMID: 33011236]
Ma Z, Liu J, Li J, Jiang H, Kong J. Klotho levels are decreased and associated with enhanced oxidative stress and inflammation in the aqueous humor in patients with exudative age-related macular degeneration. Ocul Immunol Inflamm 2020; 1-8.
[] [PMID: 33048602]
Mathieu M, Martin-Jaular L, Lavieu G, Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol 2019; 21(1): 9-17.
[] [PMID: 30602770]
Villarroya-Beltri C, Baixauli F, Mittelbrunn M, et al. ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins. Nat Commun 2016; 7: 13588.
[] [PMID: 27882925]
Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 2012; 1820(7): 940-8.
[] [PMID: 22503788]
Makler A, Asghar W. Exosomal biomarkers for cancer diagnosis and patient monitoring. Expert Rev Mol Diagn 2020; 20(4): 387-400.
[] [PMID: 32067543]
Tian Y, Gong M, Hu Y, et al. Quality and efficiency assessment of six extracellular vesicle isolation methods by nano-flow cytometry. J Extracell Vesicles 2019; 9(1): 1697028.
[] [PMID: 31839906]
Li K, Wong DK, Hong KY, Raffai RL. Cushioned-density gradient ultracentrifugation (c-dguc): A refined and high performance method for the isolation, characterization, and use of exosomes. Methods Mol Biol 2018; 1740: 69-83.
[] [PMID: 29388137]
Chang M, Chang YJ, Chao PY, Yu Q. Exosome purification based on PEG-coated Fe3O4 nanoparticles. PLoS One 2018; 13(6): e0199438.
[] [PMID: 29933408]
Kang YT, Purcell E, Palacios-Rolston C, et al. Isolation and profiling of circulating tumor-associated exosomes using extracellular vesicular lipid-protein binding affinity based microfluidic device. Small 2019; 15(47): e1903600.
[] [PMID: 31588683]
Navajas R, Corrales FJ, Paradela A. Serum exosome isolation by size-exclusion chromatography for the discovery and validation of preeclampsia-associated biomarkers. Methods Mol Biol 2019; 1959: 39-50.
[] [PMID: 30852814]
Sidhom K, Obi PO, Saleem A. A review of exosomal isolation methods: Is size exclusion chromatography the best option? Int J Mol Sci 2020; 21(18): E6466.
[] [PMID: 32899828]
Liu F, Vermesh O, Mani V, et al. The exosome total isolation chip. ACS Nano 2017; 11(11): 10712-23.
[] [PMID: 29090896]
Yang D, Zhang W, Zhang H, et al. Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics. Theranostics 2020; 10(8): 3684-707.
[] [PMID: 32206116]
Xu R, Greening DW, Zhu HJ, Takahashi N, Simpson RJ. Extracellular vesicle isolation and characterization: toward clinical application. J Clin Invest 2016; 126(4): 1152-62.
[] [PMID: 27035807]
Carreon T, van der Merwe E, Fellman RL, Johnstone M, Bhattacharya SK. Aqueous outflow - A continuum from trabecular meshwork to episcleral veins. Prog Retin Eye Res 2017; 57: 108-33.
[] [PMID: 28028002]
Kagemann L, Wollstein G, Ishikawa H, et al. 3D visualization of aqueous humor outflow structures in-situ in humans. Exp Eye Res 2011; 93(3): 308-15.
[] [PMID: 21514296]
Liu P, Thomson BR, Khalatyan N, et al. Selective permeability of mouse blood-aqueous barrier as determined by 15N-heavy isotope tracing and mass spectrometry. Proc Natl Acad Sci USA 2018; 115(36): 9032-7.
[] [PMID: 30127000]
Wierenga APA, Cao J, Mouthaan H, et al. Aqueous humor biomarkers identify three prognostic groups in uveal melanoma. Invest Ophthalmol Vis Sci 2019; 60(14): 4740-7.
[] [PMID: 31731294]
Abu El-Asrar AM, Berghmans N, Al-Obeidan SA, et al. Soluble cytokine receptor levels in aqueous humour of patients with specific autoimmune uveitic entities: Scd30 is a biomarker of granulomatous uveitis. Eye (Lond) 2019.
Cho H, Hwang M, Hong EH, et al. Micro-RNAs in the aqueous humour of patients with diabetic macular oedema. Clin Exp Ophthalmol 2020; 48(5): 624-35.
[] [PMID: 32173975]
Xie L, Mao M, Wang C, et al. Potential biomarkers for primary open-angle glaucoma identified by long noncoding RNA profiling in the aqueous humor. Am J Pathol 2019; 189(4): 739-52.
[] [PMID: 30677397]
Lerner N, Avissar S, Beit-Yannai E. Extracellular vesicles mediate signaling between the aqueous humor producing and draining cells in the ocular system. PLoS One 2017; 12(2): e0171153.
[] [PMID: 28241021]
Stamer WD, Hoffman EA, Luther JM, Hachey DL, Schey KL. Protein profile of exosomes from trabecular meshwork cells. J Proteomics 2011; 74(6): 796-804.
[] [PMID: 21362503]
Han KY, Tran JA, Chang JH, Azar DT, Zieske JD. Potential role of corneal epithelial cell-derived exosomes in corneal wound healing and neovascularization. Sci Rep 2017; 7: 40548.
[] [PMID: 28165027]
Lerner N, Chen I, Schreiber-Avissar S, Beit-Yannai E. Extracellular vesicles mediate anti-oxidative response in vitro study in the ocular drainage system. Int J Mol Sci 2020; 21(17): E6105.
[] [PMID: 32854215]
Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA 2014; 311(18): 1901-11.
[] [PMID: 24825645]
Ashok A, Chaudhary S, Kritikos AE, et al. Tgfbeta2-hepcidin feed-forward loop in the trabecular meshwork implicates iron in glaucomatous pathology. Invest Ophthalmol Vis Sci 2020; 61(3): 24.
[] [PMID: 32182331]
Tamm ER, Braunger BM, Fuchshofer R. Intraocular pressure and the mechanisms involved in resistance of the aqueous humor flow in the trabecular meshwork outflow pathways. Prog Mol Biol Transl Sci 2015; 134: 301-14.
[] [PMID: 26310162]
Agarwal P, Agarwal R. Trabecular meshwork ECM remodeling in glaucoma: could RAS be a target? Expert Opin Ther Targets 2018; 22(7): 629-38.
[] [PMID: 29883239]
Moazzeni H, Mirrahimi M, Moghadam A, Banaei-Esfahani A, Yazdani S, Elahi E. Identification of genes involved in glaucoma pathogenesis using combined network analysis and empirical studies. Hum Mol Genet 2019; 28(21): 3637-63.
[] [PMID: 31518395]
Lerner N, Schreiber-Avissar S, Beit-Yannai E. Extracellular vesicle-mediated crosstalk between NPCE cells and TM cells result in modulation of Wnt signalling pathway and ECM remodelling. J Cell Mol Med 2020; 24(8): 4646-58.
[] [PMID: 32168427]
Tabak S, Schreiber-Avissar S, Beit-Yannai E. Extracellular vesicles have variable dose-dependent effects on cultured draining cells in the eye. J Cell Mol Med 2018; 22(3): 1992-2000.
[] [PMID: 29411534]
Kasetti RB, Phan TN, Millar JC, Zode GS. Expression of mutant myocilin induces abnormal intracellular accumulation of selected extracellular matrix proteins in the trabecular meshwork. Invest Ophthalmol Vis Sci 2016; 57(14): 6058-69.
[] [PMID: 27820874]
Fingert JH. Penetrance of myocilin mutations-who gets glaucoma? JAMA Ophthalmol 2019; 137(1): 35-7.
[] [PMID: 30267050]
Tamm ER. Myocilin and glaucoma: facts and ideas. Prog Retin Eye Res 2002; 21(4): 395-428.
[] [PMID: 12150989]
Hardy KM, Hoffman EA, Gonzalez P, McKay BS, Stamer WD. Extracellular trafficking of myocilin in human trabecular meshwork cells. J Biol Chem 2005; 280(32): 28917-26.
[] [PMID: 15944158]
Perkumas KM, Hoffman EA, McKay BS, Allingham RR, Stamer WD. Myocilin-associated exosomes in human ocular samples. Exp Eye Res 2007; 84(1): 209-12.
[] [PMID: 17094967]
Fautsch MP, Bahler CK, Jewison DJ, Johnson DH. Recombinant TIGR/MYOC increases outflow resistance in the human anterior segment. Invest Ophthalmol Vis Sci 2000; 41(13): 4163-8.
[PMID: 11095610]
Caballero M, Rowlette LL, Borrás T. Altered secretion of a TIGR/MYOC mutant lacking the olfactomedin domain. Biochim Biophys Acta 2000; 1502(3): 447-60.
[] [PMID: 11068187]
Hoffman EA, Perkumas KM, Highstrom LM, Stamer WD. Regulation of myocilin-associated exosome release from human trabecular meshwork cells. Invest Ophthalmol Vis Sci 2009; 50(3): 1313-8.
[] [PMID: 18952916]
Zhang X, Clark AF, Yorio T. Regulation of glucocorticoid responsiveness in glaucomatous trabecular meshwork cells by glucocorticoid receptor-beta. Invest Ophthalmol Vis Sci 2005; 46(12): 4607-16.
[] [PMID: 16303956]
Honjo M, Igarashi N, Nishida J, et al. Role of the autotaxin-lpa pathway in dexamethasone-induced fibrotic responses and extracellular matrix production in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 2018; 59(1): 21-30.
[] [PMID: 29305605]
Yuan Y, Call MK, Yuan Y, et al. Dexamethasone induces cross-linked actin networks in trabecular meshwork cells through noncanonical wnt signaling. Invest Ophthalmol Vis Sci 2013; 54(10): 6502-9.
[] [PMID: 23963164]
Tektas OY, Lütjen-Drecoll E. Structural changes of the trabecular meshwork in different kinds of glaucoma. Exp Eye Res 2009; 88(4): 769-75.
[] [PMID: 19114037]
Hoshino A, Costa-Silva B, Shen T-L, et al. Tumour exosome integrins determine organotropic metastasis. Nature 2015; 527(7578): 329-35.
[] [PMID: 26524530]
Genschmer KR, Russell DW, Lal C, et al. Activated pmn exosomes: Pathogenic entities causing matrix destruction and disease in the lung. Cell 2019; 176(1-2): 113-126.e15.
[] [PMID: 30633902]
Balaj L, Atai NA, Chen W, et al. Heparin affinity purification of extracellular vesicles. Sci Rep 2015; 5: 10266-6.
[] [PMID: 25988257]
Dismuke WM, Klingeborn M, Stamer WD. Mechanism of fibronectin binding to human trabecular meshwork exosomes and its modulation by dexamethasone. PLoS One 2016; 11(10): e0165326.
[] [PMID: 27783649]
Wu H, Wang Q, Zhong H, et al. Differentially expressed microRNAs in exosomes of patients with breast cancer revealed by next generation sequencing. Oncol Rep 2020; 43(1): 240-50.
[PMID: 31746410]
Sundararajan V, Sarkar FH, Ramasamy TS. The multifaceted role of exosomes in cancer progression: diagnostic and therapeutic implications. Cell Oncol (Dordr) 2018; 41(3): 223-52.
[] [PMID: 29667069]
Dismuke WM, Challa P, Navarro I, Stamer WD, Liu Y. Human aqueous humor exosomes. Exp Eye Res 2015; 132: 73-7.
[] [PMID: 25619138]
Wecker T, Hoffmeier K, Plötner A, et al. Microrna profiling in aqueous humor of individual human eyes by next-generation sequencing. Invest Ophthalmol Vis Sci 2016; 57(4): 1706-13.
[] [PMID: 27064390]
Tanaka Y, Tsuda S, Kunikata H, et al. Profiles of extracellular miRNAs in the aqueous humor of glaucoma patients assessed with a microarray system. Sci Rep 2014; 4: 5089-9.
[] [PMID: 24867291]
Qiu YH, Wei YP, Shen NJ, et al. miR-204 inhibits epithelial to mesenchymal transition by targeting slug in intrahepatic cholangiocarcinoma cells. Cell Physiol Biochem 2013; 32(5): 1331-41.
[] [PMID: 24280681]
Xu Q, Li Z, Zhang H. The influence of lentivirus-miRNA-184 on epithelial-mesenchcymal transition of human lens epithelial cells in vitro. Zhonghua Yan Ke Za Zhi 2015; 51(4): 295-300.
[PMID: 26081234]
Takahashi E, Inoue T, Fujimoto T, Kojima S, Tanihara H. Epithelial mesenchymal transition-like phenomenon in trabecular meshwork cells. Exp Eye Res 2014; 118: 72-9.
[] [PMID: 24291802]
Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet 2012; 379(9827): 1728-38.
[] [PMID: 22559899]
Dinu V, Miller PL, Zhao H. Evidence for association between multiple complement pathway genes and AMD. Genet Epidemiol 2007; 31(3): 224-37.
[] [PMID: 17266113]
Shahid H, Khan JC, Cipriani V, et al. Age-related macular degeneration: the importance of family history as a risk factor. Br J Ophthalmol 2012; 96(3): 427-31.
[] [PMID: 21865200]
Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular degeneration. Nat Genet 2013; 45(4): 433-9.
Rinninella E, Mele MC, Merendino N, et al. The role of diet, micronutrients and the gut microbiota in age-related macular degeneration: New perspectives from the gut−retina axis. Nutrients 2018; 10(11): E1677.
[] [PMID: 30400586]
Laíns I, Kelly RS, Miller JB, et al. Human plasma metabolomics study across all stages of age-related macular degeneration identifies potential lipid biomarkers. Ophthalmology 2018; 125(2): 245-54.
[] [PMID: 28916333]
Noma H, Funatsu H, Yamasaki M, et al. Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion. Eye (Lond) 2008; 22(1): 42-8.
[] [PMID: 16826241]
Kim TW, Kang JW, Ahn J, et al. Proteomic analysis of the aqueous humor in age-related macular degeneration (AMD) patients. J Proteome Res 2012; 11(8): 4034-43.
[] [PMID: 22702841]
Yao J, Liu X, Yang Q, et al. Proteomic analysis of the aqueous humor in patients with wet age-related macular degeneration. Proteomics Clin Appl 2013; 7(7-8): 550-60.
[] [PMID: 23418058]
Kang GY, Bang JY, Choi AJ, et al. Exosomal proteins in the aqueous humor as novel biomarkers in patients with neovascular age-related macular degeneration. J Proteome Res 2014; 13(2): 581-95.
[] [PMID: 24400796]
Rakoczy PE, Lai CM, Baines M, Di Grandi S, Fitton JH, Constable IJ. Modulation of cathepsin d activity in retinal pigment epithelial cells. Biochem J 1997; 324(Pt 3): 935-40.
Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, Neufeld AH. Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to drusen formation and age-related macular degeneration. PLoS One 2009; 4(1): e4160.
[] [PMID: 19129916]
Fader CM, Sánchez D, Furlán M, Colombo MI. Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in k562 cells. Traffic 2008; 9(2): 230-50.
[] [PMID: 17999726]
Sekhar A, Velyvis A, Zoltsman G, Rosenzweig R, Bouvignies G, Kay LE. Conserved conformational selection mechanism of Hsp70 chaperone-substrate interactions. eLife 2018; 7: 7.
[] [PMID: 29460778]
Yang HJ, Hu R, Sun H, Bo , Chen B, Li X, Chen JB. 4-HNE induces proinflammatory cytokines of human retinal pigment epithelial cells by promoting extracellular efflux of HSP70. Exp Eye Res 2019; 188: 107792.
[] [PMID: 31499034]
McBrien NA. Regulation of scleral metabolism in myopia and the role of transforming growth factor-beta. Exp Eye Res 2013; 114: 128-40.
[] [PMID: 23399866]
Chen CF, Hua K, Woung LC, et al. Expression profiling of exosomal mirnas derived from the aqueous humor of myopia patients. Tohoku J Exp Med 2019; 249(3): 213-21.
[] [PMID: 31776299]
Barathi VA, Kwan JL, Tan QS, et al. Muscarinic cholinergic receptor (M2) plays a crucial role in the development of myopia in mice. Dis Model Mech 2013; 6(5): 1146-58.
[] [PMID: 23649821]
Ragusa M, Barbagallo C, Statello L, et al. miRNA profiling in vitreous humor, vitreal exosomes and serum from uveal melanoma patients: Pathological and diagnostic implications. Cancer Biol Ther 2015; 16(9): 1387-96.
[] [PMID: 25951497]
Zhao Y, Weber SR, Lease J, et al. Liquid biopsy of vitreous reveals an abundant vesicle population consistent with the size and morphology of exosomes. Transl Vis Sci Technol 2018; 7(3): 6.
[] [PMID: 29774170]
Galloway CA, Dalvi S, Hung SSC, et al. Drusen in patient-derived hiPSC-RPE models of macular dystrophies. Proc Natl Acad Sci USA 2017; 114(39): E8214-23.
[] [PMID: 28878022]
Klingeborn M, Dismuke WM, Skiba NP, Kelly U, Stamer WD, Bowes Rickman C. Directional exosome proteomes reflect polarity-specific functions in retinal pigmented epithelium monolayers. Sci Rep 2017; 7(1): 4901.
[] [PMID: 28687758]
Biasutto L, Chiechi A, Couch R, Liotta LA, Espina V. Retinal pigment epithelium (RPE) exosomes contain signaling phosphoproteins affected by oxidative stress. Exp Cell Res 2013; 319(13): 2113-23.
[] [PMID: 23669273]
Anderson DH, Radeke MJ, Gallo NB, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 2010; 29(2): 95-112.
[] [PMID: 19961953]
Hallam TM, Marchbank KJ, Harris CL, et al. Rare genetic variants in complement factor i lead to low fi plasma levels resulting in increased risk of age-related macular degeneration. Invest Ophthalmol Vis Sci 2020; 61(6): 18.
[] [PMID: 32516404]
Loyet KM, Deforge LE, Katschke KJ Jr, et al. Activation of the alternative complement pathway in vitreous is controlled by genetics in age-related macular degeneration. Invest Ophthalmol Vis Sci 2012; 53(10): 6628-37.
[] [PMID: 22930722]
Schori C, Trachsel C, Grossmann J, Zygoula I, Barthelmes D, Grimm C. The proteomic landscape in the vitreous of patients with age-related and diabetic retinal disease. Invest Ophthalmol Vis Sci 2018; 59(4): AMD31-40.
[] [PMID: 30025106]
Li W, Li C, Zhou T, et al. Role of exosomal proteins in cancer diagnosis. Mol Cancer 2017; 16(1): 145.
[] [PMID: 28851367]
Kang YT, Hadlock T, Lo TW, et al. Dual-isolation and profiling of circulating tumor cells and cancer exosomes from blood samples with melanoma using immunoaffinity-based microfluidic interfaces. Adv Sci (Weinh) 2020; 7(19): 2001581.
[] [PMID: 33042766]
Xiao D, Ohlendorf J, Chen Y, et al. Identifying mRNA, microRNA and protein profiles of melanoma exosomes. PLoS One 2012; 7(10): e46874.
[] [PMID: 23056502]
Kiss S, Leiderman YI, Mukai S. Diagnosis, classification, and treatment of retinoblastoma. Int Ophthalmol Clin 2008; 48(2): 135-47.
[] [PMID: 18427266]
Galardi A, Colletti M, Lavarello C, et al. Proteomic profiling of retinoblastoma-derived exosomes reveals potential biomarkers of vitreous seeding. Cancers (Basel) 2020; 12(6): E1555.
[] [PMID: 32545553]
Lo TW, Zhu Z, Purcell E, et al. Microfluidic device for high-throughput affinity-based isolation of extracellular vesicles. Lab Chip 2020; 20(10): 1762-70.
[] [PMID: 32338266]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy