Extracellular Vesicles: Biomarkers, Therapeutics, and Vehicles in the Visual System
Tóm tắt
We discuss recent advances in extracellular vesicle (EV) technology as biomarkers, therapeutics, and drug delivery vehicles in the visual system with an emphasis on the retina. Retinal cell-type specific EVs can be detected in the blood and in the aqueous humor and EV miRNA cargoes can be used diagnostically to predict retinal disease progression. Studies have now shown EVs can deliver bioactive miRNA and AAV cargoes to the inner retinal cell layers and, in some models, improve retinal ganglion cell (RGC) survival and axon regeneration. EV molecular profiles and cargoes are attractive biomarkers for retinal and optic nerve disease and trauma and EVs offer a safe and tunable platform for delivering therapies to ocular tissues. However, EVs are heterogeneous by nature with variable lipid membranes, cargoes, and biologic effects, warranting stringent characterization to understand how heterogeneous EV populations modulate positive tissue remodeling.
Tài liệu tham khảo
Kowal J, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci USA. 2016;113(8):E968–77.
Huleihel L, et al. Matrix-bound nanovesicles within ECM bioscaffolds. Sci Adv. 2016;2(6):e1600502.
Riazifar M, et al. Stem cell extracellular vesicles: extended messages of regeneration. Annu Rev Pharmacol Toxicol. 2017;57:125–54.
Yoon YJ, Kim OY, Gho YS. Extracellular vesicles as emerging intercellular communicasomes. BMB Rep. 2014;47(10):531–9.
Koniusz S, et al. Extracellular vesicles in physiology, pathology, and therapy of the immune and central nervous system, with focus on extracellular vesicles derived from mesenchymal stem cells as therapeutic tools. Front Cell Neurosci. 2016;10:109.
Subra C, et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res. 2010;51(8):2105–20.
• Klingeborn M, et al. Directional exosome proteomes reflect polarity-specific functions in retinal pigmented epithelium monolayers. Sci Rep. 2017;7(1):4901. Klingeborn et al. demonstrated epithelial polarity regulates directional exosome release; both the number of exosomes and their proteomes were polarized with respect to the apical and basolateral RPE compartments.
Mulcahy LA, Pink RC, Carter DR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;3.
• Willms E, et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci Rep. 2016;6:22519. Regardless of cellular source, EVs are heterogeneous populations with distinct surface markers, cargoes, and biologic effects.
Lopez-Verrilli MA, et al. Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth. Neuroscience. 2016;320:129–39.
Chandran R, et al. Differential expression of microRNAs in the brains of mice subjected to increasing grade of mild traumatic brain injury. Brain Inj. 2016:1–14.
Liu Y, et al. Bioinformatics analysis of microRNA time-course expression in brown rat (Rattus norvegicus): spinal cord injury self-repair. Spine (Phila Pa 1976). 2016;41(2):97–103.
Liu NK, et al. Altered microRNA expression following traumatic spinal cord injury. Exp Neurol. 2009;219(2):424–9.
Li P, Teng ZQ, Liu CM. Extrinsic and intrinsic regulation of axon regeneration by microRNAs after spinal cord injury. Neural Plast. 2016;2016:1279051.
• Tumahai P, et al. Vitreous microparticle shedding in retinal detachment: a prospective comparative study. Invest Ophthalmol Vis Sci. 2016;57(1):40–6. Tumahai, P. et al. showed vitreous EVs derived from photoreceptors were higher in the aqueous humor of patients after rhegmatogenous RD.
Ragusa M, et al. MicroRNAs in vitreus humor from patients with ocular diseases. Mol Vis. 2013;19:430–40.
Ragusa M, 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.
Santangelo A, et al. Circulating microRNAs as emerging non-invasive biomarkers for gliomas. Ann Transl Med. 2017;5(13):277.
Tanaka Y, et al. Profiles of extracellular miRNAs in the aqueous humor of glaucoma patients assessed with a microarray system. Sci Rep. 2014;4:5089.
Dismuke WM, et al. Human aqueous humor exosomes. Exp Eye Res. 2015;132:73–7.
• 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. Non-pigmented ciliary epithelium cell (NPCE)-derived EVs accumulate in trabecular meshwork cells and effect Wnt signaling, a pathway involved in intraocular pressure regulation.
Dunmire JJ, et al. MicroRNA in aqueous humor from patients with cataract. Exp Eye Res. 2013;108:68–71.
Pachler K, et al. A good manufacturing practice-grade standard protocol for exclusively human mesenchymal stromal cell-derived extracellular vesicles. Cytotherapy. 2017;19(4):458–72.
Lotvall J, et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles. 2014;3:26913.
Ko J, Carpenter E, Issadore D. Detection and isolation of circulating exosomes and microvesicles for cancer monitoring and diagnostics using micro-/nano-based devices. Analyst. 2016;141(2):450–60.
• Keerthikumar S, et al. ExoCarta: a web-based compendium of exosomal cargo. J Mol Biol. 2016;428(4):688–92. The ExoCarta database was developed.
Kang GY, 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.
Elshelmani H, Rani S. Exosomal microRNA discovery in age-related macular degeneration. Methods Mol Biol. 2017;1509:93–113.
Hu B, et al. Effect of extracellular vesicles on neural functional recovery and immunologic suppression after rat cerebral apoplexy. Cell Physiol Biochem. 2016;40(1–2):155–62.
• Mead B, Tomarev S. Bone marrow-derived mesenchymal stem cells-derived exosomes promote survival of retinal ganglion cells through miRNA-dependent mechanisms. Stem Cells Transl Med. 2017;6(4):1273–85. Mead et al. showed intravitreally injected EVs delivered their cargoes to both Müller glia and RGCs and increased RGC survival and axon regeneration after optic nerve ischemia.
• Tassew NG, et al. Exosomes mediate mobilization of autocrine Wnt10b to promote axonal regeneration in the injured CNS. Cell Rep. 2017;20(1):99–111. Fibroblast EVs were reported to increase RGC survival and growth after acute optic nerve ischemia via established axon growth regulatory pathways involving mTOR activation by GSK3β and TSC2.
Moisseiev E, et al. Protective effect of intravitreal administration of exosomes derived from mesenchymal stem cells on retinal ischemia. Curr Eye Res. 2017:1–10.
Jaimes Y, et al. Mesenchymal stem cell-derived microvesicles modulate lipopolysaccharides-induced inflammatory responses to microglia cells. Stem Cells. 2017;35(3):812–23.
Liddelow SA, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–7.
• Yu B, et al. Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1. Sci Rep. 2016;6:34562. EVs were reported to reduce monocyte chemotactic protein (MCP)-1 expression and injury, apoptosis, and inflammatory responses in a mouse model of laser induced retinopathy.
van der Merwe Y, Steketee MB. Immunomodulatory approaches to CNS injury: extracellular matrix and exosomes from extracellular matrix conditioned macrophages. Neural Regen Res. 2016;11(4):554–6.
Wassmer SJ, et al. Exosome-associated AAV2 vector mediates robust gene delivery into the murine retina upon intravitreal injection. Sci Rep. 2017;7:45329.
Kordelas L, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28(4):970–3.