外泌体在眼病发病机制和诊疗中的研究进展

Research rogress of exosomes in the pathogenesis, diagnosis and treatment in ophthalmic diseases

摘要

外泌体是由多种活细胞分泌的纳米级细胞外囊泡，具有脂质双层膜结构，广泛存在于各种体液当中。外泌体在细胞间的信息交流、免疫反应、修复再生等方面发挥重要作用，不同来源的外泌体功能不尽相同。近年来，外泌体在眼科疾病的诊断、治疗、预后评估中均取得了一定的进展，使眼病个性化治疗成为可能，并为眼病治疗方式的选择提供依据。本文就外泌体在眼病发病机制、诊断、治疗方面的研究进展作一综述。

Abstract

Exosomes are nanoscale extracellular vesicles secreted by a variety of living cells. They have a lipid bilayer membrane structure and are widely distributed in various body fluids. They play an important role in information exchange between cells, immune response, repair and regeneration, etc. Exosomes from different sources have different functions. In recent years exosomes have shown great research potential in the diagnosis, treatment and prognosis evaluation of eye diseases, which may lead to more personalised treatment for patients with eye diseases and provide a basis for the selection of treatment methods for eye diseases. This article reviews the role of exosomes in the pathogenesis, diagnosis, and treatment of ophthalmic diseases.

关键词

外泌体 / 眼病 / 发病机制 / 诊断 / 治疗

Key words

Exosomes / Ophthalmic diseases / Pathogenesis / Diagnosis / Treatment

参考文献

[1] Keele S , Müller A , Block S , et al. Keeping an eye on eye care: monitoring progress towards effective coverage [J]. Lancet Glob Health, 2021, 9(10): e1460-e1464. doi: 10.1016/S2214-109X(21)00212-6

[2] Li YT , Ren XJ , Zhang ZH , et al. Effect of small extracellular vesicles derived from IL-10-overexpressing mesenchymal stem cells on experimental autoimmune uveitis [J]. Stem Cell Res Ther, 2022, 13(1): 100. doi: 10.1186/s13287-022-02780-9

[3] Liu J , Jiang F , Jiang Y , et al. Roles of exosomes in ocular diseases [J]. Int J Nanomedicine, 2020, 15: 10519-10538. doi: 10.2147/IJN.S277190

[4] Gurunathan S , Kang MH, Jeyaraj M , et al. Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes [J]. Cells, 2021, 10(2): 462. doi: 10.3390/cells10020462

[5] Patel NJ , Ashraf A , Chung EJ . Extracellular vesicles as regulators of the extracellular matrix [J]. Bioengineering, 2023, 10(2): 136. doi: 10.3390/bioengineering10020136

[6] 郝慧强, 李姝赟, 郭松佳, 等 . 外泌体生物学发生机制的研究进展 [J]. 山东医药, 2021, 61(19): 109-112. doi: 10.3969/j.issn.1002-266X.2021.19.028

[7] HAO Huiqiang , LI Shuyun , GUO Songjia , et al. Research progress on biological mechanism of exosomes [J]. Shandong Medical Journal, 2021, 61(19): 109-112. doi: 10.3969/j.issn.1002-266X.2021.19.028

[8] Théry C , Witwer KW , Aikawa E , et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines [J]. J Extracell Vesicles, 2018, 7(1): 1535750. doi: 10.1080/20013078.2018.1535750

[9] Kalluri R. The biology and function of exosomes in cancer [J]. J Clin Invest, 2016, 126(4): 1208-1215. doi: 10.1172/JCI81135

[10] Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy [J]. Annu Rev Physiol, 2015, 77: 13-27. doi: 10.1146/annurev-physiol-021014-071641

[11] Hanus J , Anderson C , Wang SS . RPE necroptosis in response to oxidative stress and in AMD [J]. Ageing Res Rev, 2015, 24(PtB): 286-298. doi: 10.1016/j.arr.2015.09.002

[12] Hu P , Yang QX , Wang Q , et al. Mesenchymal stromal cells-exosomes: a promising cell-free therapeutic tool for wound healing and cutaneous regeneration [J]. Burns Trauma, 2019, 7: 38. doi: 10.1186/s41038-019-0178-8

[13] Lee BC , Kang I , Yu KR . Therapeutic features and updated clinical trials of mesenchymal stem cell (MSC)-derived exosomes [J]. J Clin Med, 2021, 10(4): 711. doi: 10.3390/jcm10040711

[14] 梁春兰, 师齐, 刘莲, 等 . 间充质干细胞来源的外泌体与眼免疫性疾病 [J]. 医学研究杂志, 2022, 51(9): 171-174. doi: 10.11969/j.issn.1673-548X.2022.09.037

[15] LIANG Chunlan , SHI Qi , LIU Lian , et al. Exosomes derived from mesenchymal stem cells and ocular immune diseases [J]. Journal of Medical Research, 2022, 51(9): 171-174. doi: 10.11969/j.issn.1673-548X.2022.09.037

[16] Wei C , Sun YR , Zeng FX , et al. Exosomal miR-181d-5p derived from rapamycin-conditioned MDSC alleviated allograft rejection by targeting KLF6 [J]. Adv Sci, 2023, 10(34): e2304922. doi: 10.1002/advs.202304922

[17] Xiao Y , Li Y , Yuan YH , et al. The potential of exosomes derived from colorectal cancer as a biomarker [J]. Clin Chim Acta, 2019, 490: 186-193. doi: 10.1016/j.cca.2018.09.007

[18] 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 [J]. Cancer Biol Ther, 2015, 16(9): 1387-1396. doi: 10.1080/15384047.2015.1046021

[19] Ha D , Yang NN , Nadithe V . Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges [J]. Acta Pharm Sin B, 2016, 6(4): 287-296. doi: 10.1016/j.apsb.2016.02.001

[20] Bhujel B , Oh SH , Kim CM , et al. Mesenchymal stem cells and exosomes: a novel therapeutic approach for corneal diseases [J]. Int J Mol Sci, 2023, 24(13): 10917. doi: 10.3390/ijms241310917

[21] Ong HS , Riau AK , Yam GHF , et al. Mesenchymal stem cell exosomes as immunomodulatory therapy for corneal scarring [J]. Int J Mol Sci, 2023, 24(8): 7456. doi: 10.3390/ijms24087456

[22] Liu XL , Li XR , Wu GY , et al. Umbilical cord mesenchymal stem cell-derived small extracellular vesicles deliver miR-21 to promote corneal epithelial wound healing through PTEN/PI3K/akt pathway [J]. Stem Cells Int, 2022, 2022: 1252557. doi: 10.1155/2022/1252557

[23] Sun XM , Song WJ , Teng LJ , et al. MiRNA24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogels for corneal epithelial healing [J]. Bioact Mater, 2023, 25: 640-656. doi: 10.1016/j.bioactmat.2022.07.011

[24] Lai YH , Lee PY , Lu CY , et al. Thrombospondin1-induced exosomal proteins attenuate hypoxia-induced paraptosis in corneal epithelial cells and promote wound healing [J]. FASEB J, 2021, 35(1): e21200. doi: 10.1096/fj.202001106RRR

[25] Escandon P , Liu A , Nicholas SE , et al. Unravelling novel roles of salivary exosomes in the regulation of human corneal stromal cell migration and wound healing [J]. Int J Mol Sci, 2022, 23(8): 4330. doi: 10.3390/ijms23084330

[26] 李孟婷, 何书喜, 王华 . 炎症因子在圆锥角膜中的研究进展 [J]. 山东大学耳鼻喉眼学报, 2023, 37(2): 151-158. doi: 10.6040/j.issn.1673-3770.0.2021.536

[27] LI Mengting , HE Shuxi , WANG Hua . Research progress of inflammatory factors in Keratoconus [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2023, 37(2): 151-158. doi: 10.6040/j.issn.1673-3770.0.2021.536

[28] Hadvina R , Lotfy Khaled M , Akoto T , et al. Exosomes and their miRNA/protein profile in keratoconus-derived corneal stromal cells [J]. Exp Eye Res, 2023, 236: 109642. doi: 10.1016/j.exer.2023.109642

[29] Lozano V , Martín C , Blanco N , et al. Exosomes released by corneal stromal cells show molecular alterations in keratoconus patients and induce different cellular behavior [J]. Biomedicines, 2022, 10(10): 2348. doi: 10.3390/biomedicines10102348

[30] Hefley BS , Deighan C , Vasinin B , et al. Revealing the presence of tear extracellular vesicles in Keratoconus [J]. Exp Eye Res, 2022, 224: 109242. doi: 10.1016/j.exer.2022.109242

[31] Zhou T , He C , Lai PL , et al. MiR-204-containing exosomes ameliorate GVHD-associated dry eye disease [J]. Sci Adv, 2022, 8(2): eabj9617. doi: 10.1126/sciadv.abj9617

[32] Wang GF , Li HH , Long HM , et al. Exosomes derived from mouse adipose-derived mesenchymal stem cells alleviate benzalkonium chloride-induced mouse dry eye model via inhibiting NLRP3 inflammasome [J]. Ophthalmic Res, 2022, 65(1): 40-51. doi: 10.1159/000519458

[33] Yu CQ , Chen P , Xu J , et al. hADSCs derived extracellular vesicles inhibit NLRP3 inflammasome activation and dry eye [J]. Sci Rep, 2020, 10(1): 14521. doi: 10.1038/s41598-020-71337-8

[34] Ma D , Wu ZW , Zhao XX , et al. Immunomodulatory effects of umbilical mesenchymal stem cell-derived exosomes on CD4+ T cells in patients with primary Sjgren's syndrome [J]. Inflammopharmacology, 2023, 31(4): 1823-1838. doi: 10.1007/s10787-023-01189-x

[35] Mller-Hansen M , Larsen AC , Toft PB , et al. Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease [J]. Ocul Surf, 2021, 19: 43-52. doi: 10.1016/j.jtos.2020.11.013

[36] Zhou T , He C , Lai PL , et al. MiR-204-containing exosomes ameliorate GVHD-associated dry eye disease [J]. Sci Adv, 2022, 8(2): eabj9617. doi: 10.1126/sciadv.abj9617

[37] Zhuang Z , Li L , Yu Y , et al. Targeting MicroRNA in myopia: current insights [J]. Exp Eye Res, 2024, 243: 109905. doi: 10.1016/j.exer.2024.109905

[38] Chen CF , Hua KT , Woung LC , et al. Expression profiling of exosomal miRNAs derived from the aqueous humor of myopia patients [J]. Tohoku J Exp Med, 2019, 249(3): 213-221. doi: 10.1620/tjem.249.213

[39] You J , Wu Q , Xu GZ , et al. Exosomal microRNA profiling in vitreous humor derived from pathological myopia patients [J]. Invest Ophthalmol Vis Sci, 2023, 64(1): 9. doi: 10.1167/iovs.64.1.9

[40] Li TL , Li XM , Hao YX , et al. Inhibitory effect of miR-138-5p on choroidal fibrosis in lens-induced myopia guinea pigs via suppressing the HIF-1α signaling pathway [J]. Biochem Pharmacol, 2023, 211: 115517. doi: 10.1016/j.bcp.2023.115517

[41] Tsai CY , Chen CT , Lin CH , et al. Proteomic analysis of Exosomes derived from the Aqueous Humor of Myopia Patients [J]. Int J Med Sci, 2021, 18(9): 2023-2029. doi: 10.7150/ijms.51735

[42] 邵珺, 辛瑜, 李荣秀, 等 . 病理性近视眼患者血清蛋白质组学分子标志物筛选 [J]. 中华眼科杂志, 2012, 48(3): 246-252. doi: 10.3760/cma.j.issn.0412-4081.2012.03.010

[43] SHAO Jun , XIN Yu , LI Rongxiu , et al. Proteomics analysis of serum biomarks in patients with pathological myopia [J]. Chinese Journal of Ophthalmology, 2012, 48(3): 246-252. doi: 10.3760/cma.j.issn.0412-4081.2012.03.010

[44] Mead B , Ahmed Z , Tomarev S . Mesenchymal stem cell-derived small extracellular vesicles promote neuroprotection in a genetic DBA/2J mouse model of glaucoma [J]. Invest Ophthalmol Vis Sci, 2018, 59(13): 5473-5480. doi: 10.1167/iovs.18-25310

[45] Mathew B , Ravindran S , Liu XR , et al. Mesenchymal stem cell-derived extracellular vesicles and retinal ischemia-reperfusion [J]. Biomaterials, 2019, 197: 146-160. doi: 10.1016/j.biomaterials.2019.01.016

[46] Zheng ZK , Kong L , Dai M , et al. ADSC-Exos outperform BMSC-Exos in alleviating hydrostatic pressure-induced injury to retinal ganglion cells by upregulating nerve growth factors [J]. World J Stem Cells, 2023, 15(12): 1077-1092. doi: 10.4252/wjsc.v15.i12.1077

[47] Zhang JL , Wang Y . Altered expression of extracellular vesicles miRNAs from primary human trabecular meshwork cells induced by transforming growth factor-β2 [J]. DNA Cell Biol, 2021, 40(7): 988-997. doi: 10.1089/dna.2020.6298

[48] Lerner N , Schreiber-Avissar S , Beit-Yannai E . Extracellular vesicle-mediated crosstalk between NPCE cells and TM cells result in modulation of Wnt signaling pathway and ECM remodelling [J]. J Cell Mol Med, 2020, 24(8): 4646-4658. doi: 10.1111/jcmm.15129

[49] Takahashi E , Saruwatari J , Fujimoto T , et al. The effects of exosomes derived from trabecular meshwork cells on Schlemm's canal endothelial cells [J]. Sci Rep, 2021, 11(1): 21942. doi: 10.1038/s41598-021-01450-9

[50] Kosior-Jarecka E , Czop M , Gasinska K , et al. MicroRNAs in the aqueous humor of patients with different types of glaucoma [J]. Graefe's Arch Clin Exp Ophthalmol, 2021, 259(8): 2337-2349. doi: 10.1007/s00417-021-05214-z

[51] Mead B , Tomarev S . The role of miRNA in retinal ganglion cell health and disease [J]. Neural Regen Res, 2022, 17(3): 516-522. doi: 10.4103/1673-5374.320974

[52] Greene KM , Stammer WD , Liu YT . The role of microRNAs in glaucoma [J]. Exp Eye Res, 2022, 215: 108909. doi: 10.1016/j.exer.2021.108909

[53] Plousiou M , de Vita A , Miserocchi G , et al. Growth inhibition of retinoblastoma cell line by exosome-mediated transfer of miR-142-3p [J]. Cancer Manag Res, 2022, 14: 2119-2131. doi: 10.2147/CMAR.S351979

[54] Hu Y , Zhao M , Li L , et al. MiR-491-3p is downregulated in retinoblastoma and inhibit tumour cells growth and metastasis by targeting SNN [J]. Biochem Genet, 2021, 59(2): 453-474. doi: 10.1007/s10528-020-10007-w

[55] Liu SL , Wen CT . MiR-141-3p promotes retinoblastoma progression via inhibiting sushi domain-containing protein 2 [J]. Bioengineered, 2022, 13(3): 7410-7424. doi: 10.1080/21655979.2022.2048770

[56] Fuchs B , Zhang K , Schabel A , et al. Identification of twenty-two candidate markers for human osteogenic sarcoma [J]. Gene, 2001, 278(1/2): 245-252. doi: 10.1016/s0378-1119(01)00731-4

[57] Chen SL , Chen X , Qiu J , et al. Exosomes derived from retinoblastoma cells enhance tumour deterioration by infiltrating the microenvironment [J]. Oncol Rep, 2021, 45(1): 278-290. doi: 10.3892/or.2020.7858

[58] Zhang W , Wang Y , Kong YC . Exosomes derived from mesenchymal stem cells modulate miR-126 to ameliorate hyperglycemia-induced retinal inflammation via targeting HMGB1 [J]. Invest Ophthalmol Vis Sci, 2019, 60(1): 294-303. doi: 10.1167/iovs.18-25617

[59] Liu C , Ge HM , Liu BH , et al. Targeting pericyte-endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction [J]. Proc Natl Acad Sci USA, 2019, 116(15): 7455-7464. doi: 10.1073/pnas.1814874116

[60] Safwat A , Sabry D , Ragiae A , et al. Adipose mesenchymal stem cells—derived exosomes attenuate retina degeneration of streptozotocin—induced diabetes in rabbits [J]. J Circ Biomark, 2018, 7: 1849454418807827. doi: 10.1177/1849454418807827

[61] Zhang W , Dong X , Wang T , et al. Exosomes derived from platelet—rich plasma mediate hyperglycemia—induced retinal endothelial injury via targeting the TLR4 signaling pathway [J]. Exp Eye Res, 2019, 189: 107813. doi: 10.1016/j.exer.2019.107813

[62] Kamalden TA , Macgregor—Das AM , Kannan SM , et al. Exosomal microRNA—15a transfer from the pancreas augments diabetic complications by inducing oxidative stress [J]. Antioxid Redox Signal, 2017, 27(13): 913-930. doi: 10.1089/ars.2016.6844

基金资助

国家自然科学基金(82104937)

国家重点研发计划项目(2021YFC2702103,2021YFC2702100,2021YFC2702104)

山东省中医药科技项目(M-2023010)

山东省中西医结合专病防治项目(YXH2019ZXY001)