DOI QR코드

DOI QR Code

Clinical Application of Exosomes for COVID-19 and Diagnosis

COVID-19 치료 및 진단을 위한 Exosome의 임상적 적용

  • 허준석 (세브란스병원 세포치료센터)
  • Received : 2024.02.15
  • Accepted : 2024.03.07
  • Published : 2024.03.31

Abstract

Exosomes are nano-sized membrane-bound extracellular vesicles containing various biological molecules, such as nucleic acids, proteins, and lipids, which can be used to modulate physiological processes. The exosomal molecules secreted by cells can be extensively used as tools for diagnosis and therapy. Exosomes carry specific molecules released by the cells they originate from, which can be transferred to surrounding cells or tissues by the exosome. For these reasons, exosomes can be exploited as biomarkers for diagnosis, carriers for drug delivery, as well as therapeutics. In stem cell technology, exosomes have been an attractive option because they can be used as safer therapeutic agents for stem cell-based cell-free therapy. Recently, studies have demonstrated the safety and efficacy of mesenchymal stem cell-derived exosomes in alleviating symptoms associated with coronavirus disease 2019 as they have anti-inflammatory and immunomodulatory potential. Performing multiple studies on exosomes would provide innovative next-generation options for clinical diagnostics and therapy. This review summarizes the use of exosomes focusing on their diverse roles. In addition, the potential of exosomes is illustrated with a focus on how exosomes can be exploited as powerful tools in the days to come.

엑소좀은 나노 크기의 세포외 소포체로 핵산, 단백질, 지질 등 다양한 생리활성 물질을 함유하고 있다. 엑소좀의 생리활성 물질들은 주변 세포나 조직으로 전달될 수 있을 뿐만 아니라 기원된 세포의 고유 특정 물질들을 지니고 있기 때문에 엑소좀 유래 물질들은 진단 및 치료를 위한 도구로 광범위하게 사용될 수 있음이 입증되고 있으며, 이러한 이유로 엑소좀은 진단을 위한 바이오마커, 약물 전달을 위한 운반체 및 치료제로 활용될 수 있는 가능성에 많은 연구자들의 관심이 높아지고 있다. 줄기세포 분야에서 엑소좀은 줄기세포를 기반으로 한 비세포 치료제로서 보다 안전한 치료제로 사용될 수 있다는 점에서 매력적인 소재가 되고 있으며, 최근에는 중간엽줄기세포 유래 엑소좀이 항염증 및 면역조절능이 있어 코로나-19 증상 완화 효능에 대한 안전성과 효능이 입증되기도 했다. 이렇게 계속적인 엑소좀에 대한 축적된 연구는 임상 진단 및 치료를 위한 차세대 혁신적 결과물들을 제공할 것으로 생각되며, 이 종설에서는 엑소좀의 다양한 가치에 초점을 두고 미래의학의 강력한 도구로 어떻게 활용될 수 있는지에 대한 엑소좀의 잠재력을 살펴보고자 한다.

Keywords

References

  1. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018;75:193-208. https://doi.org/10.1007/s00018-017-2595-9 
  2. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373-383. https://doi.org/10.1083/jcb.201211138 
  3. Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol. 1967;13:269-288. https://doi.org/10.1111/j.1365-2141.1967.tb08741.x 
  4. Baixauli F, Lopez-Otin C, Mittelbrunn M. Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness. Front Immunol. 2014;5:403. https://doi.org/10.3389/fimmu.2014.00403 
  5. Hessvik NP, Overbye A, Brech A, Torgersen ML, Jakobsen IS, Sandvig K, et al. PIKfyve inhibition increases exosome release and induces secretory autophagy. Cell Mol Life Sci. 2016;73:4717-4737. https://doi.org/10.1007/s00018-016-2309-8
  6. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262:9412-9420. https://doi.org/10.1016/S0021-9258(18)48095-7 
  7. Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010;73:1907-1920. https://doi.org/10.1016/j.jprot.2010.06.006 
  8. Record M, Carayon K, Poirot M, Silvente-Poirot S. Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta. 2014;1841:108-120. https://doi.org/10.1016/j.bbalip.2013.10.004 
  9. Hodgkinson CP, Bareja A, Gomez JA, Dzau VJ. Emerging concepts in paracrine mechanisms in regenerative cardiovascular medicine and biology. Circ Res. 2016;118:95-107. https://doi.org/10.1161/CIRCRESAHA.115.305373 
  10. Ratajczak MZ, Kucia M, Jadczyk T, Greco NJ, Wojakowski W, Tendera M, et al. Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies? Leukemia. 2012;26:1166-1173. https://doi.org/10.1038/leu.2011.389 
  11. Toma C, Wagner WR, Bowry S, Schwartz A, Villanueva F. Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics. Circ Res. 2009;104:398-402. https://doi.org/10.1161/CIRCRESAHA.108.187724 
  12. Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell. 2019;177:428-445.e18. https://doi.org/10.1016/j.cell.2019.02.029 
  13. Yang XX, Sun C, Wang L, Guo XL. New insight into isolation, identification techniques and medical applications of exosomes. J Control Release. 2019;308:119-129. https://doi.org/10.1016/j.jconrel.2019.07.021 
  14. Fruhbeis C, Frohlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, et al. Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol. 2013;11:e1001604. https://doi.org/10.1371/journal.pbio.1001604 
  15. Korkut C, Ataman B, Ramachandran P, Ashley J, Barria R, Gherbesi N, et al. Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless. Cell. 2009;139:393-404. https://doi.org/10.1016/j.cell.2009.07.051 
  16. Machtinger R, Laurent LC, Baccarelli AA. Extracellular vesicles: roles in gamete maturation, fertilization and embryo implantation. Hum Reprod Update. 2016;22:182-193. https://doi.org/10.1093/humupd/dmv055 
  17. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183:1161-1172. https://doi.org/10.1084/jem.183.3.1161 
  18. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14:195-208. https://doi.org/10.1038/nri3622 
  19. Ailawadi S, Wang X, Gu H, Fan GC. Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Biochim Biophys Acta. 2015;1852:1-11. https://doi.org/10.1016/j.bbadis.2014.10.008 
  20. Kadiu I, Narayanasamy P, Dash PK, Zhang W, Gendelman HE. Biochemical and biologic characterization of exosomes and microvesicles as facilitators of HIV-1 infection in macrophages. J Immunol. 2012;189:744-754. https://doi.org/10.4049/jimmunol.1102244 
  21. Kulshreshtha A, Ahmad T, Agrawal A, Ghosh B. Proinflammatory role of epithelial cell-derived exosomes in allergic airway inflammation. J Allergy Clin Immunol. 2013;131:1194-1203, 1203.e1-14. https://doi.org/10.1016/j.jaci.2012.12.1565 
  22. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10:1470-1476. https://doi.org/10.1038/ncb1800 
  23. Gyorgy B, Szabo TG, Pasztoi M, Pal Z, Misjak P, Aradi B, et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci. 2011;68:2667-2688. https://doi.org/10.1007/s00018-011-0689-3 
  24. Heo JS, Kim J. Mesenchymal stem cell-derived exosomes: applications in cell-free therapy. Korean J Clin Lab Sci. 2018;50:391-398. https://doi.org/10.15324/kjcls.2018.50.4.391 
  25. Zhang X, Yuan X, Shi H, Wu L, Qian H, Xu W. Exosomes in cancer: small particle, big player. J Hematol Oncol. 2015;8:83. https://doi.org/10.1186/s13045-015-0181-x 
  26. Keller S, Ridinger J, Rupp AK, Janssen JW, Altevogt P. Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med. 2011;9:86. https://doi.org/10.1186/1479-5876-9-86 
  27. He C, Zheng S, Luo Y, Wang B. Exosome theranostics: biology and translational medicine. Theranostics. 2018;8:237-255. https://doi.org/10.7150/thno.21945 
  28. Gupta A, Kashte S, Gupta M, Rodriguez HC, Gautam SS, Kadam S. Mesenchymal stem cells and exosome therapy for COVID-19: current status and future perspective. Hum Cell. 2020;33:907-918. https://doi.org/10.1007/s13577-020-00407-w 
  29. Yuan Y, Jiao B, Qu L, Yang D, Liu R. The development of COVID-19 treatment. Front Immunol. 2023;14:1125246. https://doi.org/10.3389/fimmu.2023.1125246 
  30. Chu M, Wang H, Bian L, Huang J, Wu D, Zhang R, et al. Nebulization therapy with umbilical cord mesenchymal stem cell-derived exosomes for COVID-19 pneumonia. Stem Cell Rev Rep. 2022;18:2152-2163. https://doi.org/10.1007/s12015-022-10398-w 
  31. Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. COVID-19 does not lead to a "typical" acute respiratory distress syndrome. Am J Respir Crit Care Med. 2020;201:1299-1300. https://doi.org/10.1164/rccm.202003-0817LE 
  32. Zhang Y, Bi J, Huang J, Tang Y, Du S, Li P. Exosome: a review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications. Int J Nanomedicine. 2020;15:6917-6934. https://doi.org/10.2147/IJN.S264498 
  33. Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3:Unit 3.22. https://doi.org/10.1002/0471143030.cb0322s30 
  34. Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A. 2016;113:E968-E977. https://doi.org/10.1073/pnas.1521230113
  35. Corsten MF, Dennert R, Jochems S, Kuznetsova T, Devaux Y, Hofstra L, et al. Circulating microRNA-208b and microRNA-499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet. 2010;3:499-506. https://doi.org/10.1161/CIRCGENETICS.110.957415 
  36. Zhang TR, Huang WQ. Angiogenic exosome-derived microRNAs: emerging roles in cardiovascular disease. J Cardiovasc Transl Res. 2021;14:824-840. https://doi.org/10.1007/s12265-020-10082-9 
  37. Heo J, Kang H. Exosome-based treatment for atherosclerosis. Int J Mol Sci. 2022;23:1002. https://doi.org/10.3390/ijms23021002 
  38. Wang GK, Zhu JQ, Zhang JT, Li Q, Li Y, He J, et al. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J. 2010;31:659-666. https://doi.org/10.1093/eurheartj/ehq013 
  39. Dong X, Gao X, Dai Y, Ran N, Yin H. Serum exosomes can restore cellular function in vitro and be used for diagnosis in dysferlinopathy. Theranostics. 2018;8:1243-1255. https://doi.org/10.7150/thno.22856 
  40. Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, et al. Low neural exosomal levels of cellular survival factors in Alzheimer's disease. Ann Clin Transl Neurol. 2015;2:769-773. https://doi.org/10.1002/acn3.211 
  41. Xu M, Feng T, Liu B, Qiu F, Xu Y, Zhao Y, et al. Engineered exosomes: desirable target-tracking characteristics for cerebrovascular and neurodegenerative disease therapies. Theranostics. 2021;11:8926-8944. https://doi.org/10.7150/thno.62330 
  42. Vella LJ, Hill AF, Cheng L. Focus on extracellular vesicles: exosomes and their role in protein trafficking and biomarker potential in Alzheimer's and Parkinson's disease. Int J Mol Sci. 2016;17:173. https://doi.org/10.3390/ijms17020173 
  43. Hannafon BN, Trigoso YD, Calloway CL, Zhao YD, Lum DH, Welm AL, et al. Plasma exosome microRNAs are indicative of breast cancer. Breast Cancer Res. 2016;18:90. https://doi.org/10.1186/s13058-016-0753-x 
  44. Liang G, Zhu Y, Ali DJ, Tian T, Xu H, Si K, et al. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. J Nanobiotechnology. 2020;18:10. https://doi.org/10.1186/s12951-019-0563-2 
  45. Yan S, Dang G, Zhang X, Jin C, Qin L, Wang Y, et al. Downregulation of circulating exosomal miR-638 predicts poor prognosis in colon cancer patients. Oncotarget. 2017;8:72220-72226. https://doi.org/10.18632/oncotarget.19689 
  46. Logozzi M, De Milito A, Lugini L, Borghi M, Calabro L, Spada M, et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One. 2009;4:e5219. https://doi.org/10.1371/journal.pone.0005219 
  47. Heo JS, Choi Y, Kim HO. Adipose-derived mesenchymal stem cells promote M2 macrophage phenotype through exosomes. Stem Cells Int. 2019;2019:7921760. https://doi.org/10.1155/2019/7921760 
  48. Jeong JO, Han JW, Kim JM, Cho HJ, Park C, Lee N, et al. Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res. 2011;108:1340-1347. https://doi.org/10.1161/CIRCRESAHA.110.239848 
  49. Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A, Leroux MA. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med. 2012;1:142-149. https://doi.org/10.5966/sctm.2011-0018 
  50. Alexander M, Hu R, Runtsch MC, Kagele DA, Mosbruger TL, Tolmachova T, et al. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. 2015;6:7321. https://doi.org/10.1038/ncomms8321 
  51. Zhou J, Li Z, Wu T, Zhao Q, Zhao Q, Cao Y. LncGBP9/miR-34a axis drives macrophages toward a phenotype conducive for spinal cord injury repair via STAT1/STAT6 and SOCS3. J Neuroinflammation. 2020;17:134. https://doi.org/10.1186/s12974-020-01805-5 
  52. Domenis R, Cifu A, Quaglia S, Pistis C, Moretti M, Vicario A, et al. Pro inflammatory stimuli enhance the immunosuppressive functions of adipose mesenchymal stem cells-derived exosomes. Sci Rep. 2018;8:13325. https://doi.org/10.1038/s41598-018-31707-9 
  53. Serra MB, Barroso WA, da Silva NN, Silva SDN, Borges ACR, Abreu IC, et al. From inflammation to current and alternative therapies involved in wound healing. Int J Inflam. 2017;2017:3406215. https://doi.org/10.1155/2017/3406215 
  54. Bodnar RJ. Chemokine regulation of angiogenesis during wound healing. Adv Wound Care. 2015;4:641-650. https://doi.org/10.1089/wound.2014.0594 
  55. Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011;13:e23. https://doi.org/10.1017/S1462399411001943 
  56. Heo JS, Kim S, Yang CE, Choi Y, Song SY, Kim HO. Human adipose mesenchymal stem cell-derived exosomes: a key player in wound healing. Tissue Eng Regen Med. 2021;18:537-548. https://doi.org/10.1007/s13770-020-00316-x 
  57. Heo JS. Selenium-stimulated exosomes enhance wound healing by modulating inflammation and angiogenesis. Int J Mol Sci. 2022;23:11543. https://doi.org/10.3390/ijms231911543 
  58. Abraham A, Krasnodembskaya A. Mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome. Stem Cells Transl Med. 2020;9:28-38. https://doi.org/10.1002/sctm.19-0205 
  59. Worthington EN, Hagood JS. Therapeutic use of extracellular vesicles for acute and chronic lung disease. Int J Mol Sci. 2020;21:2318. https://doi.org/10.3390/ijms21072318 
  60. Khatri M, Richardson LA, Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem Cell Res Ther. 2018;9:17. https://doi.org/10.1186/s13287-018-0774-8