Volume 4, Issue 1 (Winter-Spring 2021)                   Mod Med Lab J 2021, 4(1): 11-18 | Back to browse issues page

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Afshar A, Zare M, Farrar Z, Hashemi A, Baghban N, Khoradmehr A, et al . Exosomes of mesenchymal stem cells as nano-cargos for anti-SARS-CoV-2 asRNAs. Mod Med Lab J. 2021; 4 (1) :11-18
URL: http://modernmedlab.com/article-1-94-en.html
Abstract:   (323 Views)
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and rapidly spread worldwide. Since then, scientists have searched to find an effective treatment for coronavirus disease 2019 (COVID-19). In this regard, several antiviral drugs are currently undergoing clinical trial studies to evaluate their safety and efficacy in the treatment of COVID-19. Some of these drugs have been designed based on this fact that SARS-CoV-2 is a positive-sense single-stranded RNA virus and previous studies showed the efficacy of anti-RNA virus, single strand RNA inhibiting antisense RNAs (asRNAs), for silencing virus replication, in vitro. Exosomes can be suggested as a promising candidate to transfer the anti-SARS-CoV-2 asRNAs to human respiratory epithelium. Exosomes are secreted by mesenchymal stem cells (MSCs) and can be loaded by asRNAs of an anti-RNA virus. MSCs-secreted exosomes as a nano-cargo of asRNAs of anti-SARS-CoV-2 have other therapeutic potentials such as immunomodulatory effects of their cytokine contents, affinity to respiratory epithelial attachment, anti-fibrotic activity in lung, non-toxicity for normal cells, and not triggering an immune response. Moreover, inhalation of anti-SARS-CoV-2 asRNAs may stop SARS-CoV-2 replication. Producing specific anti-SARS-CoV-2 asRNAs by targeting the genome of virus and their delivery by MSCs exosomes are suggested and discussed. This approach will potentially shed light on gene therapy of the other human lung diseases via inhalational delivery using exosomes in future.
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Type of Study: Review | Subject: Infectious Diseases

1. Ferkol T, Schraufnagel D. The global burden of respiratory disease. Ann Am Thorac Soc. 2014;11(3):404-6. [DOI:10.1513/AnnalsATS.201311-405PS]
2. Gorbalenya AE, Baker SC, Baric RS, Groot RJd, Drosten C, Gulyaeva AA, et al. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;5:536-44. [DOI:10.1038/s41564-020-0695-z]
3. Liu J, Zheng X, Tong Q, Li W, Wang B, Sutter K, et al. Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS‐CoV, MERS‐CoV, and 2019‐nCoV. J Med Virol. 2020;92(5):491-4. [DOI:10.1002/jmv.25709]
4. World Health Organization, Key Messages and Actions for COVID-19 Prevention and Control in Schools. (2020). [Article]
5. Sardar T, Ghosh I, Rodó X, Chattopadhyay J. A realistic two-strain model for MERS-CoV infection uncovers the high risk for epidemic propagation. PLoS Negl Trop Dis. 2020;14(2):e0008065. [DOI:10.1371/journal.pntd.0008065]
6. Lu C-C, Chen M-Y, Chang Y-L. Potential therapeutic agents against COVID-19: What we know so far. J Chin Med Assoc. 2020;83(6):534-536. [DOI:10.1097/JCMA.0000000000000318]
7. Mirtaleb MS, Mirtaleb AH, Nosrati H, Heshmatnia J, Falak R, Emameh RZ. Potential therapeutic agents to COVID-19: An update review on antiviral therapy, immunotherapy, and cell therapy. Biomed Pharmacother. 2021:111518. [DOI:10.1016/j.biopha.2021.111518]
8. Behzadi MA, Leyva-Grado VH. Overview of current therapeutics and novel candidates against influenza, respiratory syncytial virus and Middle East respiratory syndrome coronavirus infections. Front Microbiol. 2019;10:1327. [DOI:10.3389/fmicb.2019.01327]
9. Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: Present or future. Stem Cell Rev Rep. 2020;16(3):427-33. [DOI:10.1007/s12015-020-09973-w]
10. Naseri Z, Oskuee RK, Jaafari MR, Moghadam MF. Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo. Int J Nanomedicine. 2018;13:7727. [DOI:10.2147/IJN.S182384]
11. van Dommelen SM, Vader P, Lakhal S, Kooijmans S, van Solinge WW, Wood MJ, et al. Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery. J Control Release. 2012;161(2):635-44. [DOI:10.1016/j.jconrel.2011.11.021]
12. 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. [DOI:10.1016/j.bbagen.2012.03.017]
13. Kim DK, Kang B, Kim OY, Choi Ds, Lee J, Kim SR, et al. EVpedia: an integrated database of high‐throughput data for systemic analyses of extracellular vesicles. J Extracell Vesicles. 2013;2(1):20384. [DOI:10.3402/jev.v2i0.20384]
14. Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9(1):1-18. [DOI:10.1186/s13578-019-0282-2]
15. Tang Y, Zhou Y, Li H-J. Advances in mesenchymal stem cell exosomes: a review. Stem Cell Res Ther. 2021;12(1):1-12. [DOI:10.1186/s13287-021-02138-7]
16. de Munter J, Mey J, Strekalova T, Kramer B, Wolters EC. Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail? J Neural Transm. 2020;127(5):715-27. [DOI:10.1007/s00702-020-02173-3]
17. Bulut Ö, GÜrsel İ. Mesenchymal stem cell derived extracellular vesicles: promising immunomodulators against autoimmune, autoinflammatory disorders and SARS-CoV-2 infection. Turk J Biol. 2020;44(3):273-82. [DOI:10.3906/biy-2002-79]
18. Akbari A, Rezaie J. Potential therapeutic application of mesenchymal stem cell-derived exosomes in SARS-CoV-2 pneumonia. Stem Cell Res Ther. 2020;11(1):1-10. [DOI:10.1186/s13287-020-01866-6]
19. Yu B, Ikhlas S, Ruan C, Zhong X, Cai D. Innate and adaptive immunity of murine neural stem cell-derived piRNA exosomes/microvesicles against pseudotyped SARS-CoV-2 and HIV-based lentivirus. Iscience. 2020;23(12):101806. [DOI:10.1016/j.isci.2020.101806]
20. Hassanpour M, Rezaie J, Nouri M, Panahi Y. The role of extracellular vesicles in COVID-19 virus infection. Infect Genet Evol. 2020;85:104422. [DOI:10.1016/j.meegid.2020.104422]
21. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020; covidwho-7937. [DOI:10.1093/cid/ciaa248]
22. Wang X, Chen Q, Zhang X, Ren X, Zhang X, Meng L, et al. Matrix metalloproteinase 2/9-triggered-release micelles for inhaled drug delivery to treat lung cancer: preparation and in vitro/in vivo studies. Int J Nanomedicine. 2018;13:4641-59. [DOI:10.2147/IJN.S166584]
23. Zhang D, Lee H, Wang X, Rai A, Groot M, Jin Y. Exosome-mediated small RNA delivery: a novel therapeutic approach for inflammatory lung responses. Mol Ther. 2018;26(9):2119-30. [DOI:10.1016/j.ymthe.2018.06.007]
24. Ivashchenko A, Rakhmetullina A, Aisina D. How miRNAs can protect humans from coronaviruses COVID-19, SARS-CoV, and MERS-CoV. Research Square. 2020. [DOI:10.21203/rs.3.rs-16264/v1]
25. Lee H, Abston E, Zhang D, Rai A, Jin Y. Extracellular vesicle: an emerging mediator of intercellular crosstalk in lung inflammation and injury. Front Immunol. 2018;9:924. [DOI:10.3389/fimmu.2018.00924]
26. Samanta S, Rajasingh S, Drosos N, Zhou Z, Dawn B, Rajasingh J. Exosomes: new molecular targets of diseases. Acta Pharmacol Sin. 2018;39(4):501-13. [DOI:10.1038/aps.2017.162]
27. Rezaeian L, Hosseini SE, Dianatpour M, Edalatmanesh MA, Tanideh N, Mogheiseh A, et al. Intrauterine xenotransplantation of human Wharton jelly-derived mesenchymal stem cells into the liver of rabbit fetuses: A preliminary study for in vivo expression of the human liver genes. Iranian J Basic Med Sci. 2018;21(1):89. [DOI:10.22038/IJBMS.2017.24501.6098]
28. Chudickova M, Vackova I, Machova Urdzikova L, Jancova P, Kekulova K, Rehorova M, et al. The effect of Wharton jelly-derived mesenchymal stromal cells and their conditioned media in the treatment of a rat spinal cord injury. Int J Mol Sci. 2019;20(18):4516. [DOI:10.3390/ijms20184516]
29. Lobb RJ, Becker M, Wen Wen S, Wong CS, Wiegmans AP, Leimgruber A, et al. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles. 2015;4(1):27031. [DOI:10.3402/jev.v4.27031]
30. Lv C-X, Duan H, Wang S, Gan L, Xu Q. Exosomes derived from human umbilical cord mesenchymal stem cells promote proliferation of allogeneic endometrial stromal cells. Reprod Sci. 2020:1-10. [DOI:10.1007/s43032-020-00165-y]
31. Walsh D, Mathews MB, Mohr I. Tinkering with translation: protein synthesis in virus-infected cells. Cold Spring Harb Perspect Biol. 2013;5(1):a012351. [DOI:10.1101/cshperspect.a012351]
32. Ryan EL, Hollingworth R, Grand RJ. Activation of the DNA damage response by RNA viruses. Biomolecules. 2016;6(1):2. [DOI:10.3390/biom6010002]
33. Leyssen P, De Clercq E, Neyts J. Molecular strategies to inhibit the replication of RNA viruses. Antiviral Res. 2008;78(1):9-25. [DOI:10.1016/j.antiviral.2008.01.004]
34. Burnett JC, Rossi JJ. RNA-based therapeutics: current progress and future prospects. Chem Biol. 2012;19(1):60-71. [DOI:10.1016/j.chembiol.2011.12.008]
35. Sohel MH. Extracellular/circulating microRNAs: release mechanisms, functions and challenges. Achiev Life Sci. 2016;10(2):175-86. [DOI:10.1016/j.als.2016.11.007]
36. Aagaard L, Rossi JJ. RNAi therapeutics: principles, prospects and challenges. Adv Drug Del Rev. 2007;59(2-3):75-86. [DOI:10.1016/j.addr.2007.03.005]
37. Lakhal S, Wood MJ. Exosome nanotechnology: an emerging paradigm shift in drug delivery: exploitation of exosome nanovesicles for systemic in vivo delivery of RNAi heralds new horizons for drug delivery across biological barriers. Bioessays. 2011;33(10):737-41. [DOI:10.1002/bies.201100076]
38. Wang X-W, Hao J, Guo W-T, Liao L-Q, Huang S-Y, Guo X, et al. A DGCR8-independent stable microRNA expression strategy reveals important functions of miR-290 and miR-183-182 families in mouse embryonic stem cells. Stem Cell Rep. 2017;9(5):1618-29. [DOI:10.1016/j.stemcr.2017.08.027]
39. Matsuyama S, Nao N, Shirato K, Kawase M, Saito S, Takayama I, et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc Natl Acad Sci U S A. 2020;117(13):7001-3. [DOI:10.1073/pnas.2002589117]
40. Fan J, Zhang X, Liu J, Yang Y, Zheng N, Liu Q, et al. Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients. Clin Infect Dis. 2020;71(12):3232-6. [DOI:10.1093/cid/ciaa623]
41. Catanzaro M, Fagiani F, Racchi M, Corsini E, Govoni S, Lanni C. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduct Target Ther. 2020;5(1):84. [DOI:10.1038/s41392-020-0191-1]
42. Rao YS. Mobile virology research and diagnostic laboratory (MVRDL: BSL-3) for COVID-19 screening, virus culturing and vaccine development. Trans Indian Natl Acad Eng. 2020;5(2):315-9. [DOI:10.1007/s41403-020-00150-6]
43. World Health Organization. COVID-19 Animal Models. 2020. [Article]
44. Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Transl Med. 2020;18(1):449. [DOI:10.1186/s12967-020-02622-3]
45. Van Niel G, d'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213. [DOI:10.1038/nrm.2017.125]
46. Panagiotou N, Davies RW, Selman C, Shiels PG. Microvesicles as vehicles for tissue regeneration: changing of the guards. Curr Pathobiol Rep. 2016;4(4):181-7. [DOI:10.1007/s40139-016-0115-5]
47. Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-based cell-cell communication in the tumor microenvironment. Front Cell Dev Biol. 2018;6:18. [DOI:10.3389/fcell.2018.00018]
48. Mulcahy LA, Pink RC, Carter DRF. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;3(1):24641. [DOI:10.3402/jev.v3.24641]
49. Gilligan KE, Dwyer RM. Extracellular vesicles for cancer therapy: Impact of host immune response. Cells. 2020;9(1):224. [DOI:10.3390/cells9010224]
50. Chen Y-S, Lin E-Y, Chiou T-W, Harn H-J. Exosomes in clinical trial and their production in compliance with good manufacturing practice. Tzu-chi Med J. 2019;32(2):113-20. [DOI:10.4103/tcmj.tcmj_182_19]
51. Gimona M, Pachler K, Laner-Plamberger S, Schallmoser K, Rohde E. Manufacturing of human extracellular vesicle-based therapeutics for clinical use. Int J Mol Sci. 2017;18(6):1190. [DOI:10.3390/ijms18061190]
52. Gomzikova M, James V, Rizvanov A. Therapeutic application of mesenchymal stem cells derived extracellular vesicles for immunomodulation. Front Immunol. 2019;10:2663. [DOI:10.3389/fimmu.2019.02663]
53. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838-43. [DOI:10.1182/blood.v99.10.3838]
54. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid A, Mardani K, et al. Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Cell J. 2013;15:47-54. [DOI:10.1016/j.imlet.2012.06.001]
55. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief C, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161-72. [DOI:10.1084/jem.183.3.1161]
56. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. 1998;4(5):594-600. [DOI:10.1038/nm0598-594]
57. Zhao X, Wu D, Ma X, Wang J, Hou W, Zhang W. Exosomes as drug carriers for cancer therapy and challenges regarding exosome uptake. Biomed Pharmacother. 2020;128:110237. [DOI:10.1016/j.biopha.2020.110237]
58. Maroto R, Zhao Y, Jamaluddin M, Popov VL, Wang H, Kalubowilage M, et al. Effects of storage temperature on airway exosome integrity for diagnostic and functional analyses. J Extracell Vesicles. 2017;6(1):1359478. [DOI:10.1080/20013078.2017.1359478]
59. Latini A, Borgiani P, Novelli G, Ciccacci C. miRNAs in drug response variability: potential utility as biomarkers for personalized medicine. Pharmacogenomics. 2019;20(14):1049-59. [DOI:10.2217/pgs-2019-0089]
60. Wu F, Lu F, Fan X, Chao J, Liu C, Pan Q, et al. Immune-related miRNA-mRNA regulation network in the livers of DHAV-3-infected ducklings. BMC Genomics. 2020;21(1):1-14. [DOI:10.1186/s12864-020-6539-7]
61. Trobaugh DW, Klimstra WB. MicroRNA regulation of RNA virus replication and pathogenesis. Trends Mol Med. 2017;23(1):80-93. [DOI:10.1016/j.molmed.2016.11.003]
62. Cui H, Zhang C, Zhao Z, Zhang C, Fu Y, Li J, et al. Identification of cellular microRNA miR-188-3p with broad-spectrum anti-influenza A virus activity. Virol J. 2020;17(1):12. [DOI:10.1186/s12985-020-1283-9]
63. Kemp V, Laconi A, Cocciolo G, Berends AJ, Breit TM, Verheije MH. miRNA repertoire and host immune factor regulation upon avian coronavirus infection in eggs. Arch Virol. 2020;165:835–43. [DOI:10.1007/s00705-020-04527-4]
64. Zheng B, Zhou J, Wang H. Host microRNAs and exosomes that modulate influenza virus infection. Virus Res. 2020:197885. [DOI:10.1016/j.virusres.2020.197885]
65. Sardar R, Satish D, Birla S, Gupta D. Comparative analyses of SAR-CoV2 genomes from different geographical locations and other coronavirus family genomes reveals unique features potentially consequential to host-virus interaction and pathogenesis. bioRxiv. 2020;1-22. [DOI:10.1101/2020.03.21.001586]
66. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80. [DOI:10.1016/j.cell.2020.02.052]
67. Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J. 2020;55:2000607. [DOI:10.1183/13993003.00607-2020]
68. Dinh P-UC, Paudel D, Brochu H, Popowski KD, Gracieux MC, Cores J, et al. Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis. Nat Commun. 2020;11(1):1064. [DOI:10.1038/s41467-020-14344-7]
69. Bernal JL, Andrews N, Gower C, Robertson C, Stowe J, Tessier E, et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. BMJ. 2021;373. [DOI:10.1136/bmj.n1088]
70. Shah AS, Gribben C, Bishop J, Hanlon P, Caldwell D, Wood R, et al. Effect of vaccination on transmission of COVID-19: an observational study in healthcare workers and their households. MedRxiv. 2021;1-25. [DOI:10.1101/2021.03.11.21253275]

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