Exploring extracellular vesicles as mediators of clinical disease and vehicles for viral therapeutics: Insights from the COVID-19 pandemic

Abstract

The COVID-19 pandemic has challenged researchers to rapidly understand the capabilities of the SARS-CoV-2 virus and investigate potential therapeutics for SARS-CoV-2 infection. COVID-19 has been associated with devastating lung and cardiac injury, profound inflammation, and a heightened coagulopathic state, which may, in part, be driven by cellular crosstalk facilitated by extracellular vesicles (EVs). In recent years, EVs have emerged as important biomarkers of disease, and while extracellular vesicles may contribute to the spread of COVID-19 infection from one cell to the next, they also may be engineered to play a protective or therapeutic role as decoys or “delivery drivers” for therapeutic agents. This review explores these roles and areas for future study.

Keywords

SARS-CoV-2 / EVs / tissue factor / endothelial apoptosis

References

[1] Merad M.Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages.Nat Rev Immunol2020;20:355-62 PMCID:PMC7201395

[2] Lanyu Z.Emerging role of extracellular vesicles in lung injury and inflammation.Biomed Pharmacother2019;113:108748

[3] Ragab D,Taeimah M,Salem R.The COVID-19 cytokine storm; what we know so far.Front Immunol2020;11:1446 PMCID:PMC7308649

[4] Thachil J,Gando S.ISTH interim guidance on recognition and management of coagulopathy in COVID-19.J Thromb Haemost2020;18:1023-6

[5] Gómez-Mesa JE,Montes MC.Thrombosis and coagulopathy in COVID-19.Curr Probl Cardiol2021;46:100742 PMCID:PMC7605852

[6] Sigfrid L,Pauley E.ISARIC4C investigatorsLong Covid in adults discharged from UK hospitals after Covid-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol.Lancet Reg Health Eur2021;8:100186 PMCID:PMC8343377

[7] Taquet M,Luciano S,Husain M.Incidence, co-occurrence, and evolution of long-COVID features: a 6-month retrospective cohort study of 273,618 survivors of COVID-19.PLoS Med2021;18:e1003773 PMCID:PMC8478214

[8] Bazdyrev E,Panova M,Grishagin I.Lung fibrosis after COVID-19: treatment prospects.Pharmaceuticals (Basel)2021;14:807 PMCID:PMC8398080

[9] Abbasi J.The COVID heart-one year after SARS-CoV-2 infection, patients have an array of increased cardiovascular risks.JAMA2022;327:1113-4

[10] Wu X,Zhou Y.3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study.Lancet Respir Med2021;9:747-54 PMCID:PMC8099316

[11] Krishnamachary B,Kumar A,Chalise P.Extracellular vesicle-mediated endothelial apoptosis and EV-associated proteins correlate with COVID-19 disease severity.J Extracell Vesicles2021;10:e12117 PMCID:PMC8254805

[12] Bourgonje AR,Timens W.Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19).J Pathol2020;251:228-48 PMCID:PMC7276767

[13] Shirbhate E,Patel VK.Understanding the role of ACE-2 receptor in pathogenesis of COVID-19 disease: a potential approach for therapeutic intervention.Pharmacol Rep2021;73:1539-50 PMCID:PMC8236094

[14] Scialo F,Amato F.ACE2: the major cell entry receptor for SARS-CoV-2.Lung2020;198:867-77 PMCID:PMC7653219

[15] Chan NC.COVID-19 coagulopathy, thrombosis, and bleeding.Blood2020;136:381-3 PMCID:PMC7378461

[16] Esmon CT.Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis.Baillieres Best Pract Res Clin Haematol1999;12:343-59

[17] Joffre J,Matthay ZA.COMET consortium and the Co-ACIT study groupCOVID-19-associated lung microvascular endotheliopathy: a “from the bench” perspective. Am J Respir Crit Care Med .2022;

[18] Cantuti-Castelvetri L,Pedro LD.Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity.Science2020;370:856-60 PMCID:PMC7857391

[19] Guney C.Epithelial and endothelial expressions of ACE2: SARS-CoV-2 entry routes.J Pharm Pharm Sci2021;24:84-93

[20] Kumar A,Kumari C.SARS-CoV-2 cell entry receptor ACE2 mediated endothelial dysfunction leads to vascular thrombosis in COVID-19 patients.Med Hypotheses2020;145:110320 PMCID:PMC7525265

[21] McCracken IR,He L.Lack of evidence of angiotensin-converting enzyme 2 expression and replicative infection by SARS-CoV-2 in human endothelial cells.Circulation2021;143:865-8 PMCID:PMC7899720

[22] Hamming I,Bulthuis ML,Navis G.Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.J Pathol2004;203:631-7 PMCID:PMC7167720

[23] Sarzani R,Di Pentima C,Spannella F.Disequilibrium between the classic renin-angiotensin system and its opposing arm in SARS-CoV-2-related lung injury.Am J Physiol Lung Cell Mol Physiol2020;319:L325-36 PMCID:PMC7414236

[24] Lei Y,Schiavon CR.SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2.Circ Res2021;128:1323-6 PMCID:PMC8091897

[25] Carfì A,Landi F.for the Gemelli Against COVID-19 Post-Acute Care Study GroupPersistent symptoms in patients after acute COVID-19.JAMA2020;324:603 PMCID:PMC7349096

[26] Zhao YM,Song WB.Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery.EClinicalMedicine2020;25:100463 PMCID:PMC7361108

[27] Sykes DL,Jawad N,Morice AH.Post-COVID-19 symptom burden: what is long-COVID and how should we manage it?.Lung2021;199:113-9 PMCID:PMC7875681

[28] Pfaff ER,Bennett TD.Identifying who has long COVID in the USA: a machine learning approach using N3C data.The Lancet Digital Health2022;4:e532-41 PMCID:PMC9110014

[29] Proal AD.Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms.Front Microbiol2021;12:698169 PMCID:PMC8260991

[30] Su Y,Chen DG.ISB-Swedish COVID-19 Biobanking UnitMultiple early factors anticipate post-acute COVID-19 sequelae.Cell2022;185:881-895.e20 PMCID:PMC8786632

[31] Griffin DE.Why does viral RNA sometimes persist after recovery from acute infections?.PLoS Biol2022;20:e3001687

[32] Théry C,Aikawa E.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 Extracell Vesicles2018;7:1535750 PMCID:PMC6322352

[33] Tamura T,Sakamoto S,Ochiya T.Extracellular vesicles as a promising biomarker resource in liquid biopsy for cancer. Extracell Vesicles Circ Nucleic Acids2021;2:148-74

[34] Doyle LM.Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis.Cells2019;8:727 PMCID:PMC6678302

[35] Mohan A,Clauss M,Dhillon NK.Extracellular vesicles: novel communicators in lung diseases.Respir Res2020;21:175 PMCID:PMC7341477

[36] Hristov M,Linder S.Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro.Blood2004;104:2761-6

[37] Henne WM,Emr SD.The ESCRT pathway.Dev Cell2011;21:77-91

[38] Chen G,Zhang W.Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response.Nature2018;560:382-6 PMCID:PMC6095740

[39] Murao A,Aziz M.Exosomes in sepsis.Front Immunol2020;11:2140 PMCID:PMC7509534

[40] Atay S,Milhem M,Godwin AK.Insights into the proteome of gastrointestinal stromal tumors-derived exosomes reveals new potential diagnostic biomarkers.Mol Cell Proteomics2018;17:495-515 PMCID:PMC5836374

[41] Krishnamachary B,Kumar A.Extracellular vesicle TGF-β1 is linked to cardiopulmonary dysfunction in human immunodeficiency virus.Am J Respir Cell Mol Biol2021;65:413-29 PMCID:PMC8525206

[42] Pedersen SF.SARS-CoV-2: a storm is raging.J Clin Invest2020;130:2202-5 PMCID:PMC7190904

[43] Del Valle DM,Huang HH.An inflammatory cytokine signature predicts COVID-19 severity and survival.Nat Med2020;26:1636-43 PMCID:PMC7869028

[44] West NR.Coordination of immune-stroma crosstalk by IL-6 family cytokines.Front Immunol2019;10:1093 PMCID:PMC6529849

[45] Yuan T,Chen H.New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis.Redox Biol2019;20:247-60 PMCID:PMC6205410

[46] Esquivel-Ruiz S,Lorente JA,Herrero R.Extracellular vesicles and alveolar epithelial-capillary barrier disruption in acute respiratory distress syndrome: pathophysiological role and therapeutic potential.Front Physiol2021;12:752287 PMCID:PMC8650589

[47] Yuan Z,Sadikot RT.Bronchoalveolar lavage exosomes in lipopolysaccharide-induced septic lung injury. J Vis Exp.2018; PMCID:PMC6101335

[48] Shikano S,Maruoka S.Increased extracellular vesicle miRNA-466 family in the bronchoalveolar lavage fluid as a precipitating factor of ARDS.BMC Pulm Med2019;19:110 PMCID:PMC6584994

[49] Baron A,Tran Van Nhieu J.Bronchoalveolar lavage in patients with COVID-19 with invasive mechanical ventilation for acute respiratory distress syndrome.Ann Am Thorac Soc2021;18:723-6 PMCID:PMC8009009

[50] Azoulay E,Lambert J.Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial.Am J Respir Crit Care Med2010;182:1038-46

[51] Cracco C,Prodanovic H.Safety of performing fiberoptic bronchoscopy in critically ill hypoxemic patients with acute respiratory failure.Intensive Care Med2013;39:45-52 PMCID:PMC3939027

[52] Li S,Guan Z.SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation.Signal Transduct Target Ther2020;5:235 PMCID:PMC7545816

[53] Wallach-Dayan SB,Ahdut-HaCohen R,Breuer R.sFasL-the key to a riddle: immune responses in aging lung and disease.Int J Mol Sci2021;22:2177 PMCID:PMC7926921

[54] Martinez-Lorenzo MJ,Gamen S,Lasierra P,Pineiro A,Naval J.Activated human T cells release bioactive Fas ligand and APO2 ligand in microvesicles.J Immunol1999;163:1274-1281

[55] Albertine KH,Wang Z.Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome.Am J Pathol2002;161:1783-96 PMCID:PMC1850801

[56] Suda T,Tanaka M,Nagata S.Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas ligand blocks the killing.J Exp Med1997;186:2045-50 PMCID:PMC2199173

[57] Kim JW,Taylor DD,Watkins S.Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes.Clin Cancer Res2005;11:1010-1020

[58] Klinker MW,Reed TJ,Lundy SK.Human B cell-derived lymphoblastoid cell lines constitutively produce fas ligand and secrete MHCII(+)FasL(+) killer exosomes.Front Immunol2014;5:144 PMCID:PMC3980107

[59] Tan L,Zhang D.Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study.Sig Transduct Target Ther2020;33:5 PMCID:PMC7100419

[60] Battistelli M.Apoptotic bodies: particular extracellular vesicles involved in intercellular communication.Biology (Basel)2020;9:21 PMCID:PMC7168913

[61] Caruso S.Apoptotic cell-derived extracellular vesicles: more than just debris.Front Immunol2018;9:1486 PMCID:PMC6031707

[62] Muhsin-Sharafaldine MR,Dunn AC,Kleffmann T.Procoagulant and immunogenic properties of melanoma exosomes, microvesicles and apoptotic vesicles.Oncotarget2016;7:56279-94 PMCID:PMC5302914

[63] Kakarla R,Kim YJ,Chwae YJ.Apoptotic cell-derived exosomes: messages from dying cells.Exp Mol Med2020;52:1-6 PMCID:PMC7000698

[64] Nägele MP,Tanner FC,Flammer AJ.Endothelial dysfunction in COVID-19: current findings and therapeutic implications.Atherosclerosis2020;314:58-62 PMCID:PMC7554490

[65] Varga Z,Steiger P.Endothelial cell infection and endotheliitis in COVID-19.Lancet2020;395:1417-8 PMCID:PMC7172722

[66] Shenoy V,Qi Y.The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension.Am J Respir Crit Care Med2010;182:1065-72 PMCID:PMC2970847

[67] Sur S,Isbell TS,Ray RB.Circulatory exosomes from COVID-19 patients trigger NLRP3 inflammasome in endothelial cells.mBio2022;13:e0095122

[68] Li B,Wang FR.Tumor-derived exosomal HMGB1 promotes esophageal squamous cell carcinoma progression through inducing PD1⁺ TAM expansion.Oncogenesis2019;8:17 PMCID:PMC6386749

[69] Gao W,Ren J.Exosomal HMGB1 derived from hypoxia-conditioned bone marrow mesenchymal stem cells increases angiogenesis via the JNK/HIF-1α pathway.FEBS Open Bio2021;11:1364-73 PMCID:PMC8091582

[70] Anderson G,Reiter RJ.Multiple sclerosis: melatonin, orexin, and ceramide interact with platelet activation coagulation factors and gut-microbiome-derived butyrate in the circadian dysregulation of mitochondria in glia and immune cells.Int J Mol Sci2019;20:5500 PMCID:PMC6862663

[71] Li Z,Tao J,Zhang J.Exosomes regulate NLRP3 inflammasome in diseases.Front Cell Dev Biol2021;9:802509 PMCID:PMC8762245

[72] Zareba L,Homoncik Z.EVs from BALF-mediators of inflammation and potential biomarkers in lung diseases.Int J Mol Sci2021;22:3651 PMCID:PMC8036254

[73] Brandes RP.Endothelial dysfunction and hypertension.Hypertension2014;64:924-8

[74] Villacorta H.Soluble ST2 testing: a promising biomarker in the management of heart failure.Arq Bras Cardiol2016;106:145-52 PMCID:PMC4765013

[75] Krüger-Genge A,Franke RP.Vascular endothelial cell biology: an update.Int J Mol Sci2019;20:4411 PMCID:PMC6769656

[76] Fujimoto S,Kadota T,Kuwano K.Intercellular communication by vascular endothelial cell-derived extracellular vesicles and their MicroRNAs in respiratory diseases.Front Mol Biosci2020;7:619697 PMCID:PMC7890564

[77] Green D.Coagulation cascade.Hemodial Int2006;10 Suppl 2:S2-4

[78] Reddy EC.Procoagulant phosphatidylserine-exposing platelets in vitro and in vivo.Front Cardiovasc Med2020;7:15 PMCID:PMC7062866

[79] Puhm F,Boilard E.Platelet extracellular vesicles in COVID-19: potential markers and makers.J Leukoc Biol2022;111:63-74 PMCID:PMC8667644

[80] Guervilly C,Burtey S.Dissemination of extreme levels of extracellular vesicles: tissue factor activity in patients with severe COVID-19.Blood Adv2021;5:628-34 PMCID:PMC7846479

[81] Segawa K.An apoptotic “eat me” signal: phosphatidylserine exposure.Trends Cell Biol2015;25:639-50

[82] Rosell A,von Meijenfeldt F.Patients with COVID-19 have elevated levels of circulating extracellular vesicle tissue factor activity that is associated with severity and mortality-brief report.Arterioscler Thromb Vasc Biol2021;41:878-82 PMCID:PMC7837685

[83] Mackman N.Role of tissue factor in hemostasis, thrombosis, and vascular development.Arterioscler Thromb Vasc Biol2004;24:1015-22

[84] Bern MM.Extracellular vesicles: how they interact with endothelium, potentially contributing to metastatic cancer cell implants.Clin Transl Med2017;6:33 PMCID:PMC5607152

[85] Nielsen T,Pedersen S,Kristensen SR.Investigation of procoagulant activity in extracellular vesicles isolated by differential ultracentrifugation.J Extracell Vesicles2018;7:1454777 PMCID:PMC5912197

[86] Date K,Maraveyas A.Tissue factor-bearing microparticles and inflammation: a potential mechanism for the development of venous thromboembolism in cancer.J Thromb Haemost2017;15:2289-99

[87] Kobayashi S,Takahashi T.Tissue factor and its procoagulant activity on cancer-associated thromboembolism in pancreatic cancer.Cancer Sci2021;112:4679-91 PMCID:PMC8586686

[88] Zwicker JI,Neuberg D.Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy.Clin Cancer Res2009;15:6830-40 PMCID:PMC2783253

[89] Barberis E,Falasca M.Circulating exosomes are strongly involved in SARS-CoV-2 infection.Front Mol Biosci2021;8:632290 PMCID:PMC7937875

[90] Yitbarek GY,Asnakew S.The role of C-reactive protein in predicting the severity of COVID-19 disease: a systematic review.SAGE Open Med2021;9:20503121211050755 PMCID:PMC8516378

[91] Ali N.Elevated level of C-reactive protein may be an early marker to predict risk for severity of COVID-19.J Med Virol2020;92:2409-11 PMCID:PMC7301027

[92] Cirillo P,Calabrò P.C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation.Cardiovasc Res2005;68:47-55

[93] Venugopal SK,Yuhanna I,Jialal I.Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells.Circulation2002;106:1439-41

[94] Sodhi CP,Yamaguchi Y.Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg⁹ bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration.Am J Physiol Lung Cell Mol Physiol2018;314:L17-31 PMCID:PMC5866432

[95] Chung MK,Saef J.SARS-CoV-2 and ACE2: the biology and clinical data settling the ARB and ACEI controversy.EBioMedicine2020;58:102907 PMCID:PMC7415847

[96] Roche JA.A hypothesized role for dysregulated bradykinin signaling in COVID-19 respiratory complications.FASEB J2020;34:7265-9 PMCID:PMC7267506

[97] Hofman Z,Hack CE.Bradykinin: inflammatory product of the coagulation system.Clin Rev Allergy Immunol2016;51:152-61 PMCID:PMC5025506

[98] Lipcsey M,Eriksson O.The outcome of critically Ill COVID-19 patients is linked to thromboinflammation dominated by the kallikrein/kinin system.Front Immunol2021;12:627579 PMCID:PMC7937878

[99] van de Veerdonk FL,van Deuren M.Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome.Elife2020;9:e57555 PMCID:PMC7213974

[100] Zaid Y,Allaeys I.Platelets can associate with SARS-Cov-2 RNA and are hyperactivated in COVID-19. Circ Res.2020; PMCID:PMC7641188

[101] Puhm F,Machlus KR.Platelet extracellular vesicles: beyond the blood.Arterioscler Thromb Vasc Biol2021;41:87-96 PMCID:PMC7769913

[102] Periayah MH,Mat Saad AZ.Mechanism action of platelets and crucial blood coagulation pathways in hemostasis.Int J Hematol Oncol Stem Cell Res2017;11:319-327 PMCID:PMC5767294

[103] Cappellano G,Rolla R.Circulating platelet-derived extracellular vesicles are a hallmark of SARS-Cov-2 infection.Cells2021;10:85 PMCID:PMC7825711

[104] Jansen F,Pfeifer A.Endothelial- and immune cell-derived extracellular vesicles in the regulation of cardiovascular health and disease.JACC Basic Transl Sci2017;2:790-807 PMCID:PMC6059011

[105] Zicari S,Palomino RAÑ.Human cytomegalovirus-infected cells release extracellular vesicles that carry viral surface proteins.Virology2018;524:97-105 PMCID:PMC6258833

[106] Gould SJ,Hildreth JE.The Trojan exosome hypothesis.Proc Natl Acad Sci USA2003;100:10592-7 PMCID:PMC196848

[107] Chelvanambi S,Bednorz M.HIV-nef protein persists in the lungs of aviremic patients with HIV and induces endothelial cell death.Am J Respir Cell Mol Biol2019;60:357-66 PMCID:PMC6397978

[108] Dogrammatzis C,Deighan C.Diverse populations of extracellular vesicles with opposite functions during herpes simplex virus 1 infection.J Virol2021;95:e02357-20 PMCID:PMC8094966

[109] Troyer Z,Tabler CO.Extracellular vesicles carry SARS-CoV-2 spike protein and serve as decoys for neutralizing antibodies.J Extracell Vesicles2021;10:e12112 PMCID:PMC8213968

[110] Pesce E,Cordiglieri C.Exosomes recovered from the plasma of COVID-19 patients expose SARS-CoV-2 spike-derived fragments and contribute to the adaptive immune response.Front Immunol2021;12:785941 PMCID:PMC8801440

[111] Yim KHW,Chahwan R.Serum extracellular vesicles profiling is associated with COVID-19 progression and immune responses.J Extracell Biol2022;1:e37 PMCID:PMC9088353

[112] Kwon Y,Srivastava S.Detection of viral RNA fragments in human iPSC cardiomyocytes following treatment with extracellular vesicles from SARS-CoV-2 coding sequence overexpressing lung epithelial cells.Stem Cell Res Ther2020;11:514 PMCID:PMC7703503

[113] Lee H,Pinilla-Vera M,Jin Y.Identification of miRNA-rich vesicles in bronchoalveolar lavage fluid: insights into the function and heterogeneity of extracellular vesicles.J Control Release2019;294:43-52 PMCID:PMC6372374

[114] Lee H,Wu J,Jin Y.Lung epithelial cell-derived microvesicles regulate macrophage migration via MicroRNA-17/221-induced integrin β₁ recycling.J Immunol2017;199:1453-64 PMCID:PMC5561736

[115] Frleta D,Kramer HB.HIV-1 infection-induced apoptotic microparticles inhibit human DCs via CD44.J Clin Invest2012;122:4685-97 PMCID:PMC3533550

[116] Schoeman D.Coronavirus envelope protein: current knowledge.Virol J2019;16:69 PMCID:PMC6537279

[117] Martins ST.Extracellular vesicles in viral infections: two sides of the same coin?.Front Cell Infect Microbiol2020;10:593170 PMCID:PMC7736630

[118] Garrus JE,Pornillos OW.Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding.Cell2001;107:55-65

[119] Votteler J.Virus budding and the ESCRT pathway.Cell Host Microbe2013;14:232-41 PMCID:PMC3819203

[120] McNamara RP.Modern techniques for the isolation of extracellular vesicles and viruses.J Neuroimmune Pharmacol2020;15:459-72 PMCID:PMC7065924

[121] Raposo G,Stoorvogel W.B lymphocytes secrete antigen-presenting vesicles.J Exp Med1996;183:1161-72 PMCID:PMC2192324

[122] Olson SD,Pollock K.Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington's disease affected neuronal cells for reduction of huntingtin.Mol Cell Neurosci2012;49:271-81 PMCID:PMC3784251

[123] Bruno S,Deregibus MC,Tetta C.Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth.Stem Cells Dev2013;22:758-71

[124] Cocozza F,Piovesana E.Extracellular vesicles containing ACE2 efficiently prevent infection by SARS-CoV-2 Spike protein-containing virus.J Extracell Vesicles2020;10:e12050 PMCID:PMC7769856

[125] Inal JM.Decoy ACE2-expressing extracellular vesicles that competitively bind SARS-CoV-2 as a possible COVID-19 therapy.Clin Sci (Lond)2020;134:1301-4 PMCID:PMC7298154

[126] Fu X,Halim A,Luo Q.Mesenchymal stem cell migration and tissue repair.Cells2019;8:784 PMCID:PMC6721499

[127] Lee JH,Lee JW.Therapeutic use of mesenchymal stem cell-derived extracellular vesicles in acute lung injury.Transfusion2019;59:876-83 PMCID:PMC6368889

[128] Zhang SJ,He M.Effect of TGF-beta1/SDF-1/CXCR4 signal on BM-MSCs homing in rat heart of ischemia/perfusion injury.Eur Rev Med Pharmacol Sci2019;20:899-905

[129] Ha DH,Lee J.Mesenchymal stem/stromal cell-derived exosomes for immunomodulatory therapeutics and skin regeneration.Cells2020;9:1157 PMCID:PMC7290908

[130] Al-Khawaga S.Potential application of mesenchymal stem cells and their exosomes in lung injury: an emerging therapeutic option for COVID-19 patients.Stem Cell Res Ther2020;11:437 PMCID:PMC7558244

[131] Wei X,Lv H.MicroRNA-377-3p released by mesenchymal stem cell exosomes ameliorates lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy. Cell Death Dis 2020;11:657.

[132] Liu J,Lei P,Huang P.Exosomes released by bone marrow mesenchymal stem cells attenuate lung injury induced by intestinal ischemia reperfusion via the TLR4/NF-κB pathway.Int J Med Sci2019;16:1238-44 PMCID:PMC6775266

[133] Sengupta V,Lazo A,Nolan A.Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19.Stem Cells Dev2020;29:747-54 PMCID:PMC7310206

[134] Bauer FN.CHAPTER 1. Therapeutic potential of mesenchymal stromal xell-derived small extracellular vesicles. In: Chrzanowski W, Lim CT, Kim SY, editors. Extracellular vesicles. Cambridge: Royal Society of Chemistry; 2021. pp. 1-21.

[135] Börger V,Dittrich R,Giebel B.Scaled isolation of mesenchymal stem/stromal cell-derived extracellular vesicles.Curr Protoc Stem Cell Biol2020;55:e128

[136] Staubach S,Walkenfort B.Free flow electrophoresis allows quick and reproducible preparation of extracellular vesicles from conditioned cell culture media.Extracell Vesicles Circ Nucleic Acids2022;3:31-48