Abstract
Stem cell-based therapy is a promising approach for treating acute stroke patients and stroke survivors with fixed neurological deficits. Several stem cell trials conducted in stroke patients have reported inconsistent results. Stem cells such as mesenchymal stem cells (MSCs) secrete extracellular vesicles (EVs), which harbor several molecules such as proteins and microRNAs. Recently, many preclinical studies have shown that stem cell-derived EVs can be used in stroke therapy as an alternative approach to stem cell application. This study discusses the evidence regarding the effects and underlying mechanisms of EV therapy in experimental stroke and findings of the biomarker sub-study from a randomized control trial of MSCs-based therapy in stroke patients. Moreover, the advantages and disadvantages of EVs therapy are compared with those of MSC therapy for stroke. Finally, major issues in the clinical application of EV therapeutics in stroke are discussed with relevant advances for clinical-scale EV production/enrichment, isolation/purification, and quantification/characterization. Several methods to improve the efficacy and purity of EV products have been introduced recently. This review presents the most recent advances in MSC-derived EV therapy for stroke, focusing on the application of this strategy in patients with ischemic stroke.
Abbreviations
- BBB:
-
Blood–brain barrier
- CDN:
-
Cell-derived nanovesicles
- ECM:
-
Extracellular matrix
- EGF:
-
Epidermal growth factor
- ESCs:
-
Embryonic stem cells
- EVs:
-
Extracellular vesicles
- FDA:
-
Food and Drug Administration
- FGF:
-
Fibroblast growth factor
- GMP:
-
Good Manufacturing Practice
- iPSCs:
-
Induced pluripotent stem cells
- ISEV:
-
International Society for Extracellular Vesicles
- lncRNAs:
-
Long noncoding RNAs
- MiRNA:
-
MmicroRNAs
- MISEV:
-
Minimal Information for Studies of Extracellular Vesicles
- MRI:
-
Magnetic resonance imaging
- MSC:
-
Mesenchymal stem cells
- NSCs:
-
Neural stem cells
- PDGF:
-
Platelet-derived growth factor
- PEG:
-
Polyethylene glycol
- VEGF:
-
Vascular endothelial growth factor
References
Abdeen AA, Weiss JB, Lee J et al (2014) Matrix composition and mechanics direct proangiogenic signaling from mesenchymal stem cells. Tissue Eng Part A 20:2737–2745
Anderson JD, Johansson HJ, Graham CS et al (2016) Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappaB signaling. Stem Cells 34:601–613
Angulski AB, Capriglione LG, Batista M et al (2017) The protein content of extracellular vesicles derived from expanded human umbilical cord blood-derived CD133(+) and human bone marrow-derived mesenchymal stem cells partially explains why both sources are advantageous for regenerative medicine. Stem Cell Rev Rep 13:244–257
Arora S, Srinivasan A, Leung CM et al (2020) Bio-mimicking shear stress environments for enhancing mesenchymal stem cell differentiation. Curr Stem Cell Res Ther 15:414–427
Bang OY, Kim EH (2019) Mesenchymal stem cell-derived extracellular vesicle therapy for stroke: challenges and progress. Front Neurol 10:211
Bang OY, Kim EH, Cha JM et al (2016) Adult stem cell therapy for stroke: challenges and progress. J Stroke 18:256–266
Bartosh TJ, Ylostalo JH, Mohammadipoor A et al (2010) Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc Natl Acad Sci U S A 107:13724–13729
Barzegar M, Wang Y, Eshaq RS et al (2020) Human placental mesenchymal stem cells improve stroke outcomes via extracellular vesicles-mediated preservation of cerebral blood flow. EBioMedicine 63:103161
Bian S, Zhang L, Duan L et al (2014) Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 92:387–397
Biancone L, Bruno S, Deregibus MC et al (2012) Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant 27:3037–3042
Borlongan CV, Hadman M, Sanberg CD et al (2004) Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke 35:2385–2389
Cai J, Wu J, Wang J et al (2020) Extracellular vesicles derived from different sources of mesenchymal stem cells: therapeutic effects and translational potential. Cell Biosci 10:69
Cha JM, Park H, Shin EK et al (2017) A novel cylindrical microwell featuring inverted-pyramidal opening for efficient cell spheroid formation without cell loss. Biofabrication 9:035006
Cha JM, Lee MY, Hong J (2018a) Bioreactor systems are essentially required for stem cell bioprocessing. Precis Future Med. Epub ahead of print
Cha JM, Shin EK, Sung JH et al (2018b) Efficient scalable production of therapeutic microvesicles derived from human mesenchymal stem cells. Sci Rep 8(1):1171. https://doi.org/10.1038/s41598-018-19211-6
Chaput N, Thery C (2011) Exosomes: immune properties and potential clinical implementations. Semin Immunopathol 33:419–440
Chen KH, Chen CH, Wallace CG et al (2016) Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 7:74537–74556
Chevillet JR, Kang Q, Ruf IK et al (2014) Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci U S A 111:14888–14893
Choi JS, Cho WL, Choi YJ et al (2019) Functional recovery in photo-damaged human dermal fibroblasts by human adipose-derived stem cell extracellular vesicles. J Extracell Vesicles 8:1565885
Chung JW, Chang WH, Bang OY et al (2021) Efficacy and safety of intravenous mesenchymal stem cells for ischemic stroke. Neurology 96(7):e1012–e1023
Colao IL, Corteling R, Bracewell D et al (2018) Manufacturing exosomes: a promising therapeutic platform. Trends Mol Med 24:242–256
Colombo M, Raposo G, Thery C (2014) Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 30:255–289
Costa LA, Eiro N, Fraile M et al (2021) Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: implications for further clinical uses. Cell Mol Life Sci 78(2):447–467
Cunningham CJ, Redondo-Castro E, Allan SM (2018) The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb Blood Flow Metab 38:1276–1292
de Jong OG, Kooijmans SAA, Murphy DE et al (2019) Drug delivery with extracellular vesicles: from imagination to innovation. Acc Chem Res 52:1761–1770
Dharap A, Nakka VP, Vemuganti R (2012) Effect of focal ischemia on long noncoding RNAs. Stroke 43:2800–2802
Di Rocco G, Baldari S, Toietta G (2016) Towards therapeutic delivery of extracellular vesicles: strategies for in vivo tracking and biodistribution analysis. Stem Cells Int 2016:5029619
Diaz MF, Vaidya AB, Evans SM et al (2017) Biomechanical forces promote immune regulatory function of bone marrow mesenchymal stromal cells. Stem Cells 35:1259–1272
Doeppner TR, Herz J, Gorgens A et al (2015) Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med 4:1131–1143
Doeppner TR, Bahr M, Giebel B et al (2018) Immunological and non-immunological effects of stem cell-derived extracellular vesicles on the ischaemic brain. Ther Adv Neurol Disord 11:1756286418789326
Domenis R, Cifu A, Quaglia S et al (2018) Pro inflammatory stimuli enhance the immunosuppressive functions of adipose mesenchymal stem cells-derived exosomes. Sci Rep 8:13325
Doyle LM, Wang MZ (2019) Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cell 8(7):727
Eirin A, Ferguson CM, Zhu XY et al (2020) Extracellular vesicles released by adipose tissue-derived mesenchymal stromal/stem cells from obese pigs fail to repair the injured kidney. Stem Cell Res 47:101877
Engler AJ, Sen S, Sweeney HL et al (2006) Matrix elasticity directs stem cell lineage specification. Cell 126:677–689
Fafian-Labora J, Lesende-Rodriguez I, Fernandez-Pernas P et al (2017) Effect of age on pro-inflammatory miRNAs contained in mesenchymal stem cell-derived extracellular vesicles. Sci Rep 7:43923
Fan B, Pan W, Wang X et al (2020) Long noncoding RNA mediates stroke-induced neurogenesis. Stem Cells 38:973–985
Frith JE, Thomson B, Genever PG (2010) Dynamic three-dimensional culture methods enhance mesenchymal stem cell properties and increase therapeutic potential. Tissue Eng Part C Methods 16:735–749
Fuster-Matanzo A, Gessler F, Leonardi T et al (2015) Acellular approaches for regenerative medicine: on the verge of clinical trials with extracellular membrane vesicles? Stem Cell Res Ther 6:227
Gimona M, Pachler K, Laner-Plamberger S et al (2017) Manufacturing of human extracellular vesicle-based therapeutics for clinical use. Int J Mol Sci 18(6):1190
Goh WJ, Zou S, Ong WY et al (2017) Bioinspired cell-derived nanovesicles versus exosomes as drug delivery systems: a cost-effective alternative. Sci Rep 7:14322
Gudbergsson JM, Jonsson K, Simonsen JB et al (2019) Systematic review of targeted extracellular vesicles for drug delivery – considerations on methodological and biological heterogeneity. J Control Release 306:108–120
Han C, Jeong D, Kim B et al (2019) Mesenchymal stem cell engineered nanovesicles for accelerated skin wound closure. ACS Biomater Sci Eng 5:1534–1543
Haraszti RA, Miller R, Stoppato M et al (2018) Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity. Mol Ther 26:2838–2847
Harting MT, Srivastava AK, Zhaorigetu S et al (2018) Inflammation-stimulated mesenchymal stromal cell-derived extracellular vesicles attenuate inflammation. Stem Cells 36:79–90
Hartjes TA, Mytnyk S, Jenster GW et al (2019) Extracellular vesicle quantification and characterization: common methods and emerging approaches. Bioengineering (Basel) 6(1):7
Hayakawa K, Chan SJ, Mandeville ET et al (2018) Protective effects of endothelial progenitor cell-derived extracellular mitochondria in brain endothelium. Stem Cells 36:1404–1410
Hsu C, Morohashi Y, Yoshimura S et al (2010) Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol 189:223–232
Hu GW, Li Q, Niu X et al (2015) Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Res Ther 6:10
Hyland M, Mennan C, Wilson E et al (2020) Pro-inflammatory priming of umbilical cord mesenchymal stromal cells alters the protein cargo of their extracellular vesicles. Cell 9
Jung JW, Kwon M, Choi JC et al (2013) Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei Med J 54:1293–1296
Kalani A, Chaturvedi P, Kamat PK et al (2016) Curcumin-loaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury. Int J Biochem Cell Biol 79:360–369
Kalra H, Simpson RJ, Ji H et al (2012) Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol 10:e1001450
Kalra H, Adda CG, Liem M et al (2013) Comparative proteomics evaluation of plasma exosome isolation techniques and assessment of the stability of exosomes in normal human blood plasma. Proteomics 13:3354–3364
Kang K, Ma R, Cai W et al (2015) Exosomes secreted from CXCR4 overexpressing mesenchymal stem cells promote cardioprotection via Akt signaling pathway following myocardial infarction. Stem Cells Int 2015:659890
Karp JM, Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4:206–216
KatagirI W, Osugi M, Kawai T et al (2016) First-in-human study and clinical case reports of the alveolar bone regeneration with the secretome from human mesenchymal stem cells. Head Face Med 12:5
Katsuda T, Ochiya T (2015) Molecular signatures of mesenchymal stem cell-derived extracellular vesicle-mediated tissue repair. Stem Cell Res Ther 6:212
Keerthikumar S, Chisanga D, Ariyaratne D et al (2016) ExoCarta: a web-based compendium of exosomal cargo. J Mol Biol 428:688–692
Kennedy TL, Russell AJ, Riley P (2021) Experimental limitations of extracellular vesicle-based therapies for the treatment of myocardial infarction. Trends Cardiovasc Med 31(7):405–415
Kim HS, Choi DY, Yun SJ et al (2012) Proteomic analysis of microvesicles derived from human mesenchymal stem cells. J Proteome Res 11:839–849
Kim MS, Haney MJ, Zhao Y et al (2018) Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations. Nanomedicine 14:195–204
Kim H, Kim D, Nam H et al (2020) Engineered extracellular vesicles and their mimetics for clinical translation. Methods 177:80–94
Kooijmans SAA, Fliervoet LAL, Van Der Meel R et al (2016) PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J Control Release 224:77–85
Kordelas L, Rebmann V, Ludwig AK et al (2014) MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 28:970–973
Kornilov R, Puhka M, Mannerstrom B et al (2018) Efficient ultrafiltration-based protocol to deplete extracellular vesicles from fetal bovine serum. J Extracell Vesicles 7:1422674
Krueger TEG, Thorek DLJ, Denmeade SR et al (2018) Concise review: mesenchymal stem cell-based drug delivery: the good, the bad, the ugly, and the promise. Stem Cells Transl Med 7:651–663
Kulkarni R, Bajaj M, Ghode S et al (2018) Intercellular transfer of microvesicles from young mesenchymal stromal cells rejuvenates aged murine hematopoietic stem cells. Stem Cells 36:420–433
La Greca A, Solari C, Furmento V et al (2018) Extracellular vesicles from pluripotent stem cell-derived mesenchymal stem cells acquire a stromal modulatory proteomic pattern during differentiation. Exp Mol Med 50:119
Lai RC, Tan SS, Teh BJ et al (2012) Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics 2012:971907
Lai RC, Yeo RW, Tan KH et al (2013) Mesenchymal stem cell exosome ameliorates reperfusion injury through proteomic complementation. Regen Med 8:197–209
Lam KCK, Lam MKN, Chim CS et al (2020) The functional role of surface molecules on extracellular vesicles in cancer, autoimmune diseases, and coagulopathy. J Leukoc Biol 108:1565–1573
Laulagnier K, Grand D, Dujardin A et al (2004) PLD2 is enriched on exosomes and its activity is correlated to the release of exosomes. FEBS Lett 572:11–14
Lee JY, Kim E, Choi SM et al (2016) Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke. Sci Rep 6:33038
Lener T, Gimona M, Aigner L et al (2015) Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper. J Extracell Vesicles 4:30087
Li Y, Meng Y, Zhu X et al (2020) Metabolic syndrome increases senescence-associated micro-RNAs in extracellular vesicles derived from swine and human mesenchymal stem/stromal cells. Cell Commun Signal 18:124
Lobb RJ, Becker M, Wen SW et al (2015) Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles 4:27031
Lopatina T, Bruno S, Tetta C et al (2014) Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal 12:26
Lopez-Verrilli MA, Caviedes A, Cabrera A et al (2016) Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth. Neuroscience 320:129–139
Lotvall J, Hill AF, Hochberg F et al (2014) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 3:26913
Loukogeorgakis SP, De Coppi P (2017) Concise review: amniotic fluid stem cells: the known, the unknown, and potential regenerative medicine applications. Stem Cells 35:1663–1673
Man K, Brunet MY, Jones MC et al (2020) Engineered extracellular vesicles: tailored-made nanomaterials for medical applications. Nanomaterials (Basel) 10(9):1838
Medalla M, Chang W, Calderazzo SM et al (2020) Treatment with mesenchymal-derived extracellular vesicles reduces injury-related pathology in pyramidal neurons of monkey perilesional ventral premotor cortex. J Neurosci 40:3385–3407
Mendt M, Kamerkar S, Sugimoto H et al (2018) Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 3(8):e99263
Moon GJ, Cho YH, Kim DH et al (2018) Serum-mediated activation of bone marrow-derived mesenchymal stem cells in ischemic stroke patients: a novel preconditioning method. Cell Transplant 27:485–500
Moon GJ, Sung JH, Kim DH et al (2019) Application of mesenchymal stem cell-derived extracellular vesicles for stroke: biodistribution and MicroRNA study. Transl Stroke Res 10:509–521
Mulcahy LA, Pink RC, Carter DR (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 3
Nalamolu KR, Venkatesh I, Mohandass A et al (2019) Exosomes treatment mitigates ischemic brain damage but does not improve post-stroke neurological outcome. Cell Physiol Biochem 52:1280–1291
Nam GH, Choi Y, Kim GB et al (2020) Emerging prospects of exosomes for cancer treatment: from conventional therapy to immunotherapy. Adv Mater 32:e2002440
Nassar W, El-Ansary M, Sabry D et al (2016) Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res 20:21
Nguyen PK, Neofytou E, Rhee JW et al (2016) Potential strategies to address the major clinical barriers facing stem cell regenerative therapy for cardiovascular disease: a review. JAMA Cardiol 1:953–962
Ostrowski M, Carmo NB, Krumeich S et al (2010) Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12:19–30; sup pp 1–13
Otero-Ortega L, Laso-Garcia F, Gomez-de Frutos MD et al (2017) White matter repair after extracellular vesicles administration in an experimental animal model of subcortical stroke. Sci Rep 7:44433
Otero-Ortega L, Laso-Garcia F, Frutos MCG et al (2020) Low dose of extracellular vesicles identified that promote recovery after ischemic stroke. Stem Cell Res Ther 11:70
Pardridge WM (2003) Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv 3(90–105):51
Park H, Park H, Mun D et al (2018) Extracellular vesicles derived from hypoxic human mesenchymal stem cells attenuate GSK3beta expression via miRNA-26a in an ischemia-reperfusion injury model. Yonsei Med J 59:736–745
Patel NA, Moss LD, Lee JY et al (2018) Long noncoding RNA MALAT1 in exosomes drives regenerative function and modulates inflammation-linked networks following traumatic brain injury. J Neuroinflammation 15:204
Peinado H, Aleckovic M, Lavotshkin S et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891
Pendharkar AV, Chua JY, Andres RH et al (2010) Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia. Stroke 41:2064–2070
Phan J, Kumar P, Hao D et al (2018) Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy. J Extracell Vesicles 7:1522236
Piffoux M, Nicolas-Boluda A, Mulens-Arias V et al (2019) Extracellular vesicles for personalized medicine: the input of physically triggered production, loading and theranostic properties. Adv Drug Deliv Rev 138:247–258
Placzek MR, Chung IM, MAcedo HM et al (2009) Stem cell bioprocessing: fundamentals and principles. J R Soc Interface 6:209–232
Qu Y, Dubyak GR (2009) P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways. Purinergic Signal 5:163–173
Ragni E, Banfi F, Barilani M et al (2017) Extracellular vesicle-shuttled mRNA in mesenchymal stem cell communication. Stem Cells 35:1093–1105
Rana S, Yue S, Stadel D et al (2012) Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol 44:1574–1584
Rao SK, Huynh C, Proux-Gillardeaux V et al (2004) Identification of SNAREs involved in synaptotagmin VII-regulated lysosomal exocytosis. J Biol Chem 279:20471–20479
Reiner AT, Witwer KW, Van Balkom BWM et al (2017) Concise review: developing best-practice models for the therapeutic use of extracellular vesicles. Stem Cells Transl Med 6:1730–1739
Royo F, Thery C, Falcon-Perez JM et al (2020) Methods for separation and characterization of extracellular vesicles: results of a worldwide survey performed by the ISEV rigor and standardization subcommittee. Cell 9(9):1955
Saugstad JA (2010) MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration. J Cereb Blood Flow Metab 30:1564–1576
Savitz SI (2013) Cell therapies: careful translation from animals to patients. Stroke 44:S107–S109
Sheldon H, Heikamp E, Turley H et al (2010) New mechanism for notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood 116:2385–2394
Shojaati G, Khandaker I, Funderburgh ML et al (2019) Mesenchymal stem cells reduce corneal fibrosis and inflammation via extracellular vesicle-mediated delivery of miRNA. Stem Cells Transl Med 8:1192–1201
Simons M, Raposo G (2009) Exosomes – vesicular carriers for intercellular communication. Curr Opin Cell Biol 21:575–581
Simpson RJ, Jensen SS, Lim JW (2008) Proteomic profiling of exosomes: current perspectives. Proteomics 8:4083–4099
Skotland T, Sagini K, Sandvig K et al (2020) An emerging focus on lipids in extracellular vesicles. Adv Drug Deliv Rev 159:308–321
Sokolova V, Ludwig AK, Hornung S et al (2011) Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. Colloids Surf B Biointerfaces 87:146–150
Sung DK, Chang YS, Sung SI et al (2019) Thrombin preconditioning of extracellular vesicles derived from mesenchymal stem cells accelerates cutaneous wound healing by boosting their biogenesis and enriching cargo content. J Clin Med 8(4):533
Tao SC, Guo SC, Li M et al (2017) Chitosan wound dressings incorporating exosomes derived from MicroRNA-126-overexpressing synovium mesenchymal stem cells provide sustained release of exosomes and heal full-thickness skin defects in a diabetic rat model. Stem Cells Transl Med 6:736–747
Tatsumi K, Ohashi K, Matsubara Y et al (2013) Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochem Biophys Res Commun 431:203–209
Thery C, Witwer KW, Aikawa E et al (2018) 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 Vesicles 7:1535750
Tieu A, Lalu MM, Slobodian M et al (2020) An analysis of mesenchymal stem cell-derived extracellular vesicles for preclinical use. ACS Nano 14:9728–9743
Toh WS, Lai RC, Zhang B et al (2018) MSC exosome works through a protein-based mechanism of action. Biochem Soc Trans 46:843–853
Urbanelli L, Magini A, Buratta S et al (2013) Signaling pathways in exosomes biogenesis, secretion and fate. Genes (Basel) 4:152–170
Vestad B, Llorente A, Neurauter A et al (2017) Size and concentration analyses of extracellular vesicles by nanoparticle tracking analysis: a variation study. J Extracell Vesicles 6:1344087
Wang Y, Lu X, He J et al (2015) Influence of erythropoietin on microvesicles derived from mesenchymal stem cells protecting renal function of chronic kidney disease. Stem Cell Res Ther 6:100
Wang J, Li H, Yao Y et al (2018a) Stem cell-derived mitochondria transplantation: a novel strategy and the challenges for the treatment of tissue injury. Stem Cell Res Ther 9:106
Wang Y, Zhao R, Liu D et al (2018b) Exosomes derived from miR-214-enriched bone marrow-derived mesenchymal stem cells regulate oxidative damage in cardiac stem cells by targeting CaMKII. Oxidative Med Cell Longev:4971261
Wang C, Borger V, Sardari M et al (2020) Mesenchymal stromal cell-derived small extracellular vesicles induce ischemic neuroprotection by modulating leukocytes and specifically neutrophils. Stroke 51:1825–1834
Watson DC, Yung BC, Bergamaschi C et al (2018) Scalable, cGMP-compatible purification of extracellular vesicles carrying bioactive human heterodimeric IL-15/lactadherin complexes. J Extracell Vesicles 7:1442088
Webb RL, Kaiser EE, Jurgielewicz BJ et al (2018a) Human neural stem cell extracellular vesicles improve recovery in a porcine model of ischemic stroke. Stroke 49:1248–1256
Webb RL, Kaiser EE, Scoville SL et al (2018b) Human neural stem cell extracellular vesicles improve tissue and functional recovery in the murine thromboembolic stroke model. Transl Stroke Res 9:530–539
Webber J, Clayton A (2013) How pure are your vesicles? J Extracell Vesicles 2
Wiklander OP, Nordin JZ, O’Loughlin A et al (2015) Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles 4:26316
Witwer KW, Van Balkom BWM, Bruno S et al (2019) Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles 8:1609206
Woo CH, Kim HK, Jung GY et al (2020) Small extracellular vesicles from human adipose-derived stem cells attenuate cartilage degeneration. J Extracell Vesicles 9:1735249
Xin H, Li Y, Cui Y et al (2013) Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 33:1711–1715
Xin H, Katakowski M, Wang F et al (2017a) MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke 48:747–753
Xin H, Wang F, Li Y et al (2017b) Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from MicroRNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant 26:243–257
Xing X, Han S, Cheng G et al (2020) Proteomic analysis of exosomes from adipose-derived mesenchymal stem cells: a novel therapeutic strategy for tissue injury. Biomed Res Int 2020:6094562
Zhang HC, Liu XB, Huang S et al (2012) Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells Dev 21:3289–3297
Zhang Y, Chopp M, Zhang ZG et al (2017) Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem Int 111:69–81
Zhang X, Liu J, Yu B et al (2018) Effects of mesenchymal stem cells and their exosomes on the healing of large and refractory macular holes. Graefes Arch Clin Exp Ophthalmol 256(11):2041–2052
Zhang ZG, Buller B, Chopp M (2019) Exosomes - beyond stem cells for restorative therapy in stroke and neurological injury. Nat Rev Neurol 15:193–203
Zhu YG, Feng XM, Abbott J et al (2014) Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells 32:116–125
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Bang, O.Y., Kim, E.H., Moon, G.J., Cha, J.M. (2022). Mesenchymal Stem Cell-Extracellular Vesicle Therapy in Patients with Stroke. In: Haider, K.H. (eds) Handbook of Stem Cell Therapy. Springer, Singapore. https://doi.org/10.1007/978-981-16-6016-0_45-1
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