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Stem Cell Extracellular Vesicles and their Potential to Contribute to the Repair of Damaged CNS Cells

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Abstract

Neurological diseases and disorders are leading causes of death and disability worldwide. Many of these pathologies are associated with high levels of neuroinflammation and irreparable tissue damage. As the global burden of these pathologies continues to rise there is a significant need for the development of novel therapeutics. Due to their multipotent properties, stem cells have broad applications for tissue repair; additionally, stem cells have been shown to possess both immunomodulatory and neuroprotective properties. It is now believed that paracrine factors, such as extracellular vesicles (EVs), play a critical role in the functionality associated with stem cells. The diverse biological cargo contained within EVs are proposed to mediate these effects and, to date, the reparative and regenerative effects of stem cell EVs have been demonstrated in a wide range of cell types. While a high potential for their therapeutic use exists, there is a gap of knowledge surrounding their characterization, mechanisms of action, and how they may regulate cells of the CNS. Here, we report the isolation, characterization, and functional assessment of EVs from two sources of human stem cells, mesenchymal stem cells and induced pluripotent stem cells. We demonstrate the ability of these EVs to enhance the processes of cellular migration and angiogenesis, which are critical for both normal cellular development as well as cellular repair. Furthermore, we investigate their reparative effects on damaged cells, specifically those with relevance to the central nervous system. Collectively, our data highlight the similarities and differences among these EV populations and support the view that stem cells EV can be used to repair or partially reverse cellular damage.

Stem cell-derived Extracellular Vesicles (EVs) for repair of damaged cells. EVs isolated from human induced pluripotent stem cells and mesenchymal stem cells contribute to the partial reversal of phenotypes induced by different sources of cellular damage.

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References

  • Abels ER, Breakefield XO (2016) Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell Mol Neurobiol 36:301–312

    CAS  PubMed  PubMed Central  Google Scholar 

  • Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, van Noort JM (2014) Inflammation in neurodegenerative diseases--an update. Immunology 142:151–166

    CAS  PubMed  PubMed Central  Google Scholar 

  • Andriolo G, Provasi E, Lo Cicero V, Brambilla A, Soncin S, Torre T, Milano G, Biemmi V, Vassalli G, Turchetto L, Barile L, Radrizzani M (2018) Exosomes from human cardiac progenitor cells for therapeutic applications: development of a GMP-grade manufacturing method. Front Physiol 9:1169

    PubMed  PubMed Central  Google Scholar 

  • Aust L, Devlin B, Foster SJ, Halvorsen YD, Hicok K, du Laney T, Sen A, Willingmyre GD, Gimble JM (2004) Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy 6:7–14

    CAS  PubMed  Google Scholar 

  • Banerjee PN, Filippi D, Allen Hauser W (2009) The descriptive epidemiology of epilepsy-a review. Epilepsy Res 85:31–45

    PubMed  PubMed Central  Google Scholar 

  • Baraniak PR, McDevitt TC (2010) Stem cell paracrine actions and tissue regeneration. Regen Med 5:121–143

    PubMed  Google Scholar 

  • Basu J, Ludlow JW (2016) Exosomes for repair, regeneration and rejuvenation. Expert Opin Biol Ther 16:489–506

    CAS  PubMed  Google Scholar 

  • Black IB, Woodbury D (2001) Adult rat and human bone marrow stromal stem cells differentiate into neurons. Blood Cell Mol Dis 27:632–636

    CAS  Google Scholar 

  • Börger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli O, Becic A, Giebel B (2017) Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci 18:1450

    PubMed Central  Google Scholar 

  • Braccioli L, van Velthoven C, Heijnen CJ (2014) Exosomes: a new weapon to treat the central nervous system. Mol Neurobiol 49:113–119

    CAS  PubMed  Google Scholar 

  • Brambilla L, Martorana F, Rossi D (2013) Astrocyte signaling and neurodegeneration: new insights into CNS disorders. Prion 7:28–36

    CAS  PubMed  PubMed Central  Google Scholar 

  • Burgio E, Piscitelli P, Migliore M (2018) Ionizing radiation and human health: reviewing models of exposure and mechanisms of cellular damage an epigenetic perspective. Int J Environ Res Public Health 15:1971

    PubMed Central  Google Scholar 

  • Burrello J, Monticone S, Gai C, Gomez Y, Kholia S, Camussi G (2016) Stem cell-derived extracellular vesicles and immune-modulation. Frontiers in Cell and Developmental Biology 4:83

    PubMed  PubMed Central  Google Scholar 

  • Busatto S, Vilanilam G, Ticer T, Lin WL, Dickson DW, Shapiro S, Bergese P, Wolfram J (2018) Tangential flow filtration for highly efficient concentration of extracellular vesicles from large volumes of fluid. Cells 7:273

    CAS  PubMed Central  Google Scholar 

  • Castro-Viñuelas R, Sanjurjo-Rodríguez C, Piñeiro-Ramil M, Hermida-Gómez T, Fuentes-Boquete IM, de Toro-Santos FJ, Blanco-García FJ, Díaz-Prado SM (2018) Induced pluripotent stem cells for cartilage repair: current status and future perspectives. European Cells and Materials 36:96–109

    PubMed  Google Scholar 

  • Cefalo MG, Carai A, Miele E, Po A, Ferretti E, Mastronuzzi A, Germano IM (2016) Human iPSC for therapeutic approaches to the nervous system: present and future applications. Stem Cell International 2016:4869071

    Google Scholar 

  • Cekanaviciute E, Buckwalter M (2016) Astrocytes: integrative regulators of Neuroinflammation in stroke and other neurological diseases. Neurotherapeutics 13:685–701

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chamberlain G, Fox J, Ashton B, Middleton J (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25:2739–2749

    CAS  PubMed  Google Scholar 

  • Chen WW, Zhang X, Huang WJ (2016) Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep 13:3391–3396

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cole JL (2007) Activation of PKR: an open and shut case? Trends in Biomedical Sciences 32:57–62

    CAS  Google Scholar 

  • Colombo E, Farina C (2016) Astrocytes: key regulators of Neuroinflammation. Trends Immunol 37:608–620

    CAS  PubMed  Google Scholar 

  • Dahm T, Rudolph H, Schwerk C, Schroten H, Tenenbaum T (2016) Neuroinvasion and inflammation in viral central nervous system infections. Mediat Inflamm 2016:8562805

    Google Scholar 

  • de Lange ECM, van den Brink W, Yamamoto Y, de Witte WEA, Wong YC (2017) Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics. Expert Opin Drug Discovery 12:1207–1218

    Google Scholar 

  • de Lázaro I, Yilmazer A, Kostarelos K (2014) Induced pluripotent stem (iPS) cells: a new source for cell-based therapeutics? J Control Release 185:37–44

    PubMed  Google Scholar 

  • Desouky O, Ding N, Zhou G (2015) Targeted and non-targeted effects of ionizing radiation. J Radiat Res Appl Sci 8:247–254

    CAS  Google Scholar 

  • Ding Q, Sun R, Wang P, Zhang H, Xiang M, Meng D, Sun N, Chen AF, Chen S (2018) Protective effects of human induced pluripotent stem cell-derived exosomes on high glucose-induced injury in human endothelial cells. Experimental and Therapeutic Medicine 15:4791–4797

    PubMed  PubMed Central  Google Scholar 

  • DiNunzio JC, Williams RO 3rd (2008) CNS disorders--current treatment options and the prospects for advanced therapies. Drug Dev Ind Pharm 34:1141–1167

    CAS  PubMed  Google Scholar 

  • Dittmar T, Entschladen F (2013) Migratory properties of mesenchymal stem cells. Adv Biochem Eng Biotechnol 129:117–136

    CAS  PubMed  Google Scholar 

  • Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement Cytotherapy 8:315–317

    CAS  PubMed  Google Scholar 

  • Dvorak HF (2005) Angiogenesis: update 2005. J Thromb Haemost 3:1835–1842

    CAS  PubMed  Google Scholar 

  • Fatima F, Ekstrom K, Nazarenko I, Maugen M, Valadi H, Hill AF, Camussi G, Nawaz M (2017) Non-coding RNAs in mesenchymal stem cell-derived extracellular vesicles: deciphering regulatory roles in stem cell potency, inflammatory resolve, and tissue regeneration. Front Genet 8:1–12

    Google Scholar 

  • Fei R, Zhang H, Zhong S, Xue B, Gao Y, Zhou X (2017) Anti-inflammatory activity of a thermophilic serine protease inhibitor from extremophile Pyrobaculumneutrophilum. European Journal of Inflammation 15:143–151

    CAS  Google Scholar 

  • Ferguson SW, Wang J, Lee CJ, Liu M, Neelamegham S, Canty JM, Nguyen J (2018) The microRNA regulatory landscape of MSC-derived exosomes: a systems view. Sci Rep 8:1419

    PubMed  PubMed Central  Google Scholar 

  • Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical Progress. Endocr Rev 25:581–611

    CAS  PubMed  Google Scholar 

  • Frazee A, Pertea G, Jaffe AE, Langmead B, Salzberg SL, Leek JT (2015) Ballgown bridges the gap between transcriptome assembly and expression analysis. Nat Biotechnol 33:243–246

    CAS  PubMed  PubMed Central  Google Scholar 

  • Furi I, Momen-Heravi F, Szabo G (2017) Extracellular vesicle isolation: present and future. Annals of Translational Medicine 5:263

    PubMed  PubMed Central  Google Scholar 

  • Gadani SP, Cronk JC, Norris GT, Kipnis J (2012) Interleukin-4: a cytokine to remember. J Immunol 189:4213–4219

    CAS  PubMed  Google Scholar 

  • Gao HM, Hong JS (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 29:357–365

    CAS  PubMed  PubMed Central  Google Scholar 

  • García MA, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M (2006) Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev 70:1032–1060

    PubMed  PubMed Central  Google Scholar 

  • GBD (2015) Neurological disorders collaborator group (2017) global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the global burden of disease study 2015. The Lancet Neurology 16:877–897

    Google Scholar 

  • Goldenberg MM (2012) Multiple sclerosis review. Pharmacy & Therapeutics 37:175–184

    Google Scholar 

  • Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C, Millard RW, Xiao DS, Ashraf M, Xu M (2017) Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget 8:45200–45212

    PubMed  PubMed Central  Google Scholar 

  • Gooch CL, Pracht E, Borenstein AR (2017) The burden of neurological disease in the United States: a summary report and call to action. Ann Neurol 81:479–484

    PubMed  Google Scholar 

  • Griffiths MJ, Bonnet D, Janes SM (2005) Stem cells of the alveolar epithelium. Lancet 366:249–260

    PubMed  Google Scholar 

  • Haraszti RA, Miller R, Stoppato M, Sere YY, Coles A, Didiot MC, Wollacott R, Sapp E, Dubuke ML, Li X, Shaffer SA, DiFiglia M, Wang Y, Aronin N, Khvorova A (2018) Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity. Mol Ther 26:2838–2847

    CAS  PubMed  PubMed Central  Google Scholar 

  • He Q, Wan C, Li G (2007) Concise review: multipotent mesenchymal stromal cells in blood. Stem Cells 25:69–77

    CAS  PubMed  Google Scholar 

  • Heinemann ML, Ilmer M, Silva LP, Hawke DH, Recio A, Vorontsova MA, Alt E, Vykoukal J (2014) Benchtop isolation and characterization of functional exosomes by sequential filtration. J Chromatogr A 1371:125–135

    CAS  PubMed  Google Scholar 

  • Heinemann ML, Vykoukal J (2017) Sequential filtration: a gentle method for the isolation of functional extracellular vesicles. Methods Mol Biol 1660:33–41

    CAS  PubMed  Google Scholar 

  • Hessvik NP, Llorente A (2018) Current knowledge on exosome biogenesis and release. Cell Mol Life Sci 75:193–208

    CAS  PubMed  Google Scholar 

  • Hirschi KK, Li S, Roy K (2014) Induced pluripotent stem cells for regenerative medicine. Annu Rev Biomed Eng 16:277–294

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580

    CAS  PubMed  Google Scholar 

  • Hu GW, Li Q, Niu X, Hu B, Liu J, Zhou SM, Guo SC, Lang HL, Zhang CQ, Wang Y, Deng ZF (2015) Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Research and Therapy 6:10

    PubMed  PubMed Central  Google Scholar 

  • Hung LY, Chen YJ, Mai TL, Chen CY, Yang MY, Chiang TW, Wang YD, Chuang TJ (2018) An evolutionary landscape of A-to-I RNA Editome across metazoan species. Genome Biology and Evolution 10:521–537

    CAS  PubMed  Google Scholar 

  • Husain B, Mukerji I, Cole JL (2012) Analysis of high affinity binding of PKR to dsRNA. Biochemistry 51:8764–8770

    CAS  PubMed  Google Scholar 

  • Jung JH, Fu X, Yang PC (2017) Exosomes generated from iPSC-derivatives: new direction for stem cell therapy in human heart diseases. Circ Res 120:407–417

    CAS  PubMed  PubMed Central  Google Scholar 

  • Katsuda T, Ochiya T (2015) Molecular signatures of mesenchymal stem cell-derived extracellular vesicle-mediated tissue repair. Stem Cell Research and Therapy 6:212

    PubMed  PubMed Central  Google Scholar 

  • Kaur S, Abu-Shahba AG, Paananen RO, Hongisto H, Hiidenmaa H, Skottman H, Seppänen-Kaijansinkko R, Mannerström B (2018) Small non-coding RNA landscape of extracellular vesicles from human stem cells. Sci Rep 8:15503

    PubMed  PubMed Central  Google Scholar 

  • Kesselheim AS, Hwang TJ, Franklin JM (2015) Two decades of new drug development for central nervous system disorders. Nat Rev Drug Discov 14:815–816

    CAS  PubMed  Google Scholar 

  • Kobayashi H, Ebisawa K, Kambe M, Kasai T, Suga H, Nakamura K, Narita Y, Ogata A, Kamei Y (2018) Effects of exosomes derived from the induced pluripotent stem cells on skin wound healing. Nagoya J Med Sci 80:141–153

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koniusz S, Andrzejewska A, Muraca M, Sriwastava AK, Janowski M, Lukomska B (2016) Extracellular vesicles in physiology, pathology, and therapy of the immune and central nervous system, with focus on extracellular vesicles derived from mesenchymal stem cells as therapeutic tools. Front Cell Neurosci 10:109

    PubMed  PubMed Central  Google Scholar 

  • Konoshenko MY, Lekchnov EA, Vlassov AV, Laktionov PP (2018) Isolation of extracellular vesicles: general methodologies and latest trends. Biomed Res Int 2018:8545347

    PubMed  PubMed Central  Google Scholar 

  • Koyuncu OO, Hogue IB, Enquist LW (2013) Virus infections in the nervous system. Cell Host Microbe 13:379–393

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lai RC, Yeo WWY, Lim SK (2015) Mesenchymal stem cell exosomes. Semin Cell Dev Biol 40:82–88

    CAS  PubMed  Google Scholar 

  • Liu S, Mahairaki V, Bai H, Ding Z, Li J, Witwer KW, Cheng L (2019) Highly purified human extracellular vesicles produced by stem cells alleviate aging cellular phenotypes of senescent human cells. Stem Cells 37:779–790

    CAS  PubMed  PubMed Central  Google Scholar 

  • Luzina IG, Keegan AD, Heller NM, Rook GA, Shea-Donohue T, Atamas SP (2012) Regulation of inflammation by interleukin-4: a review of "alternatives". J Leukoc Biol 92:753–764

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ma T, Chen Y, Chen Y, Meng Q, Sun J, Shao L, Yu Y, Huang H, Hu Y, Yang Z, Yang J, Shen Z (2018) MicroRNA-132, delivered by mesenchymal stem cell-derived exosomes, promote angiogenesis in myocardial infarction. Stem Cells Int 2018:3290372

    PubMed  PubMed Central  Google Scholar 

  • Maas SLN, Breakefield XO, Weaver AM (2017) Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol 27:172–188

    CAS  PubMed  Google Scholar 

  • Marote A, Teixeira FG, Mendes-Pinheiro B, Salgado AJ (2016) MSCs-derived exosomes: cell-secreted Nanovesicles with regenerative potential. Front Pharmacol 7:231

    PubMed  PubMed Central  Google Scholar 

  • Marquez-Curtis LA, Janowska-Wieczorek A, McGann LE, Elliott JA (2015) Mesenchymal stromal cells derived from various tissues: biological, clinical and cryopreservation aspects. Cryobiology 71:181–197

    CAS  PubMed  Google Scholar 

  • Martínez-Morales PL, Revilla A, Ocaña I, González C, Sainz P, McGuire D, Liste I (2013) Progress in stem cell therapy for major human neurological disorders. Stem Cell Rev 9:685–699

    Google Scholar 

  • McNamara RP, Caro-Vegas CP, Costantini LM, Landis JT, Griffith JD, Damania BA, Dittmer DP (2018) Large-scale, cross-flow based isolation of highly pure and endocytosis-competent extracellular vesicles. Journal of Extracellular Vesicles 7:1541396

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murakami M, Simons M (2008) Fibroblast growth factor regulation of neovascularization. Curr Opin Hematol 15:215–220

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nugent MA, Iozzo RV (2000) Fibroblast growth factor-2. Int J Biochem Cell Biol 32:115–120

    CAS  PubMed  Google Scholar 

  • Nussbaum RL, Ellis CE (2003) Alzheimer's disease and Parkinson's disease. N Engl J Med 348:1356–1364

    CAS  PubMed  Google Scholar 

  • O'Connell MA, Krause S, Higuchi M, Hsuan JJ, Totty NF, Jenny A, Keller W (1995) Cloning of cDNAs encoding mammalian double-stranded RNA-specific adenosine deaminase. Mol Cell Biol 15:1389–1397

    CAS  PubMed  PubMed Central  Google Scholar 

  • Olejniczak M, Galka P, Krzyzosiak WJ (2010) Sequence-non-specific effects of RNA interference triggers and microRNA regulators. Nucleic Acids Res 38:1–16

    CAS  PubMed  Google Scholar 

  • Omole AE, Fakoya AOJ (2018) Ten years of progress and promise of induced pluripotent stem cells: historical origins, characteristics, mechanisms, limitations, and potential applications. PeerJ 6:e4370

    PubMed  PubMed Central  Google Scholar 

  • Oswald J, Boxberger S, Jørgensen B, Feldmann S, Ehninger G, Bornhäuser M, Werner C (2004) Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22:277–384

    Google Scholar 

  • Păunescu V, Deak E, Herman D, Siska IR, Tănasie G, Bunu C, Anghel S, Tatu CA, Oprea TI, Henschler R, Rüster B, Bistrian R, Seifried E (2007) In vitro differentiation of human mesenchymal stem cells to epithelial lineage. J Cell Mol Med 11:502–508

    PubMed  PubMed Central  Google Scholar 

  • Pekny M, Pekna M, Messing A, Steinhäuser C, Lee JM, Parpura V, Hol EM, Sofroniew MV, Verkhratsky A (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345

    CAS  PubMed  Google Scholar 

  • Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL (2015) StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol 33:290–295

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pfaller CK, Li Z, George CX, Samuel CE (2011) Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old players as modulators of the interferon response. Curr Opin Immunol 23:573–582

    CAS  PubMed  PubMed Central  Google Scholar 

  • Phatnani H, Maniatis T (2015) Astrocytes in neurodegenerative disease. Cold Spring Harb Perspect Biol 7:6

    Google Scholar 

  • Phinney DG, Pittenger MF (2017) Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells 35:851–858

    CAS  PubMed  Google Scholar 

  • Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    CAS  PubMed  Google Scholar 

  • Prockop DJ, Oh JY (2012) Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther 20:14–20

    CAS  PubMed  Google Scholar 

  • Przybylski M (2009) A review of the current research on the role of bFGF and VEGF in angiogenesis. J Wound Care 18:516–519

    CAS  PubMed  Google Scholar 

  • Qi X, Zhang J, Yuan H, Xu Z, Li Q, Niu X, Hu B, Wang Y, Li X (2016) Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int J Biol Sci 12:836–849

    CAS  PubMed  PubMed Central  Google Scholar 

  • Radetskyy R, Daher A, Gatignol (2018) ADAR1 and PKR, interferon stimulated genes with clashing effects on HIV-1 replication. Cytokine Growth Factor Rev 40:48–58

  • Rankovic Z (2014) CNS drug design: balancing physicochemical properties for optimal brain exposure. J Med Chem 58:2584–2608

    Google Scholar 

  • Riazifar M, Pone EJ, Lötvall J, Zhao W (2017) Stem cell extracellular vesicles: extended messages of regeneration. Annu Rev Pharmacol Toxicol 57:125–154

    CAS  PubMed  Google Scholar 

  • Robinton DA, Daley GQ (2013) The promise of induced pluripotent stem cells in research and therapy. Nature 481:295–305

    Google Scholar 

  • Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM (2017) Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med 6:2173–2185

    PubMed  PubMed Central  Google Scholar 

  • Sayed N, Liu C, Wu JC (2016) Translation of human iPSCs: from clinical trial in a dish to precision medicine. J Am Coll Cardiol 67:2161–2176

    PubMed  PubMed Central  Google Scholar 

  • Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, Shapiro RL, Galloway AC, Rifkin DB, Mignatti P (1998) Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol 141:1659–1673

    CAS  PubMed  PubMed Central  Google Scholar 

  • Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, Young M, Robey PG, Wang CY, Shi S (2004) Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 364:149–155

    CAS  PubMed  Google Scholar 

  • Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Van Badiavas E (2015) Mesenchymal stem cell exosomes induce proliferation and migration of Normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev 24:1635–1647

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shah V, Kochar P (2018) Brain Cancer: implication to disease, therapeutic strategies and tumor targeted drug delivery approaches. Recent Patents on Anti-cancer Drug Discovery 13:70–85

    CAS  PubMed  Google Scholar 

  • Slotkin W, Nishikura K (2013) Adenosine-to-inosine RNA editing and human disease. Genome Medicine 5:105

    PubMed  PubMed Central  Google Scholar 

  • Song CG, Zhang YZ, Wu HN, Cao XL, Guo CJ, Li YQ, Zheng MH, Han H (2018) Stem cells: a promising candidate to treat neurological disorders. Neural Regen Res 13:1294–1304

    PubMed  PubMed Central  Google Scholar 

  • Soualmia F, El Amri C (2018) Serine protease inhibitors to treat inflammation: a patent review (2011-2016). Expert Opinion on Therapeutic Patents 28:93–110

    CAS  PubMed  Google Scholar 

  • Stephenson J, Nutma E, van der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative diseases. Immunology 154:204–219

    CAS  PubMed  PubMed Central  Google Scholar 

  • Swanson PA 2nd, McGavern DB (2015) Viral diseases of the central nervous system. Current Opinion in Virology 11:44–54

    PubMed  PubMed Central  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    CAS  PubMed  Google Scholar 

  • Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    CAS  PubMed  Google Scholar 

  • Toh WS, Lai RC, Zhang B, Lim SK (2018) MSC exosome works through a protein-based mechanism of action. Biochem Soc Trans 46:843–853

    CAS  PubMed  PubMed Central  Google Scholar 

  • Trounson A, McDonald C (2015) Stem cell therapies in clinical trials: Progress and challenges. Cell Stem Cell 17:11–22

    CAS  PubMed  Google Scholar 

  • Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8:726–736

    CAS  PubMed  Google Scholar 

  • Ullah I, Subbarao RB, Rho GJ (2015) Human mesenchymal stem cells - current trends and future prospective. Biosci Rep 35:2

    Google Scholar 

  • van Niel G, D'Angelo G, Raposo G (2018) Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19:213–228

    PubMed  Google Scholar 

  • Wang Y, Zhang L, Li Y, Chen L, Wang X, Guo W, Zhang X, Qin G, He SH, Zimmerman A, Liu Y, Kim IM, Weintraub NL, Tang Y (2015) Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol 192:61–69

    PubMed  PubMed Central  Google Scholar 

  • Wang N, Chen C, Yang D, Liao Q, Luo H, Wang X, Zhou F, Yang X, Yang J, Zeng C, Wang WE (2017) Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis. Biochim Biophys Acta Mol basis Dis 1863:2085–2092

    CAS  PubMed  Google Scholar 

  • Watson DC, Yung BC, Bergamaschi C, Chowdhury B, Bear J, Stellas D, Morales-Kastresana A, Jones JC, Felber BK, Chen X, Pavlakis GN (2018) Scalable, cGMP-compatible purification of extracellular vesicles carrying bioactive human heterodimeric IL-15/lactadherin complexes. Journal of Extracellular Vesicles 7:144208

    Google Scholar 

  • Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF (2013) Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin 34:747–754

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu L, Xia YP, Roth SI, Gruskin E, Mustoe TA (1999) Transforming growth factor-beta1 fails to stimulate wound healing and impairs its signal transduction in an aged ischemic ulcer model: importance of oxygen and age. Am J Pathol 154:301–309

    PubMed  PubMed Central  Google Scholar 

  • Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30:1556–1564

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M (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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Cai Y, Zhang Y, Liu J, Xu Z (2018) Exosomes secreted by adipose-derived stem cells contribute to angiogenesis of brain microvascular endothelial cells following oxygen-glucose deprivation in vitro through MicroRNA-181b/TRPM7 Axis. J Mol Neurosci 65:74–83

    CAS  PubMed  Google Scholar 

  • Yin PT, Han E, Lee KB (2016) Engineering stem cells for biomedical applications. Advanced Healthcare Materials 5:10–55

    CAS  PubMed  Google Scholar 

  • Yu B, Zhang X, Li X (2014) Exosomes derived from mesenchymal stem cells. Int J Mol Sci 15:4142–4157

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yun YR, Won JE, Jeon E, Lee S, Kang W, Jo H, Jang JH, Shin US, Kim HW (2010) Fibroblast growth factors: biology, function, and application for tissue regeneration. Journal of Tissue Engineering 2010:218142

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank all members of the Kashanchi lab, especially Catherine DeMarino, Michelle Pleet, and Gwen Cox for their contributions, as well as former ATCC colleague Alexei Miagkov for his contributions. We also would like express gratitude to members of ATCC senior management, especially Drs. Mindy Goldsborough and James Kramer for supporting this work. This work was further supported by National Institutes of Health (NIH) Grants (AI078859, AI074410, AI127351-01, AI043894, and NS099029 to FK) and (R33 CA206937 and R01AR068436 to LAL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd, Manassas, VA, 20110, USA

    Heather Branscome, Pooja Khatkar, Yuriy Kim, Robert A. Barclay, Daniel O. Pinto & Fatah Kashanchi

  2. American Type Culture Collection (ATCC), Manassas, VA, USA

    Heather Branscome

  3. ATCC Cell Systems, Gaithersburg, MD, USA

    Siddhartha Paul & Dezhong Yin

  4. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA

    Weidong Zhou & Lance A. Liotta

  5. Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA

    Nazira El-Hage

Authors
  1. Heather Branscome
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  2. Siddhartha Paul
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  11. Fatah Kashanchi
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Contributions

HB wrote and edited the manuscript. HB, SP, and DY contributed to the production of EVs used in these experiments. HB, SP, PK, DOP, RAB, YK, and WZ carried out experiments and contributed to data analysis. LAL contributed to the use of nanoparticles and NEH contributed to the experimental designs on repair. FK contributed to the overall direction and coordination of the study as well as contributions to experimental design and data analysis.

Corresponding author

Correspondence to Fatah Kashanchi.

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Competing Interests

HB, SP, and DY are employed by ATCC and LAL is affiliated with Ceres Nanosciences, Inc. All other authors declare no potential conflicts of interest.

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Branscome, H., Paul, S., Khatkar, P. et al. Stem Cell Extracellular Vesicles and their Potential to Contribute to the Repair of Damaged CNS Cells. J Neuroimmune Pharmacol 15, 520–537 (2020). https://doi.org/10.1007/s11481-019-09865-y

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