Exosomes and Stem Cells in Degenerative Disease Diagnosis and Therapy

Cell Transplantation

Volumn 27, Issue 3, 2018, Pages 349-363

  Chang, Yu Hsun ^a,b   Wu, Kung Chi ^a   Harn, Horng Jyh ^a   Lin, Shinn Zong ^a   Ding, Dah Ching ^a,b  

^a BUDDHIST TZU CHI GENERAL HOSPITAL   (Taiwan)

^b TZU CHI UNIVERSITY   (Taiwan)

Author keywords

exosomes; mesenchymal stem cells; miRNA; osteoarthritis; Parkinson s disease; stroke

Indexed keywords

ALPHA SYNUCLEIN; MICRORNA;

CELL COMMUNICATION; CELL DIFFERENTIATION; CEREBROSPINAL FLUID; CEREBROVASCULAR ACCIDENT; DEGENERATIVE DISEASE; EXOSOME; GENE CONTROL; HUMAN; IMMUNE RESPONSE; MESENCHYMAL STEM CELL TRANSPLANTATION; OSTEOARTHRITIS; PARKINSON DISEASE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; ANIMAL; MESENCHYMAL STEM CELL; METABOLISM; STEM CELL;

ANIMALS; EXOSOMES; EXTRACELLULAR VESICLES; HUMANS; MESENCHYMAL STEM CELLS; MICRORNAS; OSTEOARTHRITIS; PARKINSON DISEASE; STEM CELLS; STROKE;

EID: 85048269463     PISSN: 09636897     EISSN: 15553892     Source Type: Journal    
DOI: 10.1177/0963689717723636     Document Type: Review

References (200)

1. Lackland DT, Roccella EJ, Deutsch AF, Fornage M, George MG, Howard G, Kissela BM, Kittner SJ, Lichtman JH, Lisabeth LD. Factors influencing the decline in stroke mortality: a statement from the American heart association/American stroke association. Stroke. 2014;45(1):315–353.
2. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317–1329.
3. Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke. 2011;42(7):1952–1955.
4. Zivin JA. Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. Food and Drug Administration (FDA). Ann Neurol. 2009;66(1):6–10.
5. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–1030.
6. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, Yan B, Dowling RJ, Parsons MW, Oxley TJ. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–1018.
7. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20.
8. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4(5):399–415.
9. Gao LL, Wu T. The study of brain functional connectivity in Parkinson’s disease. Transl Neurodegener. 2016;5:18.
10. Pagonabarraga J, Kulisevsky J, Strafella AP, Krack P. Apathy in Parkinson’s disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol. 2015;14(5):518–531.
11. Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet. 2009;373(9680):2055–2066.
12. Murphy L, Helmick CG. The impact of osteoarthritis in the United States: a population-health perspective. Am J Nurs. 2012;112(3 suppl 1): S13–S19.
13. Yoshimura N, Muraki S, Nakamura K, Tanaka S. Epidemiology of the locomotive syndrome: the research on osteoarthritis/osteoporosis against disability study 2005-2015. Mod Rheumatol. 2017;27(1):1–7
14. Poulet B, Staines KA. New developments in osteoarthritis and cartilage biology. Curr Opin Pharmacol. 2016;28:8–13.
15. Xie F, Kovic B, Jin X, He X, Wang M, Silvestre C. Economic and humanistic burden of osteoarthritis: a systematic review of large sample studies. Pharmacoeconomics. 2016;34(11):1087–1100.
16. Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM, Kington RS, Lane NE, Nevitt MC, Zhang Y. Osteoarthritis: new insights. part 1: the disease and its risk factors. Ann Intern Med. 2000;133(8):635–646.
17. Palazzo C, Nguyen C, Lefevre-Colau MM, Rannou F, Poiraudeau S. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59(3):134–138.
18. Sinusas K. Osteoarthritis: diagnosis and treatment. Am Fam Physician. 2012;85(1):49–56.
19. Vissers MM, Bussmann JB, Verhaar JA, Arends LR, Furlan AD, Reijman M. Recovery of physical functioning after total hip arthroplasty: systematic review and meta-analysis of the literature. Phys Ther. 2011;91(5):615–629.
20. Liu XW, Zi Y, Xiang LB, Wang Y. Total hip arthroplasty: areview of advances, advantages and limitations. Int J Clin Exp Med. 2015;8(1):27–36.
21. Stiehler M, Goronzy J, Gunther KP. Total hip arthroplasty in overweight osteoarthritis patients. Orthopade. 2015;44(7):523–530.
22. Chang YH, Liu HW, Wu KC, Ding DC. Mesenchymal stem cells and their clinical applications in osteoarthritis. Cell Transplant. 2016;25(5):937–950.
23. Khillan JS. Generation of chondrocytes from embryonic stem cells. Methods Mol Biol. 2006;330:161–170.
24. Singh Khillan J. Differentiation of embryonic stem cells into cartilage cells. Curr Protoc Stem Cell Biol. 2007;Chapter 1: Unit 1F.1.
25. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–676.
26. Illich DJ, Demir N, Stojkovic M, Scheer M, Rothamel D, Neugebauer J, Hescheler J, Zoller JE. Concise review: induced pluripotent stem cells and lineage reprogramming: prospects for bone regeneration. Stem Cells. 2011;29(4):555–563.
27. Inui A, Iwakura T, Reddi AH. Human stem cells and articular cartilage regeneration. Cells. 2012;1(4):994–1009.
28. Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, Kim JE, Shim H, Shin JS, Shin IS. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014;32(5):1254–1266.
29. Baglio SR, Pegtel DM, Baldini N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol. 2012;3:359.
30. Lai CP, Breakefield XO. Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front Physiol. 2012;3:228.
31. Gyorgy B, Hung ME, Breakefield XO, Leonard JN. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol. 2015;55:439–464.
32. Zhang ZG, Zhang L, Tsang W, Goussev A, Powers C, Ho KL, Morris D, Smyth SS, Coller BS, Chopp M. Dynamic platelet accumulation at the site of the occluded middle cerebral artery and in downstream microvessels is associated with loss of microvascular integrity after embolic middle cerebral artery occlusion. Brain Res. 2001;912(2):181–194.
33. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359(9):938–949.
34. Garcia JH, Yoshida Y, Chen H, Li Y, Zhang ZG, Lian J, Chen S, Chopp M. Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Am J Pathol. 1993;142(2):623–635.
35. Rosenberg GA. Neurological diseases in relation to the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32(7):1139–1151.
36. Ding DC, Lin CH, Shyu WC, Lin SZ. Neural stem cells and stroke. Cell Transplant. 2013;22(4):619–630.
37. Nudo RJ. Postinfarct cortical plasticity and behavioral recovery. Stroke. 2007;38(suppl 2):840–845.
38. Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 2000;106(7):829–838.
39. Risau W. Mechanisms of angiogenesis. Nature. 1997;386(6626):671–674.
40. Carmeliet P. VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med. 2000;6(10):1102–1103.
41. Zhang ZG, Zhang L, Jiang Q, Chopp M. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res. 2002;90(3):284–288.
42. Plate KH. Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol. 1999;58(4):313–320.
43. Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009;8(5):491–500.
44. Miller FD, Gauthier-Fisher A. Home at last: neural stem cell niches defined. Cell Stem Cell. 2009;4(6):507–510.
45. Iwai M, Sato K, Kamada H, Omori N, Nagano I, Shoji M, Abe K. Temporal profile of stem cell division, migration, and differentiation from subventricular zone to olfactory bulb after transient forebrain ischemia in gerbils. J Cereb Blood Flow Metab. 2003;23(3):331–341.
46. Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26(50):13007–13016.
47. Silva-Vargas V, Crouch EE, Doetsch F. Adult neural stem cells and their niche: a dynamic duo during homeostasis, regeneration, and aging. Curr Opin Neurobiol. 2013;23(6):935–942.
48. Wang X, Mao X, Xie L, Sun F, Greenberg DA, Jin K. Conditional depletion of neurogenesis inhibits long-term recovery after experimental stroke in mice. PLoS One. 2012;7(6): e38932.
49. Young KM, Psachoulia K, Tripathi RB, Dunn SJ, Cossell L, Attwell D, Tohyama K, Richardson WD. Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling. Neuron. 2013;77(5):873–885.
50. Zatorre RJ, Fields RD, Johansen-Berg H. Plasticity in gray and white: neuroimaging changes in brain structure during learning. Nat Neurosci. 2012;15(4):528–536.
51. Zhang RL, Chopp M, Roberts C, Jia L, Wei M, Lu M, Wang X, Pourabdollah S, Zhang ZG. Ascl1 lineage cells contribute to ischemia-induced neurogenesis and oligodendrogenesis. J Cereb Blood Flow Metab. 2011;31(2):614–625.
52. Zhang RL, Chopp M, Roberts C, Wei M, Wang X, Liu X, Lu M, Zhang ZG. Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse. PLoS One. 2012;7(10): e48141.
53. Miyamoto N, Pham LD, Seo JH, Kim KW, Lo EH, Arai K. Crosstalk between cerebral endothelium and oligodendrocyte. Cell Mol Life Sci. 2014;71(6):1055–1066.
54. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5(6):525–535.
55. Goedert M, Jakes R, Anthony Crowther R, Grazia Spillantini M. Parkinson’s disease, dementia with lewy bodies, and multiple system atrophy as alpha-Synucleinopathies. Methods Mol Med. 2001;62:33–59.
56. Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature. 1988;334(6180):345–348.
57. Fortin DL, Nemani VM, Voglmaier SM, Anthony MD, Ryan TA, Edwards RH. Neural activity controls the synaptic accumulation of alpha-synuclein. J Neurosci. 2005;25(47):10913–10921.
58. Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;14(1):38–48.
59. Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN. Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci U S A. 2015;112(38): E5308–E5317.
60. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197–211.
61. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L. Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci U S A. 2001;98(21):12245–12250.
62. Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW. Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol. 2003;62(4):389–397.
63. Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM. Synergistic interactions between abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010;30(21):7281–7289.
64. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44(4):601–607.
65. Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y. A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2). Genomics. 1998;49(1):143–146.
66. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304(5674):1158–1160.
67. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299(5604):256–259.
68. Multiple-System Atrophy Research C. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med. 2013;369(3):233–244.
69. German DC, Manaye KF, White CL, IIIWoodward DJ, McIntire DD, Smith WK, Kalaria RN, Mann DM. Disease-specific patterns of locus coeruleus cell loss. Ann Neurol. 1992;32(5):667–676.
70. Jellinger KA. Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol. 1991;14(3):153–197.
71. Takahashi M, Yamada T. Viral etiology for Parkinson’s disease—a possible role of influenza A virus infection. Jpn J Infect Dis. 1999;52(3):89–98.
72. Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M, Panov AV, Cookson MR, Greenamyre JT. An in vitro model of Parkinson’s disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci. 2002;22(16):7006–7015.
73. Mizuno Y, Hattori N, Kitada T, Matsumine H, Mori H, Shimura H, Kubo S, Kobayashi H, Asakawa S, Minoshima S. Familial Parkinson’s disease. Alpha-synuclein and parkin. Adv Neurol. 2001;86:13–21.
74. Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS. Environmental risk factors and Parkinson’s disease: a metaanalysis. Environ Res. 2001;86(2):122–127.
75. Gordon GV, Villanueva T, Schumacher HR, Gohel V. Autopsy study correlating degree of osteoarthritis, synovitis and evidence of articular calcification. J Rheumatol. 1984;11(5):681–686.
76. Lindblad S, Hedfors E. Arthroscopic and immunohistologic characterization of knee joint synovitis in osteoarthritis. Arthritis Rheum. 1987;30(10):1081–1088.
77. Myers SL, Brandt KD, Ehlich JW, Braunstein EM, Shelbourne KD, Heck DA, Kalasinski LA. Synovial inflammation in patients with early osteoarthritis of the knee. J Rheumatol. 1990;17(12):1662–1669.
78. Liu-Bryan R. Inflammation and intracellular metabolism: new targets in OA. Osteoarthritis Cartilage. 2015;23(11):1835–1842.
79. Farahat MN, Yanni G, Poston R, Panayi GS. Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. Ann Rheum Dis. 1993;52(12):870–875.
80. Martel-Pelletier J, McCollum R, Fujimoto N, Obata K, Cloutier JM, Pelletier JP. Excess of metalloproteases over tissue inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis. Lab Invest. 1994;70(6):807–815.
81. Chevalier X, Conrozier T, Gehrmann M, Claudepierre P, Mathieu P, Unger S, Vignon E. Tissue inhibitor of metalloprotease-1 (TIMP-1) serum level may predict progression of hip osteoarthritis. Osteoarthritis Cartilage. 2001;9(4):300–307.
82. Bondeson J, Wainwright SD, Lauder S, Amos N, Hughes CE. The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Res Ther. 2006;8(6): R187.
83. Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA, American Heart A. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American heart association. Circulation. 2007;115(12):1634–1642.
84. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006;332(7553):1302–1308.
85. Philp AM, Davis ET, Jones SW. Developing anti-inflammatory therapeutics for patients with osteoarthritis. Rheumatology (Oxford), 2017;56(6):869–881.
86. Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant. 2011;20(1):5–14.
87. Ding DC, Shyu WC, Chiang MF, Lin SZ, Chang YC, Wang HJ, Su CY, Li H. Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis. 2007;27(3):339–353.
88. Liu SP, Ding DC, Wang HJ, Su CY, Lin SZ, Li H, Shyu WC. Nonsenescent Hsp27-upregulated MSCs implantation promotes neuroplasticity in stroke model. Cell Transplant. 2010;19(10):1261–1279.
89. Shyu WC, Lin SZ, Chiang MF, Su CY, Li H. Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. J Neurosci. 2006;26(13):3444–3453.
90. Shyu WC, Liu DD, Lin SZ, Li WW, Su CY, Chang YC, Wang HJ, Wang HW, Tsai CH, Li H. Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke. J Clin Invest. 2008;118(7):2482–2495.
91. Shyu WC, Lin SZ, Lee CC, Liu DD, Li H. Granulocyte colony-stimulating factor for acute ischemic stroke: a randomized controlled trial. CMAJ. 2006;174(7):927–933.
92. Chen DC, Lin SZ, Fan JR, Lin CH, Lee W, Lin CC, Liu YJ, Tsai CH, Chen JC, Cho DY. Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized phase II study. Cell Transplant. 2014;23(12):1599–1612.
93. Ding DC, Shyu WC, Lin SZ, Li H. Current concepts in adult stem cell therapy for stroke. Curr Med Chem. 2006;13(29):3565–3574.
94. Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res. 2000;61(4):364–370.
95. Offen D, Barhum Y, Levy YS, Burshtein A, Panet H, Cherlow T, Melamed E. Intrastriatal transplantation of mouse bone marrow-derived stem cells improves motor behavior in a mouse model of Parkinson’s disease. J Neural Transm Suppl 2007(72):133–143.
96. Bouchez G, Sensebe L, Vourc’h P, Garreau L, Bodard S, Rico A, Guilloteau D, Charbord P, Besnard JC, Chalon S. Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson’s disease. Neurochem Int. 2008;52(7):1332–1342.
97. Ye M, Wang XJ, Zhang YH, Lu GQ, Liang L, Xu JY, Sheng-Di C. Therapeutic effects of differentiated bone marrow stromal cell transplantation on rat models of Parkinson’s disease. Parkinsonism Relat Disord. 2007;13(1):44–49.
98. Delcroix GJ, Garbayo E, Sindji L, Thomas O, Vanpouille-Box C, Schiller PC, Montero-Menei CN. The therapeutic potential of human multipotent mesenchymal stromal cells combined with pharmacologically active microcarriers transplanted in hemi-parkinsonian rats. Biomaterials. 2011;32(6):1560–1573.
99. McCoy MK, Martinez TN, Ruhn KA, Wrage PC, Keefer EW, Botterman BR, Tansey KE, Tansey MG. Autologous transplants of adipose-derived adult stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson’s disease. Exp Neurol. 2008;210(1):14–29.
100. Mathieu P, Roca V, Gamba C, Del Pozo A, Pitossi F. Neuroprotective effects of human umbilical cord mesenchymal stromal cells in an immunocompetent animal model of Parkinson’s disease. J Neuroimmunol. 2012;246(1-2):43–50.
101. Fierro FA, Kalomoiris S, Sondergaard CS, Nolta JA. Effects on proliferation and differentiation of multipotent bone marrow stromal cells engineered to express growth factors for combined cell and gene therapy. Stem Cells. 2011;29(11):1727–1737.
102. Eberling JL, Kells AP, Pivirotto P, Beyer J, Bringas J, Federoff HJ, Forsayeth J, Bankiewicz KS. Functional effects of AAV2-GDNF on the dopaminergic nigrostriatal pathway in parkinsonian rhesus monkeys. Hum Gene Ther. 2009;20(5):511–518.
103. McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988;38(8):1285–1291.
104. Nagatsu T, Mogi M, Ichinose H, Togari A. Cytokines in Parkinson’s disease. J Neural Transm Suppl. 2000;58(7):143–151.
105. Kitamura Y, Itano Y, Kubo T, Nomura Y. Suppressive effect of FK-506, a novel immunosuppressant, against MPTP-induced dopamine depletion in the striatum of young C57BL/6 mice. J Neuroimmunol. 1994;50(2):221–224.
106. Matsumoto T, Cooper GM, Gharaibeh B, Meszaros LB, Li G, Usas A, Fu FH, Huard J. Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble Flt-1. Arthritis Rheum. 2009;60(5):1390–1405.
107. Toghraie FS, Chenari N, Gholipour MA, Faghih Z, Torabinejad S, Dehghani S, Ghaderi A. Treatment of osteoarthritis with infrapatellar fat pad derived mesenchymal stem cells in Rabbit. Knee. 2011;18(2):71–75.
108. Roberts S, Genever P, McCaskie A, De Bari C. Prospects of stem cell therapy in osteoarthritis. Regen Med. 2011;6(3):351–366.
109. Weissman IL. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science. 2000;287(5457):1442–1446.
110. Pers YM, Ruiz M, Noel D, Jorgensen C. Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives. Osteoarthritis Cartilage. 2015;23(11):2027–2035.
111. Luz-Crawford P, Noel D, Fernandez X, Khoury M, Figueroa F, Carrion F, Jorgensen C, Djouad F. Mesenchymal stem cells repress Th17 molecular program through the PD-1 pathway. PLoS One. 2012;7(9): e45272.
112. Jorgensen C, Noel D, Apparailly F, Sany J. Stem cells for repair of cartilage and bone: the next challenge in osteoarthritis and rheumatoid arthritis. Ann Rheum Dis. 2001;60(4):305–309.
113. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98(5):1076–1084.
114. Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol. 2007;213(2):341–347.
115. Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther. 2015;23(5):812–823.
116. Simpson RJ, Jensen SS, Lim JW. Proteomic profiling of exosomes: current perspectives. Proteomics. 2008;8(19):4083–4099.
117. Thery C. Exosomes: secreted vesicles and intercellular communications. F1000 Biol Rep. 2011;3:15.
118. Fruhbeis C, Frohlich D, Kuo WP, Kramer-Albers EM. Extracellular vesicles as mediators of neuron-glia communication. Front Cell Neurosci. 2013;7:182.
119. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–659.
120. Marote A, Teixeira FG, Mendes-Pinheiro B, Salgado AJ. MSCs-derived exosomes: cell-secreted nanovesicles with regenerative potential. Front Pharmacol. 2016;7:231.
121. Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C, Camussi G. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant. 2011;26(5):1474–1483.
122. Yeo RW, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, Lim SK. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65(3):336–341.
123. Chen TS, Arslan F, Yin Y, Tan SS, Lai RC, Choo AB, Padmanabhan J, Lee CN, de Kleijn DP, Lim SK. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med. 2011;9:47.
124. Clayton A, Mason MD. Exosomes in tumour immunity. Curr Oncol. 2009;16(3):46–49.
125. Anand PK. Exosomal membrane molecules are potent immune response modulators. Commun Integr Biol. 2010;3(5):405–408.
126. Bobrie A, Colombo M, Raposo G, Thery C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic. 2011;12(12):1659–1668.
127. Chaput N, Thery C. Exosomes: immune properties and potential clinical implementations. Semin Immunopathol. 2011;33(5):419–440.
128. Cossetti C, Smith JA, Iraci N, Leonardi T, Alfaro-Cervello C, Pluchino S. Extracellular membrane vesicles and immune regulation in the brain. Front Physiol. 2012;3:117.
129. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–593.
130. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161–1172.
131. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. 1998;4(5):594–600.
132. Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol. 1999;147(3):599–610.
133. Clayton A, Court J, Navabi H, Adams M, Mason MD, Hobot JA, Newman GR, Jasani B. Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. J Immunol Methods. 2001;247(1-2):163–174.
134. Bhatnagar S, Shinagawa K, Castellino FJ, Schorey JS. Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood. 2007;110(9):3234–3244.
135. Segura E, Amigorena S, Thery C. Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses. Blood Cells Mol Dis. 2005;35(2):89–93.
136. Muntasell A, Berger AC, Roche PA. T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J. 2007;26(19):4263–4272.
137. Denzer K, van Eijk M, Kleijmeer MJ, Jakobson E, de Groot C, Geuze HJ. Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J Immunol. 2000;165(3):1259–1265.
138. O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010;10(2):111–122.
139. Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, Gonzalez MA, Bernad A, Sanchez-Madrid F. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2011;2:282.
140. Koppler B, Cohen C, Schlondorff D, Mack M. Differential mechanisms of microparticle transfer toB cells and monocytes: anti-inflammatory propertiesof microparticles. Eur J Immunol. 2006;36(3):648–660.
141. Brown K, Sacks SH, Wong W. Extensive and bidirectional transfer of major histocompatibility complex class II molecules between donor and recipient cells in vivo following solid organ transplantation. FASEB J. 2008;22(11):3776–3784.
142. Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, Corbelli A, Fais S, Parmiani G, Rivoltini L. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res. 2006;66(18):9290–9298.
143. Wieckowski E, Whiteside TL. Human tumor-derived vs dendritic cell-derived exosomes have distinct biologic roles and molecular profiles. Immunol Res. 2006;36(1-3):247–254.
144. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J, Zhang L, Steinman L. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther. 2011;19(10):1769–1779.
145. Chen X, Liang H, Zhang J, Zen K, Zhang CY. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol. 2012;22(3):125–132.
146. Potolicchio I, Carven GJ, Xu X, Stipp C, Riese RJ, Stern LJ, Santambrogio L. Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J Immunol. 2005;175(4):2237–2243.
147. Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E. Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J. 2009;28(8):1043–1054.
148. Bianco F, Pravettoni E, Colombo A, Schenk U, Moller T, Matteoli M, Verderio C. Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol. 2005;174(11):7268–7277.
149. MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A. Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity. 2001;15(5):825–835.
150. Antonucci F, Turola E, Riganti L, Caleo M, Gabrielli M, Perrotta C, Novellino L, Clementi E, Giussani P, Viani P. Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. EMBO J. 2012;31(5):1231–1240.
151. Chironi GN, Boulanger CM, Simon A, Dignat-George F, Freyssinet JM, Tedgui A. Endothelial microparticles in diseases. Cell Tissue Res. 2009;335(1):143–151.
152. Morel O, Morel N, Jesel L, Freyssinet JM, Toti F. Microparticles: a critical component in the nexus between inflammation, immunity, and thrombosis. Semin Immunopathol. 2011;33(5):469–486.
153. Minagar A, Jy W, Jimenez JJ, Sheremata WA, Mauro LM, Mao WW, Horstman LL, Ahn YS. Elevated plasma endothelial microparticles in multiple sclerosis. Neurology. 2001;56(10):1319–1324.
154. Graner MW, Alzate O, Dechkovskaia AM, Keene JD, Sampson JH, Mitchell DA, Bigner DD. Proteomic and immunologic analyses of brain tumor exosomes. FASEB J. 2009;23(5):1541–1557.
155. Bu N, Wu H, Sun B, Zhang G, Zhan S, Zhang R, Zhou L. Exosome-loaded dendritic cells elicit tumor-specific CD8+ cytotoxic T cells in patients with glioma. J Neurooncol. 2011;104(3):659–667.
156. Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol. 2007;25(16):2288–2294.
157. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT, JrCarter BS, Krichevsky AM, Breakefield XO. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470–1476.
158. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10(5):619–624.
159. Iero M, Valenti R, Huber V, Filipazzi P, Parmiani G, Fais S, Rivoltini L. Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ. 2008;15(1):80–88.
160. Penfornis P, Vallabhaneni KC, Whitt J, Pochampally R. Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment. Int J Cancer. 2016;138(1):14–21.
161. Vallabhaneni KC, Penfornis P, Dhule S, Guillonneau F, Adams KV, Mo YY, Xu R, Liu Y, Watabe K, Vemuri MC. Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites. Oncotarget. 2015;6(7):4953–4967.
162. Zhang ZG, Chopp M. Promoting brain remodeling to aid in stroke recovery. Trends Mol Med. 2015;21(9):543–548.
163. Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33(11):1711–1715.
164. Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, Zhang ZG, Chopp M. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013;31(12):2737–2746.
165. Wong CH, Jenne CN, Lee WY, Leger C, Kubes P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science. 2011;334(6052):101–105.
166. Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, Ruscher K, Victorov IV, Priller J, Dirnagl U. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med. 2003;198(5):725–736.
167. Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig AK, Radtke S, de Miroschedji K, Horn PA, Giebel B, Hermann DM. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015;4(10):1131–1143.
168. Xin H, Wang F, Li Y, Lu QE, Cheung WL, Zhang Y, Zhang ZG, Chopp M. 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-overexpressed multipotent mesenchymal stromal cells. Cell Transplant. 2017;26(2):243–257.
169. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30(7):1556–1564.
170. Holtje M, Djalali S, Hofmann F, Munster-Wandowski A, Hendrix S, Boato F, Dreger SC, Grosse G, Henneberger C, Grantyn R. A 29-amino acid fragment of Clostridium botulinum C3 protein enhances neuronal outgrowth, connectivity, and reinnervation. FASEB J. 2009;23(4):1115–1126.
171. El Bassit G, Patel RS, Carter G, Shibu V, Patel A, Song S, Murr M, Cooper DR, Bickford PC, Patel NA. MALAT1 in human adipose stem cells modulates survival and alternative splicing of PKCdeltaII in HT22 cells. Endocrinology. 2017;158(1):183–195. doi:10.1210/en.2016-1819.
172. Chen KH, Chen CH, Wallace CG, Yuen CM, Kao GS, Chen YL, Shao PL, Chen YL, Chai HT, Lin KC. 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. 2016;7(46):74537–74556.
173. Cui C, Ye X, Chopp M, Venkat P, Zacharek A, Yan T, Ning R, Yu P, Cui G, Chen J. miR-145 Regulates diabetes-bone marrow stromal cell-induced neurorestorative effects in diabetes stroke rats. Stem Cells Transl Med. 2016;5(12):1656–1667.
174. Ji Q, Ji Y, Peng J, Zhou X, Chen X, Zhao H, Xu T, Chen L, Xu Y. Increased brain-specific MiR-9 and MiR-124 in the serum exosomes of acute Ischemic stroke patients. PLoS One. 2016;11(9): e0163645.
175. Fraser KB, Moehle MS, Alcalay RN, West AB, Consortium LC. Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019 S LRRK2 carriers. Neurology. 2016;86(11):994–999.
176. Fraser KB, Rawlins AB, Clark RG, Alcalay RN, Standaert DG, Liu N, Parkinson’s Disease Biomarker Program C, West AB. Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson’s disease. Mov Disord. 2016;31(10):1543–1550.
177. Ho DH, Yi S, Seo H, Son I, Seol W. Increased DJ-1 in urine exosome of Korean males with Parkinson’s disease. Biomed Res Int. 2014;2014:704678.
178. Shi M, Kovac A, Korff A, Cook TJ, Ginghina C, Bullock KM, Yang L, Stewart T, Zheng D, Aro P. CNS tau efflux via exosomes is likely increased in Parkinson’s disease but not in Alzheimer’s disease. Alzheimers Dement. 2016;12(11):1125–1131.
179. Grey M, Dunning CJ, Gaspar R, Grey C, Brundin P, Sparr E, Linse S. Acceleration of alpha-synuclein aggregation by exosomes. J Biol Chem. 2015;290(5):2969–2982.
180. Stuendl A, Kunadt M, Kruse N, Bartels C, Moebius W, Danzer KM, Mollenhauer B, Schneider A. Induction of alpha-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies. Brain. 2016;139(Pt 2):481–494.
181. Bliederhaeuser C, Grozdanov V, Speidel A, Zondler L, Ruf WP, Bayer H, Kiechle M, Feiler MS, Freischmidt A, Brenner D. Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. Acta Neuropathol. 2016;131(3):379–391.
182. Gui Y, Liu H, Zhang L, Lv W, Hu X. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget. 2015;6(35):37043–7053.
183. Jarmalaviciute A, Tunaitis V, Pivoraite U, Venalis A, Pivoriunas A. Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis. Cytotherapy. 2015;17(7):932–939.
184. Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A, Sokolsky M, Kabanov AV. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. 2015;207:18–30.
185. Heldens GT, Blaney Davidson EN, Vitters EL, Schreurs BW, Piek E, van den Berg WB, van der Kraan PM. Catabolic factors and osteoarthritis-conditioned medium inhibit chondrogenesis of human mesenchymal stem cells. Tissue Eng Part A. 2012;18(1-2):45–54.
186. Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, Li H, Liu Z, Shi C, Duan F. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res. 2016;64(4):831–840.
187. Zhang S, Chu WC, Lai RC, Lim SK, Hui JH, Toh WS. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis Cartilage. 2016;24(12):2135–2140.
188. Le LT, Swingler TE, Clark IM. Review: the role of microRNAs in osteoarthritis and chondrogenesis. Arthritis Rheum. 2013;65(8):1963–1974.
189. Miyaki S, Nakasa T, Otsuki S, Grogan SP, Higashiyama R, Inoue A, Kato Y, Sato T, Lotz MK, Asahara H. MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum. 2009;60(9):2723–2730.
190. Meng F, Zhang Z, Chen W, Huang G, He A, Hou C, Long Y, Yang Z, Zhang Z, Liao W. MicroRNA-320 regulates matrix metalloproteinase-13 expression in chondrogenesis and interleukin-1beta-induced chondrocyte responses. Osteoarthritis Cartilage. 2016;24(5):932–941.
191. Swingler TE, Wheeler G, Carmont V, Elliott HR, Barter MJ, Abu-Elmagd M, Donell ST, Boot-Handford RP, Hajihosseini MK, Munsterberg A. The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis Rheum. 2012;64(6):1909–1919.
192. Song J, Lee M, Kim D, Han J, Chun CH, Jin EJ. MicroRNA-181b regulates articular chondrocytes differentiation and cartilage integrity. Biochem Biophys Res Commun. 2013;431(2):210–214.
193. Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Perez Lanzon M, Zini N, Naaijkens B, Perut F, Niessen HW, Baldini N. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 2015;6:127.
194. Salomon C, Ryan J, Sobrevia L, Kobayashi M, Ashman K, Mitchell M, Rice GE. Exosomal signaling during hypoxia mediates microvascular endothelial cell migration and vasculogenesis. PLoS One. 2013;8(7): e68451.
195. Zhou Y, Xu H, Xu W, Wang B, Wu H, Tao Y, Zhang B, Wang M, Mao F, Yan Y. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther. 2013;4(2):34.
196. Hess DC, Borlongan CV. Cell-based therapy in ischemic stroke. Expert Rev Neurother. 2008;8(8):1193–1201.
197. Meckes DG, JrGunawardena HP, Dekroon RM, Heaton PR, Edwards RH, Ozgur S, Griffith JD, Damania B, Raab-Traub N. Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proc Natl Acad Sci U S A. 2013;110(31): E2925–E2933.
198. Gheldof D, Mullier F, Chatelain B, Dogne JM, Chatelain C. Inhibition of tissue factor pathway inhibitor increases the sensitivity of thrombin generation assay to procoagulant microvesicles. Blood Coagul Fibrinolysis. 2013;24(5):567–572.
199. Chen K, Page JG, Schwartz AM, Lee TN, DeWall SL, Sikkema DJ, Wang C. False-positive immunogenicity responses are caused by CD20+ B cell membrane fragments in an anti-ofatumumab antibody bridging assay. J Immunol Methods. 2013;394(1-2):22–31.
200. Lai RC, Yeo RW, Tan KH, Lim SK. Exosomes for drug delivery - a novel application for the mesenchymal stem cell. Biotechnol Adv. 2013;31(5):543–551.