BMB Reports

생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
권호 표지
DOI QR코드

DOI QR Code

Stem cell-derived extracellular vesicle therapy for acute brain insults and neurodegenerative diseases

  • Bang, Oh Young (Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Ji-Eun (Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center)
  • 투고 : 2021.10.21
  • 심사 : 2021.12.26
  • 발행 : 2022.01.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Stem cell-based therapy is a promising approach for treating a variety of disorders, including acute brain insults and neurodegenerative diseases. Stem cells such as mesenchymal stem cells (MSCs) secrete extracellular vesicles (EVs), circular membrane fragments (30 nm-1 ㎛) that are shed from the cell surface, carrying several therapeutic molecules such as proteins and microRNAs. Because EV-based therapy is superior to cell therapy in terms of scalable production, biodistribution, and safety profiles, it can be used to treat brain diseases as an alternative to stem cell therapy. This review presents evidences evaluating the role of stem cell-derived EVs in stroke, traumatic brain injury, and degenerative brain diseases, such as Alzheimer's disease and Parkinson' disease. In addition, stem cell-derived EVs have better profiles in biocompatibility, immunogenicity, and safety than those of small chemical and macromolecules. The advantages and disadvantages of EVs compared with other strategies are discussed. Even though EVs obtained from native stem cells have potential in the treatment of brain diseases, the successful clinical application is limited by the short half-life, limited targeting, rapid clearance after application, and insufficient payload. We discuss the strategies to enhance the efficacy of EV therapeutics. Finally, EV therapies have yet to be approved by the regulatory authorities. Major issues are discussed together with relevant advances in the clinical application of EV therapeutics.

키워드

과제정보

This research was in part supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C3484).

참고문헌

  1. Bang OY (2017) Neuroprotective strategies for acute ischemic stroke: recent progress and future perspectives. Precis Future Med 1, 115-121 https://doi.org/10.23838/pfm.2017.00149
  2. Kordower JH and Bjorklund A (2013) Trophic factor gene therapy for Parkinson's disease. Mov Disord 28, 96-109 https://doi.org/10.1002/mds.25344
  3. Lo EH (2008) A new penumbra: transitioning from injury into repair after stroke. Nat Med 14, 497-500 https://doi.org/10.1038/nm1735
  4. Lyden PD (2021) Cerebroprotection for acute ischemic stroke: looking ahead. Stroke 52, 3033-3044 https://doi.org/10.1161/STROKEAHA.121.032241
  5. Rufino-Ramos D, Albuquerque PR, Carmona V, Perfeito R, Nobre RJ and Pereira de Almeida L (2017) Extracellular vesicles: novel promising delivery systems for therapy of brain diseases. J Control Release 262, 247-258 https://doi.org/10.1016/j.jconrel.2017.07.001
  6. Lee JS, Hong JM, Moon GJ et al (2010) A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28, 1099-1106 https://doi.org/10.1002/stem.430
  7. Prasad K, Sharma A, Garg A et al (2014) Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke 45, 3618-3624 https://doi.org/10.1161/STROKEAHA.114.007028
  8. Hess DC, Wechsler LR, Clark WM et al (2017) Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 16, 360-368 https://doi.org/10.1016/S1474-4422(17)30046-7
  9. Chung JW, Chang WH, Bang OY et al (2021) Efficacy and safety of intravenous mesenchymal stem cells for ischemic stroke. Neurology 96, e1012-e1023 https://doi.org/10.1212/WNL.0000000000011440
  10. Zagrean AM, Hermann DM, Opris I, Zagrean L and Popa-Wagner A (2018) Multicellular crosstalk between exosomes and the neurovascular unit after cerebral ischemia. Therapeutic implications. Front Neurosci 12, 811 https://doi.org/10.3389/fnins.2018.00811
  11. Brites D (2020) Regulatory function of microRNAs in microglia. Glia 68, 1631-1642 https://doi.org/10.1002/glia.23846
  12. Choi Y, Kim SM, Heo Y, Lee G, Kang JY and Yoon DS (2021) Nanoelectrical characterization of individual exosomes secreted by Abeta42-ingested cells using electrostatic force microscopy. Nanotechnology 32, 025705 https://doi.org/10.1088/1361-6528/abba58
  13. Crewe C, Funcke JB, Li S et al (2021) Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab 33, 1853-1868 e1811 https://doi.org/10.1016/j.cmet.2021.08.002
  14. O'Brien CG, Ozen MO, Ikeda G et al (2021) Mitochondria-rich extracellular vesicles rescue patient-specific cardiomyocytes from doxorubicin injury: insights into the SENECA trial. JACC CardioOncol 3, 428-440 https://doi.org/10.1016/j.jaccao.2021.05.006
  15. D'Souza A, Burch A, Dave KM et al (2021) Microvesicles transfer mitochondria and increase mitochondrial function in brain endothelial cells. J Control Release 338, 505-526 https://doi.org/10.1016/j.jconrel.2021.08.038
  16. Nam GH, Choi Y, Kim GB, Kim S, Kim SA and Kim IS (2020) Emerging prospects of exosomes for cancer treatment: from conventional therapy to immunotherapy. Adv Mater 32, e2002440
  17. 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 https://doi.org/10.1186/s13287-020-01601-1
  18. Wen S, Dooner M, Papa E et al (2019) Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a radiation injury bone marrow murine model. Int J Mol Sci 20, 5468 https://doi.org/10.3390/ijms20215468
  19. Mirzaaghasi A, Han Y, Ahn SH, Choi C and Park JH (2021) Biodistribution and pharmacokinectics of liposomes and exosomes in a mouse model of sepsis. Pharmaceutics 13, 427 https://doi.org/10.3390/pharmaceutics13030427
  20. 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 https://doi.org/10.1155/2012/971907
  21. Biancone L, Bruno S, Deregibus MC, Tetta C and Camussi G (2012) Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant 27, 3037-3042 https://doi.org/10.1093/ndt/gfs168
  22. Karp JM and Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4, 206-216 https://doi.org/10.1016/j.stem.2009.02.001
  23. Le Saux S, Aubert-Pouessel A, Mohamed KE et al (2021) Interest of extracellular vesicles in regards to lipid nanoparticle based systems for intracellular protein delivery. Adv Drug Deliv Rev 176, 113837 https://doi.org/10.1016/j.addr.2021.113837
  24. Muhammad SA, Nordin N, Mehat MZ and Fakurazi S (2019) Comparative efficacy of stem cells and secretome in articular cartilage regeneration: a systematic review and meta-analysis. Cell Tissue Res 375, 329-344 https://doi.org/10.1007/s00441-018-2884-0
  25. Zheng X, Hermann DM, Bahr M and Doeppner TR (2021) The role of small extracellular vesicles in cerebral and myocardial ischemia-Molecular signals, treatment targets, and future clinical translation. Stem Cells 39, 403-413 https://doi.org/10.1002/stem.3329
  26. 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 https://doi.org/10.1186/s13578-020-00427-x
  27. Loukogeorgakis SP and De Coppi P (2017) Concise review: amniotic fluid stem cells: the known, the unknown, and potential regenerative medicine applications. Stem Cells 35, 1663-1673 https://doi.org/10.1002/stem.2553
  28. Johnson J, Shojaee M, Mitchell Crow J and Khanabdali R (2021) From mesenchymal stromal cells to engineered extracellular vesicles: a new therapeutic paradigm. Front Cell Dev Biol 9, 705676 https://doi.org/10.3389/fcell.2021.705676
  29. Upadhya R, Madhu LN, Attaluri S et al (2020) Extracellular vesicles from human iPSC-derived neural stem cells: miRNA and protein signatures, and anti-inflammatory and neurogenic properties. J Extracell Vesicles 9, 1809064 https://doi.org/10.1080/20013078.2020.1809064
  30. Webb RL, Kaiser EE, Scoville SL et al (2018) Human neural stem cell extracellular vesicles improve tissue and functional recovery in the murine thromboembolic stroke model. Transl Stroke Res 9, 530-539 https://doi.org/10.1007/s12975-017-0599-2
  31. Bang OY and Kim EH (2019) Mesenchymal stem cell-derived extracellular vesicle therapy for stroke: challenges and progress. Front Neurol 10, 211 https://doi.org/10.3389/fneur.2019.00211
  32. Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG and 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 https://doi.org/10.1038/jcbfm.2013.152
  33. Kalani A, Chaturvedi P, Kamat PK et al (2016) Curcuminloaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury. Int J Biochem Cell Biol 79, 360-369 https://doi.org/10.1016/j.biocel.2016.09.002
  34. Webb RL, Kaiser EE, Jurgielewicz BJ et al (2018) Human neural stem cell extracellular vesicles improve recovery in a porcine model of ischemic stroke. Stroke 49, 1248-1256 https://doi.org/10.1161/STROKEAHA.117.020353
  35. Cha JM, Shin EK, Sung JH et al (2018) Efficient scalable production of therapeutic microvesicles derived from human mesenchymal stem cells. Sci Rep 8, 1171 https://doi.org/10.1038/s41598-018-19211-6
  36. 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 https://doi.org/10.1007/s12975-018-0668-1
  37. 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 https://doi.org/10.1038/srep33038
  38. 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 https://doi.org/10.1523/jneurosci.2226-19.2020
  39. Gao W, Li F, Liu L et al (2018) Endothelial colony-forming cell-derived exosomes restore blood-brain barrier continuity in mice subjected to traumatic brain injury. Exp Neurol 307, 99-108 https://doi.org/10.1016/j.expneurol.2018.06.001
  40. Chen W, Zheng P, Hong T et al (2020) Astrocytes-derived exosomes induce neuronal recovery after traumatic brain injury via delivering gap junction alpha 1-20 k. J Tissue Eng Regen Med 14, 412-423 https://doi.org/10.1002/term.3002
  41. 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 https://doi.org/10.1016/j.neuint.2016.08.003
  42. Williams AM, Bhatti UF, Brown JF et al (2020) Early single-dose treatment with exosomes provides neuroprotection and improves blood-brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock. J Trauma Acute Care Surg 88, 207-218 https://doi.org/10.1097/ta.0000000000002563
  43. Yin Z, Han Z, Hu T et al (2020) Neuron-derived exosomes with high miR-21-5p expression promoted polarization of M1 microglia in culture. Brain Behav Immun 83, 270-282 https://doi.org/10.1016/j.bbi.2019.11.004
  44. Long X, Yao X, Jiang Q et al (2020) Astrocyte-derived exosomes enriched with miR-873a-5p inhibit neuroinflammation via microglia phenotype modulation after traumatic brain injury. J Neuroinflammation 17, 89 https://doi.org/10.1186/s12974-020-01761-0
  45. Soares Martins T, Trindade D, Vaz M et al (2021) Diagnostic and therapeutic potential of exosomes in Alzheimer's disease. J Neurochem 156, 162-181 https://doi.org/10.1111/jnc.15112
  46. Elia CA, Tamborini M, Rasile M et al (2019) Intracerebral injection of extracellular vesicles from mesenchymal stem cells exerts reduced abeta plaque burden in early stages of a preclinical model of Alzheimer's disease. Cells 8, 1059 https://doi.org/10.3390/cells8091059
  47. Losurdo M, Pedrazzoli M, D'Agostino C et al (2020) Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer's disease. Stem Cells Transl Med 9, 1068-1084 https://doi.org/10.1002/sctm.19-0327
  48. Ma X, Huang M, Zheng M et al (2020) ADSCs-derived extracellular vesicles alleviate neuronal damage, promote neurogenesis and rescue memory loss in mice with Alzheimer's disease. J Control Release 327, 688-702 https://doi.org/10.1016/j.jconrel.2020.09.019
  49. Cone AS, Yuan X, Sun L et al (2021) Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer's disease-like phenotypes in a preclinical mouse model. Theranostics 11, 8129-8142 https://doi.org/10.7150/thno.62069
  50. Cui GH, Wu J, Mou FF et al (2018) Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J 32, 654-668 https://doi.org/10.1096/fj.201700600r
  51. Narbute K, Pilipenko V, Pupure J et al (2019) Intranasal administration of extracellular vesicles derived from human teeth stem cells improves motor symptoms and normalizes tyrosine hydroxylase expression in the substantia nigra and striatum of the 6-Hydroxydopamine-treated rats. Stem Cells Transl Med 8, 490-499 https://doi.org/10.1002/sctm.18-0162
  52. Cui GH, Zhu J, Wang YC, Wu J, Liu JR and Guo HD (2021) Effects of exosomal miRNAs in the diagnosis and treatment of Alzheimer's disease. Mech Ageing Dev 200, 111593 https://doi.org/10.1016/j.mad.2021.111593
  53. Katsuda T, Tsuchiya R, Kosaka N et al (2013) Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep 3, 1197 https://doi.org/10.1038/srep01197
  54. Li X, Zhang J, Zhang X and Dong M (2020) Puerarin suppresses MPP(+)/MPTP-induced oxidative stress through an Nrf2-dependent mechanism. Food Chem Toxicol 144, 111644 https://doi.org/10.1016/j.fct.2020.111644
  55. Izco M, Blesa J, Schleef M et al (2019) Systemic exosomal delivery of shRNA minicircles prevents parkinsonian pathology. Mol Ther 27, 2111-2122 https://doi.org/10.1016/j.ymthe.2019.08.010
  56. Chen HX, Liang FC, Gu P et al (2020) Exosomes derived from mesenchymal stem cells repair a Parkinson's disease model by inducing autophagy. Cell Death Dis 11, 288 https://doi.org/10.1038/s41419-020-2473-5
  57. Akkoc Y and Gozuacik D (2020) MicroRNAs as major regulators of the autophagy pathway. Biochim Biophys Acta Mol Cell Res 1867, 118662 https://doi.org/10.1016/j.bbamcr.2020.118662
  58. Jeon I, Cicchetti F, Cisbani G et al (2016) Human-to-mouse prion-like propagation of mutant huntingtin protein. Acta Neuropathol 132, 577-592 https://doi.org/10.1007/s00401-016-1582-9
  59. Didiot MC, Hall LM, Coles AH et al (2016) Exosome-mediated delivery of hydrophobically modified siRNA for Huntingtin mRNA silencing. Mol Ther 24, 1836-1847 https://doi.org/10.1038/mt.2016.126
  60. 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 https://doi.org/10.1161/STROKEAHA.119.028012
  61. 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, 447-467 https://doi.org/10.1007/s00018-020-03600-0
  62. de Almeida Fuzeta M, Bernardes N, Oliveira FD et al (2020) Scalable production of human mesenchymal stromal cell-derived extracellular vesicles under serum-/xenofree conditions in a microcarrier-based bioreactor culture system. Front Cell Dev Biol 8, 553444 https://doi.org/10.3389/fcell.2020.553444
  63. 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 https://doi.org/10.33594/000000090
  64. Khan H, Pan JJ, Li Y, Zhang Z and Yang GY (2021) Native and bioengineered exosomes for ischemic stroke therapy. Front Cell Dev Biol 9, 619565 https://doi.org/10.3389/fcell.2021.619565
  65. Chen CC, Liu L, Ma F et al (2016) Elucidation of exosome migration across the blood-brain barrier model in vitro. Cell Mol Bioeng 9, 509-529 https://doi.org/10.1007/s12195-016-0458-3
  66. Yuan D, Zhao Y, Banks WA et al (2017) Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials 142, 1-12 https://doi.org/10.1016/j.biomaterials.2017.07.011
  67. 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 https://doi.org/10.3402/jev.v4.26316
  68. Gholamrezanezhad A, Mirpour S, Bagheri M et al (2011) In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl Med Biol 38, 961-967 https://doi.org/10.1016/j.nucmedbio.2011.03.008
  69. Banks WA, Sharma P, Bullock KM, Hansen KM, Ludwig N and Whiteside TL (2020) Transport of extracellular vesicles across the blood-brain barrier: brain pharmacokinetics and effects of inflammation. Int J Mol Sci 21, 4407 https://doi.org/10.3390/ijms21124407
  70. Saint-Pol J, Gosselet F, Duban-Deweer S, Pottiez G and Karamanos Y (2020) Targeting and crossing the bloodbrain barrier with extracellular vesicles. Cells 9, 851 https://doi.org/10.3390/cells9040851
  71. Zhao Z and Zlokovic BV (2017) Remote control of BBB: A tale of exosomes and microRNA. Cell Res 27, 849- 850 https://doi.org/10.1038/cr.2017.71
  72. Zhao C, Wang H, Xiong C and Liu Y (2018) Hypoxic glioblastoma release exosomal VEGF-A induce the permeability of blood-brain barrier. Biochem Biophys Res Commun 502, 324-331 https://doi.org/10.1016/j.bbrc.2018.05.140
  73. Durcin M, Fleury A, Taillebois E et al (2017) Characterisation of adipocyte-derived extracellular vesicle subtypes identifies distinct protein and lipid signatures for large and small extracellular vesicles. J Extracell Vesicles 6, 1305677 https://doi.org/10.1080/20013078.2017.1305677
  74. Wei Z, Chen Z, Zhao Y et al (2021) Mononuclear phagocyte system blockade using extracellular vesicles modified with CD47 on membrane surface for myocardial infarction reperfusion injury treatment. Biomaterials 275, 121000 https://doi.org/10.1016/j.biomaterials.2021.121000
  75. Murphy DE, de Jong OG, Brouwer M et al (2019) Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking. Exp Mol Med 51, 1-12
  76. Cunningham CJ, Redondo-Castro E and Allan SM (2018) The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb Blood Flow Metab 38, 1276-1292 https://doi.org/10.1177/0271678X18776802
  77. Park KS, Bandeira E, Shelke GV, Lasser C and Lotvall J (2019) Enhancement of therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther 10, 288 https://doi.org/10.1186/s13287-019-1398-3
  78. Millan C, Prause L, Vallmajo-Martin Q, Hensky N and Eberli D (2021) Extracellular vesicles from 3D engineered microtissues harbor disease-related cargo absent in EVs from 2D cultures. Adv Healthc Mater, e2002067
  79. Pauwels MJ, Vandendriessche C and Vandenbroucke RE (2021) Special delEVery: extracellular vesicles as promising delivery platform to the brain. Biomedicines 9, 1734 https://doi.org/10.3390/biomedicines9111734
  80. Wiklander OPB, Brennan MA, Lotvall J, Breakefield XO and El Andaloussi S (2019) Advances in therapeutic applications of extracellular vesicles. Sci Transl Med 11, eaav8521 https://doi.org/10.1126/scitranslmed.aav8521
  81. Lino MM, Simoes S, Tomatis F et al (2021) Engineered extracellular vesicles as brain therapeutics. J Control Release 338, 472-485 https://doi.org/10.1016/j.jconrel.2021.08.037
  82. Pedrioli G, Piovesana E, Vacchi E and Balbi C (2021) Extracellular vesicles as promising carriers in drug delivery: considerations from a cell biologist's perspective. Biology (Basel) 10, 376
  83. Crescitelli R, Lasser C, Szabo TG et al (2013) Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles 2, 1-10
  84. Zhang ZG, Buller B and Chopp M (2019) Exosomes - beyond stem cells for restorative therapy in stroke and neurological injury. Nat Rev Neurol 15, 193-203 https://doi.org/10.1038/s41582-018-0126-4
  85. Yang J, Zhang X, Chen X, Wang L and Yang G (2017) Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia. Mol Ther Nucleic Acids 7, 278-287 https://doi.org/10.1016/j.omtn.2017.04.010
  86. Xin H, Li Y, Liu Z et al (2013) 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 31, 2737-2746 https://doi.org/10.1002/stem.1409
  87. Xin H, Katakowski M, Wang F et al (2017) MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke 48, 747-753 https://doi.org/10.1161/STROKEAHA.116.015204
  88. D'Souza A, Dave KM, Stetler RA and D SM (2021) Targeting the blood-brain barrier for the delivery of stroke therapies. Adv Drug Deliv Rev 171, 332-351 https://doi.org/10.1016/j.addr.2021.01.015
  89. Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2, 24-32 https://doi.org/10.1038/35049004
  90. Ahn EH, Kang SS and Ye K (2021) Netrin-1/receptors regulate the pathogenesis in Parkinson's diseases. Precis Future Med 5, 50-61 https://doi.org/10.23838/pfm.2020.00177
  91. Yang J, Wu S, Hou L et al (2020) Therapeutic effects of simultaneous delivery of nerve growth factor mRNA and protein via exosomes on cerebral ischemia. Mol Ther Nucleic Acids 21, 512-522 https://doi.org/10.1016/j.omtn.2020.06.013
  92. Zha Y, Li Y, Lin T, Chen J, Zhang S and Wang J (2021) Progenitor cell-derived exosomes endowed with VEGF plasmids enhance osteogenic induction and vascular remodeling in large segmental bone defects. Theranostics 11, 397-409 https://doi.org/10.7150/thno.50741
  93. Haney MJ, Klyachko NL, Zhao Y et al (2015) Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release 207, 18-30 https://doi.org/10.1016/j.jconrel.2015.03.033
  94. Kang JY, Kim H, Mun D, Yun N and Joung B (2021) Co-delivery of curcumin and miRNA-144-3p using heart-targeted extracellular vesicles enhances the therapeutic efficacy for myocardial infarction. J Control Release 331, 62-73 https://doi.org/10.1016/j.jconrel.2021.01.018
  95. Li S, Stockl S, Lukas C et al (2021) Curcumin-primed human BMSC-derived extracellular vesicles reverse IL-1beta-induced catabolic responses of OA chondrocytes by upregulating miR-126-3p. Stem Cell Res Ther 12, 252 https://doi.org/10.1186/s13287-021-02317-6
  96. Hahm J, Kim J and Park J (2021) Strategies to enhance extracellular vesicle production. Tissue Eng Regen Med 18, 513-524 https://doi.org/10.1007/s13770-021-00364-x
  97. Grangier A, Branchu J, Volatron J et al (2021) Technological advances towards extracellular vesicles mass production. Adv Drug Deliv Rev 176, 113843 https://doi.org/10.1016/j.addr.2021.113843
  98. 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 https://doi.org/10.1016/j.ymthe.2018.09.015
  99. 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 https://doi.org/10.1038/leu.2014.41
  100. 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 https://doi.org/10.1186/s40824-016-0068-0
  101. Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A and Bremer N (2020) Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem Cells Dev 29, 747-754 https://doi.org/10.1089/scd.2020.0080
  102. Katagiri W, Osugi M, Kawai T and Hibi H (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 https://doi.org/10.1186/s13005-016-0101-5
  103. Fukuoka H and Suga H (2015) Hair regeneration treatment using adipose-derived stem cell conditioned medium: follow-up with trichograms. Eplasty 15, e10
  104. Warnecke A, Prenzler N, Harre J et al (2021) First-inhuman intracochlear application of human stromal cell-derived extracellular vesicles. J Extracell Vesicles 10, e12094
  105. Zhang X, Liu J, Yu B, Ma F, Ren X and Li X (2018) Effects of mesenchymal stem cells and their exosomes on the healing of large and refractory macular holes. Graefes Arch Clin Exp Ophthalmol 256, 2041-2052 https://doi.org/10.1007/s00417-018-4097-3
  106. Szebeni J, Muggia F, Gabizon A and Barenholz Y (2011) Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev 63, 1020-1030 https://doi.org/10.1016/j.addr.2011.06.017