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

다국어 초록 (Multilingual Abstract)

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 μm) 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. [BMB Reports 2022; 55(1): 20-29]

참고문헌 (Reference)

1 Wael Nassar ; Mervat El-Ansary ; Dina Sabry ; Mostafa A. Mostafa ; Tarek Fayad ; Esam Kotb ; Mahmoud Temraz ; Abdel-Naser Saad ; Wael Essa ; Heba Adel, "Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases" 한국생체재료학회 20 (20): 200-210, 2016

2 Kordower JH, "Trophic factor gene therapy for Parkinson’s disease" 28 : 96-109, 2013

3 Medalla M, "Treatment with mesenchymal-derived extracellular vesicles reduces injury-related pathology in pyramidal neurons of monkey perilesional ventral premotor cortex" 40 : 3385-3407, 2020

4 Banks WA, "Transport of extracellular vesicles across the blood-brain barrier : brain pharmacokinetics and effects of inflammation" 21 : 4407-, 2020

5 Biancone L, "Therapeutic potential of mesenchymal stem cell-derived microvesicles" 27 : 3037-3042, 2012

6 Yang J, "Therapeutic effects of simultaneous delivery of nerve growth factor mRNA and protein via exosomes on cerebral ischemia" 21 : 512-522, 2020

7 Cunningham CJ, "The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke" 38 : 1276-1292, 2018

8 Zheng X, "The role of small extracellular vesicles in cerebral and myocardial ischemia-Molecular signals, treatment targets, and future clinical translation" 39 : 403-413, 2021

9 Grangier A, "Technological advances towards extracellular vesicles mass production" 176 : 113843-, 2021

10 D’Souza A, "Targeting the blood-brain barrier for the delivery of stroke therapies" 171 : 332-351, 2021

11 Saint-Pol J, "Targeting and crossing the bloodbrain barrier with extracellular vesicles" 9 : 851-, 2020

12 Izco M, "Systemic exosomal delivery of shRNA minicircles prevents parkinsonian pathology" 27 : 2111-2122, 2019

13 Xin H, "Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats" 33 : 1711-1715, 2013

14 Zhang Y, "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" 111 : 69-81, 2017

15 함주희 ; Kim Jonghoon ; 박종민, "Strategies to Enhance Extracellular Vesicle Production" 한국조직공학과 재생의학회 18 (18): 513-524, 2021

16 Pauwels MJ, "Special delEVery : extracellular vesicles as promising delivery platform to the brain" 9 : 1734-, 2021

17 de Almeida Fuzeta M, "Scalable production of human mesenchymal stromal cell-derived extracellular vesicles under serum-/xenofree conditions in a microcarrier-based bioreactor culture system" 8 : 553444-, 2020

18 Hess DC, "Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke(MASTERS) : a randomised, doubleblind, placebo-controlled, phase 2 trial" 16 : 360-368, 2017

19 Zhao Z, "Remote control of BBB : A tale of exosomes and microRNA" 27 : 849-850, 2017

20 Brites D, "Regulatory function of microRNAs in microglia" 68 : 1631-1642, 2020

21 Li X, "Puerarin suppresses MPP(+)/MPTP-induced oxidative stress through an Nrf2-dependent mechanism" 144 : 111644-, 2020

22 Lai RC, "Proteolytic potential of the MSc exosome proteome : implications for an exosome-mediated delivery of therapeutic proteasome" 2012 : 971907-, 2012

23 Zha Y, "Progenitor cell-derived exosomes endowed with VEGF plasmids enhance osteogenic induction and vascular remodeling in large segmental bone defects" 11 : 397-409, 2021

24 Poo MM, "Neurotrophins as synaptic modulators" 2 : 24-32, 2001

25 Bang OY, "Neuroprotective strategies for acute ischemic stroke : recent progress and future perspectives" 1 : 115-121, 2017

26 Yin Z, "Neuron-derived exosomes with high miR-21-5p expression promoted polarization of M1 microglia in culture" 83 : 270-282, 2020

27 Ahn EH, "Netrin-1/receptors regulate the pathogenesis in Parkinson’s diseases" 5 : 50-61, 2021

28 Khan H, "Native and bioengineered exosomes for ischemic stroke therapy" 9 : 619565-, 2021

29 Choi Y, "Nanoelectrical characterization of individual exosomes secreted by Abeta42-ingested cells using electrostatic force microscopy" 32 : 025705-, 2021

30 Zagrean AM, "Multicellular crosstalk between exosomes and the neurovascular unit after cerebral ischemia. Therapeutic implications" 12 : 811-, 2018

31 Wei Z, "Mononuclear phagocyte system blockade using extracellular vesicles modified with CD47 on membrane surface for myocardial infarction reperfusion injury treatment" 275 : 121000-, 2021

32 O’Brien CG, "Mitochondria-rich extracellular vesicles rescue patient-specific cardiomyocytes from doxorubicin injury : insights into the SENECA trial" 3 : 428-440, 2021

33 D’Souza A, "Microvesicles transfer mitochondria and increase mitochondrial function in brain endothelial cells" 338 : 505-526, 2021

34 Lee JY, "Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke" 6 : 33038-, 2016

35 Akkoc Y, "MicroRNAs as major regulators of the autophagy pathway" 1867 : 118662-, 2020

36 Xin H, "MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats" 48 : 747-753, 2017

37 Xin H, "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" 31 : 2737-2746, 2013

38 Wang C, "Mesenchymal stromal cell-derived small extracellular vesicles induce ischemic neuroprotection by modulating leukocytes and specifically neutrophils" 51 : 1825-1834, 2020

39 Cone AS, "Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer’s disease-like phenotypes in a preclinical mouse model" 11 : 8129-8142, 2021

40 Bang OY, "Mesenchymal stem cell-derived extracellular vesicle therapy for stroke : challenges and progress" 10 : 211-, 2019

41 Karp JM, "Mesenchymal stem cell homing : the devil is in the details" 4 : 206-216, 2009

42 Yuan D, "Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain" 142 : 1-12, 2017

43 Kordelas L, "MSCderived exosomes : a novel tool to treat therapy-refractory graft-versus-host disease" 28 : 970-973, 2014

44 Otero-Ortega L, "Low dose of extracellular vesicles identified that promote recovery after ischemic stroke" 11 : 70-, 2020

45 Prasad K, "Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke : a multicentric, randomized trial" 45 : 3618-3624, 2014

46 Losurdo M, "Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer’s disease" 9 : 1068-1084, 2020

47 Narbute K, "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-Hydroxydopaminetreated rats" 8 : 490-499, 2019

48 Elia CA, "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" 8 : 1059-, 2019

49 Le Saux S, "Interest of extracellular vesicles in regards to lipid nanoparticle based systems for intracellular protein delivery" 176 : 113837-, 2021

50 Gholamrezanezhad A, "In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis" 38 : 961-967, 2011

51 Zhao C, "Hypoxic glioblastoma release exosomal VEGF-A induce the permeability of blood-brain barrier" 502 : 324-331, 2018

52 Jeon I, "Human-tomouse prion-like propagation of mutant huntingtin protein" 132 : 577-592, 2016

53 Webb RL, "Human neural stem cell extracellular vesicles improve tissue and functional recovery in the murine thromboembolic stroke model" 9 : 530-539, 2018

54 Webb RL, "Human neural stem cell extracellular vesicles improve recovery in a porcine model of ischemic stroke" 49 : 1248-1256, 2018

55 Katsuda T, "Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes" 3 : 1197-, 2013

56 Fukuoka H, "Hair regeneration treatment using adipose-derived stem cell conditioned medium : follow-up with trichograms" 15 : e10-, 2015

57 Costa LA, "Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions : implications for further clinical uses" 78 : 447-467, 2021

58 Johnson J, "From mesenchymal stromal cells to engineered extracellular vesicles : a new therapeutic paradigm" 9 : 705676-, 2021

59 Warnecke A, "First-inhuman intracochlear application of human stromal cellderived extracellular vesicles" 10 : e12094-, 2021

60 Katagiri W, "First-in-human study and clinical case reports of the alveolar bone regeneration with the secretome from human mesenchymal stem cells" 12 : 5-, 2016

61 Upadhya R, "Extracellular vesicles from human iPSC-derived neural stem cells : miRNA and protein signatures, and anti-inflammatory and neurogenic properties" 9 : 1809064-, 2020

62 Millan C, "Extracellular vesicles from 3D engineered microtissues harbor disease-related cargo absent in EVs from 2D cultures" e2002067-, 2021

63 Cai J, "Extracellular vesicles derived from different sources of mesenchymal stem cells : therapeutic effects and translational potential" 10 : 69-, 2020

64 Pedrioli G, "Extracellular vesicles as promising carriers in drug delivery : considerations from a cell biologist’s perspective" 10 : 376-, 2021

65 Rufino-Ramos D, "Extracellular vesicles : novel promising delivery systems for therapy of brain diseases" 262 : 247-258, 2017

66 Daniel E. Murphy ; Olivier G. de Jong ; Maarten Brouwer ; Matthew J. Wood ; Grégory Lavieu ; Raymond M. Schiffelers ; Pieter Vader, "Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking" 생화학분자생물학회 51 : 1-12, 2019

67 Crewe C, "Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes" 33 : 1853-1868, 2021

68 Wiklander OP, "Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting" 4 : 26316-, 2015

69 Zhang ZG, "Exosomes-beyond stem cells for restorative therapy in stroke and neurological injury" 15 : 193-203, 2019

70 Nalamolu KR, "Exosomes treatment mitigates ischemic brain damage but does not improve post-stroke neurological outcome" 52 : 1280-1291, 2019

71 Haraszti RA, "Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity" 26 : 2838-2847, 2018

72 Chen HX, "Exosomes derived from mesenchymal stem cells repair a Parkinson’s disease model by inducing autophagy" 11 : 288-, 2020

73 Cui GH, "Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice" 32 : 654-668, 2018

74 Sengupta V, "Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19" 29 : 747-754, 2020

75 Haney MJ, "Exosomes as drug delivery vehicles for Parkinson’s disease therapy" 207 : 18-30, 2015

76 Didiot MC, "Exosomemediated delivery of hydrophobically modified siRNA for Huntingtin mRNA silencing" 24 : 1836-1847, 2016

77 Yang J, "Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia" 7 : 278-287, 2017

78 Park KS, "Enhancement of therapeutic potential of mesenchymal stem cell-derived extracellular vesicles" 10 : 288-, 2019

79 Lino MM, "Engineered extracellular vesicles as brain therapeutics" 338 : 472-485, 2021

80 Gao W, "Endothelial colonyforming cell-derived exosomes restore blood-brain barrier continuity in mice subjected to traumatic brain injury" 307 : 99-108, 2018

81 Nam GH, "Emerging prospects of exosomes for cancer treatment : from conventional therapy to immunotherapy" 32 : e2002440-, 2020

82 Chen CC, "Elucidation of exosome migration across the blood-brain barrier model in vitro" 9 : 509-529, 2016

83 Cha JM, "Efficient scalable production of therapeutic microvesicles derived from human mesenchymal stem cells" 8 : 1171-, 2018

84 Chung JW, "Efficacy and safety of intravenous mesenchymal stem cells for ischemic stroke" 96 : e1012-, 2021

85 Zhang X, "Effects of mesenchymal stem cells and their exosomes on the healing of large and refractory macular holes" 256 : 2041-2052, 2018

86 Cui GH, "Effects of exosomal miRNAs in the diagnosis and treatment of Alzheimer’s disease" 200 : 111593-, 2021

87 Williams AM, "Early single-dose treatment with exosomes provides neuroprotection and improves blood-brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock" 88 : 207-218, 2020

88 Crescitelli R, "Distinct RNA profiles in subpopulations of extracellular vesicles : apoptotic bodies, microvesicles and exosomes" 2 : 1-10, 2013

89 Soares Martins T, "Diagnostic and therapeutic potential of exosomes in Alzheimer’s disease" 156 : 162-181, 2021

90 Kalani A, "Curcuminloaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury" 79 : 360-369, 2016

91 Li S, "Curcumin-primed human BMSC-derived extracellular vesicles reverse IL-1beta-induced catabolic responses of OA chondrocytes by upregulating miR-126-3p" 12 : 252-, 2021

92 Loukogeorgakis SP, "Concise review : amniotic fluid stem cells : the known, the unknown, and potential regenerative medicine applications" 35 : 1663-1673, 2017

93 Muhammad SA, "Comparative efficacy of stem cells and secretome in articular cartilage regeneration : a systematic review and meta-analysis" 375 : 329-344, 2019

94 Kang JY, "Co-delivery of curcumin and miRNA-144-3p using hearttargeted extracellular vesicles enhances the therapeutic efficacy for myocardial infarction" 331 : 62-73, 2021

95 Durcin M, "Characterisation of adipocyte-derived extracellular vesicle subtypes identifies distinct protein and lipid signatures for large and small extracellular vesicles" 6 : 1305677-, 2017

96 Lyden PD, "Cerebroprotection for acute ischemic stroke : looking ahead" 52 : 3033-3044, 2021

97 Wen S, "Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a radiation injury bone marrow murine model" 20 : 5468-, 2019

98 Mirzaaghasi A, "Biodistribution and pharmacokinectics of liposomes and exosomes in a mouse model of sepsis" 13 : 427-, 2021

99 Chen W, "Astrocytesderived exosomes induce neuronal recovery after traumatic brain injury via delivering gap junction alpha 1-20 k" 14 : 412-423, 2020

100 Long X, "Astrocyte-derived exosomes enriched with miR-873a-5p inhibit neuroinflammation via microglia phenotype modulation after traumatic brain injury" 17 : 89-, 2020

101 Moon GJ, "Application of mesenchymal stem cell-derived extracellular vesicles for stroke : biodistribution and microRNA Study" 10 : 509-521, 2019

102 Wiklander OPB, "Advances in therapeutic applications of extracellular vesicles" 11 : eaav8521-, 2019

103 Szebeni J, "Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products : prediction and prevention" 63 : 1020-1030, 2011

104 Ma X, "ADSCs-derived extracellular vesicles alleviate neuronal damage, promote neurogenesis and rescue memory loss in mice with Alzheimer’s disease" 327 : 688-702, 2020

105 Lo EH, "A new penumbra : transitioning from injury into repair after stroke" 14 : 497-500, 2008

106 Lee JS, "A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke" 28 : 1099-1106, 2010