Exploration of Neuroscience

Table 1. Registered clinical trials of MSCs and MSC-EVs as therapeutics in ischemic stroke

Identifier	Country	Intervention	Tissue source	Origin	Route	Phase	Status
NTC00875654	France	MSCs	Bone marrow	Autologous	Intravenous	II	Completed
NTC00908856	United States	MSCs	Bone marrow	Autologous	Intravenous	I	Withdrawn
NTC01091701	Malaysia	MSCs	Not defined	Allogeneic	Intravenous	I/II	Withdrawn
NCT01297413	United States	MSCs	Bone marrow	Allogeneic	Intravenous	I/II	Completed
NCT01461720	Malaysia	MSCs	Bone marrow	Autologous	Intravenous	II	Unknown
NCT01468064	China	MSCs	Bone marrow	Autologous	Intravenous	I/II	Completed
NCT01678534	Spain	MSCS	Adipose tissue	Allogeneic	intravenous	II	Completed
NCT01714167	China	MSCs	Bone marrow	Autologous	Intracerebral	I	Unknown
NTC01716481	South Korea	MSCs	Bone marrow	Autologous	Intravenous	III	Unknown
NCT01849887	United States	MSCs	Bone marrow	Allogeneic	Intravenous	I/II	Withdrawn
NCT01922908	United States	MSCs	Bone marrow	Allogeneic	Intravenous	I/II	Withdrawn
NCT02378974	South Korea	MSCs	Umbilical cord	Not defined	Intravenous	I/II	Completed
NCT02564328	China	MSCs	Bone marrow	Autologous	Intravenous	I	Unknown
NTC02580019	China	MSCs	Umbilical cord	Not defined	Intravenous	II	Unknown
NTC03176498	China	MSCs	Umbilical cord	Allogeneic	Intravenous	I/II	Suspended
NTC03186456	China	MSCs	Umbilical cord	Allogeneic	Intravenous	I	Suspended
NCT03356821	Netherlands	MSCs	Bone marrow	Allogeneic	Intranasal	I/II	Completed
NCT03384433	Iran	MSC-EVs	Not defined	Allogeneic	Intraparenchymal	I/II	Recruiting
NCT04093336	China	MSCs	Umbilical cord	Allogeneic	Intravenous	I/II	Recruiting
NCT04097652	China	MSCs	Umbilical cord	Not defined	Intravenous	I	Recruiting
NCT04280003	Spain	MSCs	Adipose tissue	Allogeneic	Intravenous	II	Recruiting
NCT04434768	China	MSCs	Umbilical cord	Allogeneic	Intravenous and intraarterial	I	Recruiting
NCT04590118	China	MSCs	Not defined	Allogeneic	Intravenous	I/II	Recruiting
NCT04811651	China	MSCs	Umbilical cord	Not defined	Intravenous	II	Recruiting
NCT04953663	China	MSCs	Bone marrow	Allogeneic	Intravenous	I/II	Recruiting
NTC05008588	Indonesia	MSCs	Umbilical cord	Not defined	Intraparenchymal	I/II	Not yet recruiting
NCT05158101	Antigua and Barbuda	MSCs	Umbilical cord	Allogeneic	Intravenous	I	Recruiting
NCT05292625	Vietnam	MSCs	Umbilical cord	Allogeneic	Intravenous and intrathecal	I/II	Recruiting

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Declarations

Author contributions

CW drafted the manuscript. All authors revised it and approved the submitted version.

Conflicts of interest

DMH and BG hold U.S. and E.U. patents on extracellular vesicles for the treatment of inflammatory conditions (US9877989B2; EP2874634B1).

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Supported by German Research Foundation (389030878, 405358801) and Federal Ministry of Education and Science (3DOS; 161L0278B). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al.; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2021 update: a report from the American Heart Association. Circulation. 2021;143:e254–743. [DOI] [PubMed]

GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20:795–820. [DOI] [PubMed] [PMC]

Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17:796–808. [DOI] [PubMed] [PMC]

Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab. 2014;34:1573–84. [DOI] [PubMed] [PMC]

Hermann DM, Gunzer M. Polymorphonuclear neutrophils play a decisive role for brain injury and neurological recovery poststroke. Stroke. 2019;50:e40–1. [DOI] [PubMed]

Mohamud Yusuf A, Hagemann N, Ludewig P, Gunzer M, Hermann DM. Roles of polymorphonuclear neutrophils in ischemic brain injury and post-ischemic brain remodeling. Front Immunol. 2022;12:825572. [DOI] [PubMed] [PMC]

Veltkamp R, Gill D. Clinical trials of immunomodulation in ischemic stroke. Neurotherapeutics. 2016;13:791–800. [DOI] [PubMed] [PMC]

Börger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli O, Becic A, et al. Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci. 2017;18:1450. [DOI] [PubMed] [PMC]

Cocozza F, Grisard E, Martin-Jaular L, Mathieu M, Théry C. Snapshot: extracellular vesicles. Cell. 2020;182:262–262.e1. [DOI] [PubMed]

10.

GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–22. Erratum in: Lancet. 2020;396:1562. [DOI] [PubMed] [PMC]

11.

Gorelick PB. The global burden of stroke: persistent and disabling. Lancet Neurol. 2019;18:417–8. [DOI] [PubMed]

12.

GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18:439–58. [DOI] [PubMed] [PMC]

13.

Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al.; GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 Study. J Am Coll Cardiol. 2020;76:2982–3021. Erratum in: J Am Coll Cardiol. 2021;77:1958–9. [DOI] [PubMed] [PMC]

14.

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–8. [DOI] [PubMed]

15.

Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al.; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–29. [DOI] [PubMed]

16.

Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, et al.; WAKE-UP Investigators. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379:611–22. [DOI]

17.

Schwamm LH, Ali SF, Reeves MJ, Smith EE, Saver JL, Messe S, et al. Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With The Guidelines-Stroke hospitals. Circ Cardiovasc Qual Outcomes. 2013;6:543–9. [DOI] [PubMed]

18.

Decker-Palmer M, Wu N, Biscossi M, Savitz SI. Abstract TP6: current trends in thrombolytic use for acute ischemic stroke. Stroke. 2020;51:ATP6. [DOI]

19.

Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al.; DEFUSE 3 Investigators. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378:708–18. [DOI] [PubMed] [PMC]

20.

Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al.; DAWN Trial Investigators. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378:11–21. [DOI] [PubMed]

21.

Evans MRB, White P, Cowley P, Werring DJ. Revolution in acute ischaemic stroke care: a practical guide to mechanical thrombectomy. Pract Neurol. 2017;17:252–65. [DOI] [PubMed] [PMC]

22.

Josephson SA, Kamel H. The acute stroke care revolution: enhancing access to therapeutic advances. JAMA. 2018;320:1239–40. [DOI] [PubMed]

23.

Candio P, Violato M, Leal J, Luengo-Fernandez R. Cost-effectiveness of mechanical thrombectomy for treatment of nonminor ischemic stroke across Europe. Stroke. 2021;52:664–73. [DOI] [PubMed] [PMC]

24.

Weber R, Krogias C, Eyding J, Bartig D, Meves SH, Katsanos AH, et al. Age and sex differences in ischemic stroke treatment in a nationwide analysis of 1.11 million hospitalized cases. Stroke. 2019;50:3494–502. [DOI] [PubMed]

25.

MacKenzie IER, Moeini-Naghani I, Sigounas D. Trends in endovascular mechanical thrombectomy in treatment of acute ischemic stroke in the United States. World Neurosurg. 2020;138:e839–46. [DOI] [PubMed]

26.

Wang C, Liu XX, Huang KB, Yin SB, Wei JJ, Hu YF, et al. Preconditioning with recombinant high-mobility group box 1 induces ischemic tolerance in a rat model of focal cerebral ischemia-reperfusion. J Neurochem. 2016;137:576–88. [DOI] [PubMed]

27.

Schuhmann MK, Kollikowski AM, März AG, Bieber M, Pham M, Stoll G. Danger-associated molecular patterns are locally released during occlusion in hyper-acute stroke. Brain Behav Immun Health. 2021;15:100270. [DOI] [PubMed] [PMC]

28.

Yamaguchi A, Jitsuishi T, Hozumi T, Iwanami J, Kitajo K, Yamaguchi H, et al. Temporal expression profiling of DAMPs-related genes revealed the biphasic post-ischemic inflammation in the experimental stroke model. Mol Brain. 2020;13:57. [DOI] [PubMed] [PMC]

29.

Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 2012;43:3063–70. [DOI] [PubMed]

30.

Sardari M, Dzyubenko E, Schmermund B, Yin D, Qi Y, Kleinschnitz C, et al. Dose-dependent microglial and astrocytic responses associated with post-ischemic neuroprotection after lipopolysaccharide-induced sepsis-like state in mice. Front Cell Neurosci. 2020;14:26. [DOI] [PubMed] [PMC]

31.

Manrique-Castano D, Dzyubenko E, Borbor M, Vasileiadou P, Kleinschnitz C, Roll L, et al. Tenascin-C preserves microglia surveillance and restricts leukocyte and, more specifically, T cell infiltration of the ischemic brain. Brain Behav Immun. 2021;91:639–48. [DOI] [PubMed]

32.

Herz J, Sabellek P, Lane TE, Gunzer M, Hermann DM, Doeppner TR. Role of neutrophils in exacerbation of brain injury after focal cerebral ischemia in hyperlipidemic mice. Stroke. 2015;46:2916–25. [DOI] [PubMed] [PMC]

33.

Huber JD, Campos CR, Mark KS, Davis TP. Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after λ-carrageenan-induced inflammatory pain. Am J Physiol Heart Circ Physiol. 2006;290:H732–40. [DOI] [PubMed] [PMC]

34.

Lindsberg PJ, Carpe′n O, Paetau A, Karjalainen-Lindsberg ML, Kaste M. Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation. 1996;94:939–45. [DOI] [PubMed]

35.

Shi K, Zou M, Jia DM, Shi S, Yang X, Liu Q, et al. tPA mobilizes immune cells that exacerbate hemorrhagic transformation in stroke. Circ Res. 2021;128:62–75. [DOI] [PubMed]

36.

Salas-Perdomo A, Miró-Mur F, Urra X, Justicia C, Gallizioli M, Zhao Y, et al. T cells prevent hemorrhagic transformation in ischemic stroke by P-selectin binding. Arterioscler Thromb Vasc Biol. 2018;38:1761–71. [DOI] [PubMed]

37.

Casas AI, Geuss E, Kleikers PWM, Mencl S, Herrmann AM, Buendia I, et al. NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage. Proc Natl Acad Sci U S A. 2017;114:12315–20. [DOI] [PubMed] [PMC]

38.

Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats. Stroke. 1998;29:1020–30. [DOI] [PubMed]

39.

Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol. 2005;289:H558–68. [DOI] [PubMed]

40.

Yu L, Su X, Li S, Zhao F, Mu D, Qu Y. Microglia and their promising role in ischemic brain injuries: an update. Front Cell Neurosci. 2020;14:211. [DOI] [PubMed] [PMC]

41.

Shi K, Wood K, Shi FD, Wang X, Liu Q. Stroke-induced immunosuppression and poststroke infection. Stroke Vasc Neurol. 2018;3:34–41. [DOI] [PubMed] [PMC]

42.

Marino Lee S, Hudobenko J, McCullough LD, Chauhan A. Microglia depletion increase brain injury after acute ischemic stroke in aged mice. Exp Neurol. 2021;336:113530. [DOI] [PubMed] [PMC]

43.

Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, del Zoppo GJ. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol. 1994;144:188–99. [PubMed] [PMC]

44.

Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, et al. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke. 2009;40:1849–57. [DOI] [PubMed]

45.

Wang C, Börger V, Sardari M, Murke F, Skuljec J, Pul R, et al. Mesenchymal stromal cell-derived small extracellular vesicles induce ischemic neuroprotection by modulating leukocytes and specifically neutrophils. Stroke. 2020;51:1825–34. [DOI] [PubMed]

46.

Otxoa-de-Amezaga A, Miró-Mur F, Pedragosa J, Gallizioli M, Justicia C, Gaja-Capdevila N, et al. Microglial cell loss after ischemic stroke favors brain neutrophil accumulation. Acta Neuropathol. 2019;137:321–41. [DOI] [PubMed] [PMC]

47.

Xue J, Huang W, Chen X, Li Q, Cai Z, Yu T, et al. Neutrophil-to-lymphocyte ratio is a prognostic marker in acute ischemic stroke. J Stroke Cerebrovasc Dis. 2017;26:650–7. [DOI] [PubMed]

48.

Neumann J, Riek-Burchardt M, Herz J, Doeppner TR, König R, Hütten H, et al. Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke. Acta Neuropathol. 2015;129:259–77. [DOI] [PubMed]

49.

Gregorius J, Wang C, Stambouli O, Hussner T, Qi Y, Tertel T, et al. Small extracellular vesicles obtained from hypoxic mesenchymal stromal cells have unique characteristics that promote cerebral angiogenesis, brain remodeling and neurological recovery after focal cerebral ischemia in mice. Basic Res Cardiol. 2021;116:40. [DOI] [PubMed] [PMC]

50.

Kleinschnitz C, Schwab N, Kraft P, Hagedorn I, Dreykluft A, Schwarz T, et al. Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood. 2010;115:3835–42. [DOI] [PubMed]

51.

Yilmaz G, Arumugam TV, Stokes KY, Granger DN. Role of T lymphocytes and interferon-γ in ischemic stroke. Circulation. 2006;113:2105–12. [DOI] [PubMed]

52.

Jander S, Kraemer M, Schroeter M, Witte OW, Stoll G. Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab. 1995;15:42–51. [DOI] [PubMed]

53.

Hum PD, Subramanian S, Parker SM, Afentoulis ME, Kaler LJ, Vandenbark AA, et al. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab. 2007;27:1798–805. [DOI] [PubMed] [PMC]

54.

Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, et al. Pivotal role of cerebral interleukin-17–producing γδT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15:946–50. [DOI] [PubMed]

55.

Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15:192–9. [DOI] [PubMed]

56.

Elkins J, Veltkamp R, Montaner J, Johnston SC, Singhal AB, Becker K, et al. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 2017;16:217–26. [DOI] [PubMed]

57.

Enlimomab Acute Stroke Trial Investigators. Use of anti-ICAM-1 therapy in ischemic stroke: results of the enlimomab acute stroke trial. Neurology. 2001;57:1428–34. [DOI] [PubMed]

58.

Wang C, Börger V, Mohamud Yusuf A, Tertel T, Stambouli O, Murke F, et al. Postischemic neuroprotection associated with anti-inflammatory effects by mesenchymal stromal cell-derived small extracellular vesicles in aged mice. Stroke. 2022;53:e14–8. [DOI] [PubMed] [PMC]

59.

Dumbrava DA, Surugiu R, Börger V, Ruscu M, Tertel T, Giebel B, et al. Mesenchymal stromal cell-derived small extracellular vesicles promote neurological recovery and brain remodeling after distal middle cerebral artery occlusion in aged rats. GeroScience. 2022;44:293–310. [DOI] [PubMed] [PMC]

60.

Menet R, Bernard M, ElAli A. Hyperlipidemia in stroke pathobiology and therapy: insights and perspectives. Front Physiol. 2018;9:488. [DOI] [PubMed] [PMC]

61.

ElAli A, Doeppner TR, Zechariah A, Hermann DM. Increased blood-brain barrier permeability and brain edema after focal cerebral ischemia induced by hyperlipidemia: role of lipid peroxidation and calpain-1/2, matrix metalloproteinase-2/9, and RhoA overactivation. Stroke. 2011;42:3238–44. [DOI] [PubMed]

62.

Zechariah A, ElAli A, Hagemann N, Jin F, Doeppner TR, Helfrich I, et al. Hyperlipidemia attenuates vascular endothelial growth factor-induced angiogenesis, impairs cerebral blood flow, and disturbs stroke recovery via decreased pericyte coverage of brain endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33:1561–7. [DOI] [PubMed]

63.

Herz J, Hagen SI, Bergmüller E, Sabellek P, Göthert JR, Buer J, et al. Exacerbation of ischemic brain injury in hypercholesterolemic mice is associated with pronounced changes in peripheral and cerebral immune responses. Neurobiol Dis. 2014;62:456–68. [DOI] [PubMed]

64.

Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32:252–60. [DOI] [PubMed] [PMC]

65.

Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6:230–47. [DOI] [PubMed]

66.

Gimona M, Brizzi MF, Choo ABH, Dominici M, Davidson SM, Grillari J, et al. Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles. Cytotherapy. 2021;23:373–80. [DOI] [PubMed]

67.

Zhou T, Yuan Z, Weng J, Pei D, Du X, He C, et al. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol. 2021;14:24. [DOI] [PubMed] [PMC]

68.

Shi Y, Wang Y, Li Q, Liu K, Hou J, Shao C, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14:493–507. [DOI] [PubMed]

69.

Doeppner TR, Herz J, Görgens A, Schlechter J, Ludwig AK, Radtke S, et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015;4:1131–43. [DOI] [PubMed] [PMC]

70.

Brenneman M, Sharma S, Harting M, Strong R, Cox CS Jr, Aronowski J, et al. Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. J Cereb Blood Flow Metab. 2010;30:140–9. [DOI] [PubMed] [PMC]

71.

Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, et al. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology. 2002;59:514–23. [DOI] [PubMed]

72.

Wei L, Fraser JL, Lu ZY, Hu X, Yu SP. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis. 2012;46:635–45. [DOI] [PubMed] [PMC]

73.

Sarmah D, Agrawal V, Rane P, Bhute S, Watanabe M, Kalia K, et al. Mesenchymal stem cell therapy in ischemic stroke: a meta-analysis of preclinical studies. Clin Pharmacol Ther. 2018;103:990–8. [DOI] [PubMed]

74.

Anderson JD, Pham MT, Contreras Z, Hoon M, Fink KD, Johansson HJ, et al. Mesenchymal stem cell-based therapy for ischemic stroke. Chin Neurosurg J. 2016;2:36. [DOI]

75.

Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84. [DOI] [PubMed]

76.

Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the international society for extracellular vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750. [DOI] [PubMed] [PMC]

77.

Shah R, Patel T, Freedman JE. Circulating extracellular vesicles in human disease. N Engl J Med. 2018;379:958–66. [DOI] [PubMed]

78.

Kuang Y, Zheng X, Zhang L, Ai X, Venkataramani V, Kilic E, et al. Adipose-derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR-25. J Extracell Vesicles. 2020;10:e12024. [DOI] [PubMed] [PMC]

79.

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;33:1711–5. [DOI] [PubMed] [PMC]

80.

Xin H, Katakowski M, Wang F, Qian JY, Liu XS, Ali MM, et al. MicroRNA-17–92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke. 2017;48:747–53. Erratum in: Stroke. 2017;48:e137. [DOI] [PubMed] [PMC]

81.

Xin H, Wang F, Li Y, Lu QE, Cheung WL, Zhang Y, et al. Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from MicroRNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant. 2017;26:243–57. [DOI] [PubMed] [PMC]

82.

Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, et al. 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;31:2737–46. [DOI] [PubMed] [PMC]

83.

Zhang ZG, Buller B, Chopp M. Exosomes — beyond stem cells for restorative therapy in stroke and neurological injury. Nat Rev Neurol. 2019;15:193–203. [DOI] [PubMed]

84.

Moore TL, Bowley BGE, Pessina MA, Calderazzo SM, Medalla M, Go V, et al. Mesenchymal derived exosomes enhance recovery of motor function in a monkey model of cortical injury. Restor Neurol Neurosci. 2019;37:347–62. [DOI] [PubMed] [PMC]

85.

Go V, Bowley BGE, Pessina MA, Zhang ZG, Chopp M, Finklestein SP, et al. Extracellular vesicles from mesenchymal stem cells reduce microglial-mediated neuroinflammation after cortical injury in aged Rhesus monkeys. GeroScience. 2020;42:1–17. [DOI] [PubMed] [PMC]

86.

Go V, Sarikaya D, Zhou Y, Bowley BGE, Pessina MA, Rosene DL, et al. Extracellular vesicles derived from bone marrow mesenchymal stem cells enhance myelin maintenance after cortical injury in aged rhesus monkeys. Exp Neurol. 2021;337:113540. [DOI] [PubMed] [PMC]

87.

Webb RL, Kaiser EE, Scoville SL, Thompson TA, Fatima S, Pandya C, et al. Human neural stem cell extracellular vesicles improve tissue and functional recovery in the murine thromboembolic stroke model. Transl Stroke Res. 2018;9:530–9. [DOI] [PubMed] [PMC]

88.

Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28:970–3. [DOI] [PubMed]

89.

Venkat P, Zacharek A, Landschoot-Ward J, Wang F, Culmone L, Chen Z, et al. Exosomes derived from bone marrow mesenchymal stem cells harvested from type two diabetes rats promotes neurorestorative effects after stroke in type two diabetes rats. Exp Neurol. 2020;334:113456. [DOI] [PubMed]

90.

Liu X, Zhang M, Liu H, Zhu R, He H, Zhou Y, et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate cerebral ischemia-reperfusion injury-induced neuroinflammation and pyroptosis by modulating microglia M1/M2 phenotypes. Exp Neurol. 2021;341:113700. [DOI] [PubMed]

91.

Zhao Y, Gan Y, Xu G, Hua K, Liu D. Exosomes from MSCs overexpressing microRNA-223-3p attenuate cerebral ischemia through inhibiting microglial M1 polarization mediated inflammation. Life Sci. 2020;260:118403. [DOI] [PubMed]

92.

Yang HC, Zhang M, Wu R, Zheng HQ, Zhang LY, Luo J, et al. C-C chemokine receptor type 2-overexpressing exosomes alleviated experimental post-stroke cognitive impairment by enhancing microglia/macrophage M2 polarization. World J Stem Cells. 2020;12:152–67. [DOI] [PubMed] [PMC]

93.

Dabrowska S, Andrzejewska A, Strzemecki D, Muraca M, Janowski M, Lukomska B. Human bone marrow mesenchymal stem cell-derived extracellular vesicles attenuate neuroinflammation evoked by focal brain injury in rats. J Neuroinflamm. 2019;16:216. [DOI] [PubMed] [PMC]

94.

Haupt M, Zheng X, Kuang Y, Lieschke S, Janssen L, Bosche B, et al. Lithium modulates miR-1906 levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation. Stem Cells Transl Med. 2021;10:357–73. [DOI] [PubMed] [PMC]

95.

Ai Z, Cheng C, Zhou L, Yin S, Wang L, Liu Y. Bone marrow mesenchymal stem cells-derived extracellular vesicles carrying microRNA-221-3p protect against ischemic stroke via ATF3. Brain Res Bull. 2021;172:220–8. [DOI] [PubMed]

96.

Levy ML, Crawford JR, Dib N, Verkh L, Tankovich N, Cramer SC. Phase I/II study of safety and preliminary efficacy of intravenous allogeneic mesenchymal stem cells in chronic stroke. Stroke. 2019;50:2835–41. [DOI] [PubMed]

97.

Díez-Tejedor E, Gutiérrez-Fernández M, Martínez-Sánchez P, Rodríguez-Frutos B, Ruiz-Ares G, Lara ML, et al. Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: a phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. J Stroke Cerebrovasc Dis. 2014;23:2694–700. [DOI] [PubMed]

98.

Phinney DG. Functional heterogeneity of mesenchymal stem cells: implications for cell therapy. J Cell Biochem. 2012;113:2806–12. [DOI] [PubMed]

99.

Giebel B. On the function and heterogeneity of extracellular vesicles. Ann Transl Med. 2017;5:150. [DOI] [PubMed] [PMC]