Table 2.
Functions of native SC-EVs
| Disease | Source of EVs | Animal Model | Administration Route | Therapeutic Effects | Mechanism of Action | Reference |
|---|---|---|---|---|---|---|
| AD | hUCMSCs | APP/PS1 mice | tail vein | ↑cognitive impairments | ↓Nrf2 | 57 |
| ↓hippocampal Aβ aggregation | ||||||
| ↓neuronal loss | ||||||
| mBMSCs | STZ mice | lateral ventricle | ↑behaviors function | ↑synapse-related proteins | 58 | |
| tail vein | ↓hyperactivation of microglia and astrocytes | ↑BDNF | ||||
| ↓imflammation | ||||||
| hiMSCs | STZ mice | intracisternal | ↓neuroinflammation | containing miR-223-3p | 59 | |
| ↓amyloid deposition | ↓NLRP3/GSDMD | |||||
| ↓neuronal apoptosis | ||||||
| ↓cognitive dysfunction | ||||||
| rBMSCs | Aβ1-42-injected rats | lateral ventricle | ↑cognitive function | containing miR-29c-3p | 60 | |
| ↓Aβ plaques, Aβ deposition areas and levels of Aβ1-42-injected | ↓BACE1 | |||||
| ↑NEP and IDE | ↑Wnt/β-catenin | |||||
| ↓inflammatory cytokine | ||||||
| hBMSCs | 5XFAD mice | intranasally | ↑cognitive function | NA | 61 | |
| ↓Aβ plaque | ||||||
| mNSCs | APP/PS1 mice | lateral ventricle | ↑cognitive behavior | ↑SIRT1 | 62 | |
| ↑mitochondrial biogenesis | ↑PGC1c | |||||
| ↓astrocyte activation | ↑NRF1 | |||||
| ↑COXIV | ||||||
| PD | TMSCs | MPTP mice | intraperitoneally | ↓the loss of DA neurons | containing miR-100-5p | 63 |
| ↑nigro-striatal system function | ↓NOX4 | |||||
| ↑moter function | ↓ROS | |||||
| ↓oxidative stress | ↑Nrf2 | |||||
| hUCMSCs | 6-OHDA rats | tail vein | ↑moter function | contain MiR-7, miR-125-5p, miR-122-5p, miR-126-3p, miR-199-3p | 64 | |
| lateral ventricle | ↑dopamine content | |||||
| ↓neuronal damage | ||||||
| ↓microglial activation | ||||||
| hBMECs | MPTP mice | intraperitoneally | ↑angiogenesis | ↑ICAM1-SMAD3/P38MAPK | 65 | |
| hNSCs | 6-OHDA mice | intracerebral | ↑neuroprotection | containing hsa-mir-182-5p, hsa-mir-183-5p, hsa-mir-9, hsa-let-7 | 66 | |
| ↓dopaminergic neuronal loss | ↓ROS | |||||
| ↓pro-inflammatory cytokines | ↓associated apoptotic pathways | |||||
| stroke | rADMSCs | MCAO rats | lateral ventricle | ↓brain injury | containing miR-22-3p | 67 |
| ↑neuron viability | ↓KDM6B | |||||
| ↓apoptosis | ↓BMP2/BMF axis | |||||
| mBMSCs | MCAO mice | tail vein | ↓infarct area | containing KLF4 | 68 | |
| ↓neuronal injury | ↑lncRNA-ZFAS1 | |||||
| ↓apoptosis | ↓Drp1 m6A modification by targeting FTO | |||||
| mNPCs | MCAO mice | femoral vein | ↑neurological recovery | NA | 69 | |
| mADMSCs | retroorbital | ↑neuroprotection | ||||
| ↑cell proliferation | ||||||
| ↓pro-inflammatory | ||||||
| rBMSCs | MCAO mice | tail vein | ↓infarct volume | ↑miR-21-5p | 70 | |
| ↑neurological functions | ↑VEGF, VEGFR2, Ang-1, and Tie-2 | |||||
| ↑microvessel density | ||||||
| BMSCs | MCAO rats | tail vein | ↓cerebral infarction | ↑ZO-1 | 71 | |
| ↓BBB leakage | ↑Occludin | |||||
| ↓neurological function deficits | ↓MMP activity | |||||
| ↓Caveolin-1 | ||||||
| ↓CD147 | ||||||
| ↓VEGFR2 | ||||||
| ↓VEGFA | ||||||
| hBMSCs | MCAO rats | tail vein | ↓infarct volum | NA | 72 | |
| ↓motor-coordination deficits | ||||||
| ↓macrophage infiltrates | ||||||
| ↑angiogenesis | ||||||
| ↑neurogenesis | ||||||
| BMSCs | pMCAO rats | tail vein | ↓cerebral infarction volume | ↓Cav-1 | 73 | |
| ↓BBB permeability | ↑ZO-1 | |||||
| ↑neurological function | ↑Claudin-5 | |||||
| hADMSC | MCAO rats | intranasally | ↓infarct volume | NA | 74 | |
| ↑long-term motor | ||||||
| ↑behavioral impairment | ||||||
| hUCMSCs | MCAO mice | tail vein | ↓ tPA-induced disruption of BBB integrity | miR-125b-5p targete TLR4 | 75 | |
| ↓ hemorrhage | ↓NF-KB signaling in astrocytes | |||||
| ↓ astrocyte activation and inflammation | ||||||
| mNPCs | MCAO mice | femoral vein | ↑poststroke BBB integrity | ↓ABCB1 and MMP-9 regulation | 76 | |
| ↓inflammatory cell recruitment | ↓NF-κB pathway | |||||
| mBMSCs | tMCAO P9 mice | ventricle | ↓injury volume | NA | 77 | |
| intranasally | ↓cytokine/ chemokine accumulation | |||||
| hBMSCs | MCAO rats | tail vein | ↓infarct volume | ↑IL-33 | 78 | |
| ↑neurological function | ↓ST2 | |||||
| ↓neuronal deat | ||||||
| hBMSCs | MCAO young mice | intravenously | ↓neurological deficits | NA | 79 | |
| MCAO aged mice | ↓infarct volume | |||||
| ↓brain edema | ||||||
| ↓neuronal injury | ||||||
| ↑anti-inflammation | ||||||
| ↓leukocyte infiltrate | ||||||
| ↓monocytes and activated T cells | ||||||
| rBMSCs | MCAO rats | tail vein | ↓brain infarct area | ↓NLRP3 inflammasome-related proteins | 80 | |
| ↓brain water content | ↓pyroptosis-related proteins | |||||
| ↑neurological function | ||||||
| ↑M1-polarized microglia shifting toward M2 phenotype | ||||||
| hUCMSCs | MCAO mice | tail vein | ↓infarct volume | containing miR-146a-5p | 81 | |
| ↓behavioral deficits | ↓IRAK1/TRAF6 pathway | |||||
| ↓microglia activation | ||||||
| ↓neuroinflammation | ||||||
| hiNSCs | MCAO mice | lateral ventricle | ↓inflammatory response | containing hsa-miR-30a-5p | 82 | |
| ↓oxidative stress | containing hsa-miR-7-5p | |||||
| ↑NSCs differentiation | ||||||
| ↓cerebral infarction | ||||||
| ↓neuronal death | ||||||
| ↓glial scarring | ||||||
| ↑recovery of motor function | ||||||
| rNSCs | MCAO/R Rat | tail vein | ↓the infarction of brain tissues | carrying YBX1 | 83 | |
| ↓neuronal pyroptosis | ↑stability of m6A-modified GPR30 by interacting with IGF2BP1 | |||||
| ↑GPR30 | ||||||
| ↓activation of NLRP3 inflammasome through promoting NLRP3 ubiquitination by SPOP | ||||||
| BMSCs of young monkey | cortical injury aged monkeys | intravenous | ↑functional recovery | ↑myelin-related genes | 84 | |
| ↓damaged oligodendrocytes | ↑actively myelinating oligodendrocytes in sublesional white matter | |||||
| ↑myelin maintenance | ||||||
| mNSCs | MCAO mice | left stratum | ↓infarct volume | containing miR-128-3p | 85 | |
| ↓neurological function | ↑myelin basic protein expression | |||||
| ↑OPC differentiation | ↓BMP signaling |
AD, Alzheimer's Disease; PD, Parkinson's Disease; h, human; r, rat; m, mouse; BMSCs, bone marrow-derived mesenchymal stem cells; UCMSCs, Umbilical cord mesenchymal stem cells; ADMSCs, adipose-derived stem cells; iMSCs, induced pluripotent stem cell-derived mesenchymal stem cells; NSCs, neural stem cells; T-MSCs, trophoblast stage-derived mesenchymal stem cells; NPCs, neural progenitor cells; iNSCs, induced pluripotent stem cell-derived neural stem cells; 5XFAD mice, 5 familial Alzheimer's disease mutations; MCAO, middle cerebral artery occlusion; pMCAO, permanent middle cerebral artery occlusion; 6-OHDA, 6-hydroxy-dopamine; Nrf2, nuclear factor E2-related factor 2; STZ, streptozotocin; BDNF, brain-derived neurotrophic factor; Aβ, amyloid β; BACE1, β-site amyloid precursor protein cleaving enzyme 1; SIRT1, sirtuin 1; PGC1c, peroxisome proliferator-activated receptor-γ coactivator-1ɑ; NRF1, nuclear respiratory factor 1; COXIV, cytochrome C oxidase IV; ROS, reactive oxygen species; NOX4, nicotinamide adenine dinucleotide phosphate oxidase 4; BMP2, Bone morphogenetic protein 2; BMF, Bcl-2 modifying factor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; MMP, matrix metalloproteinase; Cav-1, Caveolin-1; BBB, blood-brain barrier; ABCB1, ATP-binding cassette transporter B1; MMP-9, matrix metalloproteinase 9; NF-κB, nuclear factor-kappa B; IL, interleukin; ST2, suppression of tumorigenicity 2 receptor; NLRP3, NACHT, LRR and PYD domain-containing protein 3; IRAK1, interleukin-1 receptor-associated kinase 1; TRAF6, TNF receptor-associated factor 6; YBX1, Y box binding protein; GPR30, G protein-coupled receptor 30; SPOP, speckle-type POZ protein; BMP, bone morphogenetic protein; OPCs, oligodendrocyte progenitor cells; MAPK, mitogen-activated kinase; KLF4, Kruuppel-like factor 4; ZFAS1, zinc finger antisense 1; FTO, targeting obe- sity-associated protein; NA, not available.