Table 2 Protective and healing effects or potential therapeutic value of BEV on TBIa
EV Sources: Cell type/ Tissue/species | Subset of BEV | Key component of BEV | Animal model/ Sampling time point | Protective and healing effects of BEV | Mechanisms/Main findings | Ref |
|---|---|---|---|---|---|---|
Stem cells from human exfoliated deciduous teeth (SHED)/culture medium/human | SHED-derived EVs | miR-330-5p | TBI/48 h after treatments, within 21 days after treatments | •Anti-inflammatory •Improve neurological function | SHED-EVs carrying miR-330-5p inhibited the secretion of inflammatory cytokines and promoted the recovery of motor function in TBI rats | Li Y et al. [107] |
Astrocytes/culture medium/mouse | Astrocytes derived EVs | miR-873a-5p | TBI/ 1, 3, 7 and 14 days post-injury | •Anti-inflammatory •Improve neurological function | Astrocyte-derived EVs carrying miR-873a-5p inhibited the NF-κB signaling pathway, thereby attenuating microglia-mediated neuroinflammation and improving neurological deficits after TBI | Long X et al. [108] |
BV2 microglial cells/ culture medium/mouse | Microglia-derived EVs | miR-124-3p | TBI/3, 7, 14 , 21, 28,32 and 35 days post-injury | •Anti-inflammatory •Neuroreparative functions | Microglia-derived EVs carrying miR-124-3p can suppress neuronal inflammation and promote neurite outgrowth after TBI | Huang S et al. [109] |
Astrocytes/culture medium/Rat | Astrocytes-derived EVs | Specific subset of miRNAs | — | Neuroprotective function | •Astrocytes modify miRNAs in EVs in response to changes in the extracellular microenvironment •Modified miRNAs regulate synaptic stability and neuronal excitability to reduce the activity of target neurons | Chaudhuri AD et al. [110] |
Neuron/cerebral cortex/Rat | Neuron-derived EVs | miR-181c-3p | Ischemic brain injury/1–5 days after surgery | •Anti-inflammatory | Cortical neuron-derived EVs carrying miR-181c-3p downregulate CXCL1-associated neuroinflammation and thus exert protective effect on IBI rats | Song H et al. [111] |
Neutrophils /plasma/human | Neutrophils-derived EVs | PS on membrane | — | Anti-inflammatory | Neutrophils release potent anti-inflammatory factors in the form of EVs at the earliest stages of inflammation and provide the impetus for resolution of inflammation | Gasser O et al. [112] |
Mesenchymal stem cells /culture medium/Rat | MSC-EV | — | TBI/1, 4, 7, 14, 21, 28, and 35 days post-injury | •Anti-inflammatory •Neuroreparative functions •Improve neurological function | MSC-derived EVs promote endogenous angiogenesis and neurogenesis and reduce inflammation after TBI are important reasons for functional recovery of TBI rats | Zhang Y et al. [113] |
Mesenchymal stem cells /culture medium/Rat | MSC-EV | miR-133b | Stroke/1, 3, 7, 14 days after surgery | •Neuroreparative functions •Improve neurological function | MSCs-derived EVs transfer miR-133b to astrocytes and neurons, promoting neurite remodeling and functional recovery after stroke | Xin H et al. [114] |
Astrocyte/brain/Mouse | Astrocyte-EV | Synapsin | — | •Neuroreparative functions •Neuroprotective function | Under conditions of high neuronal activity and/or oxidative stress, synapsin released by glial cell-derived EVs promote neurite outgrowth and neuronal survival by modulating the interaction between glial cells and neurons | Wang S et al. [115] |
Astrocytes/culture medium /Mouse | Astrocytes-EV | GJA1-20 k | TBI/6 days after treatments | Neuroprotective function | Compared with the GJA1-20 k-knockout EV control group, GJA1-20 k-carrying EVs were taken up by neurons and downregulated the apoptosis rate and upregulated the mitochondrial function to promote neuronal recovery | Chen W et al. [116] |
Schwann cells/culture medium /Rat | Schwann cells-EV | p75-Neurotrophin Receptor | Sciatic nerve injury/1–5 days post-injury | Neuroreparative functions | SC-derived EVs significantly enhanced axonal regeneration in vitro and promoted repair of injured sciatic nerves in vivo | Lopez-Verrilli MA et al. [117] |
Schwann cell/culture medium /Rat | rSC-EV | miRNA-21 | — | Neuroreparative functions | The expression of miRNA-21 is responsible for the pro-regenerative ability of rSC-EVs, which is associated with PTEN downregulation and PI3 kinase activation in neurons | Lopez-Leal R et al. [118] |
Adipose-derived stem cells/culture medium /Rat | ADSC-EV | miRNA-26b | Sciatic nerve injury/ 8 weeks after treatment | Neuroreparative functions | miRNA-26b in ADSC-EVs moderately reduces autophagy of damaged SCs by downregulating Kpna2, thereby promoting remyelination | Yin G et al. [119] |
Adipose stem cell/culture medium/Rat | ADSC-EV | — | — | Neuroreparative functions | The proliferation of SCs was significantly enhanced after ingesting ADSC-EVs, which may be an important mechanism for ADSC-EVs to promote sciatic nerve repair | Haertinger M et al. [120] |
Human umbilical vein endothelial cell-derived cell line EA.hy926 and human lung fibroblasts /culture medium /Human | HucMSC-EV | Wnt4 | Rat skin burn model/ 1 week and 2 weeks after treatment | Cutaneous wound healing | hucMSC-EV-mediated Wnt4 induces β-catenin activation in endothelial cells and promotes angiogenesis, which may be an important mechanism of cutaneous wound healing | Zhang B et al. [121] |
Human umbilical cord mesenchymal stem cells/culture medium /Human | HucMSC derived EV | — | Spinal cord injury/1 and 8 weeks after injury | •Anti-inflammatory, •Improve neurological function | hucMSC-derived EVs reduce inflammation to promote healing of the injured spinal cord | Sun G et al. [122] |
Human umbilical cord mesenchymal stem cells/culture medium /Human | HUCMSC‐EVs | — | Sciatic nerve injury/2, 4, 6 and 8 weeks after injury | •Anti-inflammatory •Neuroreparative functions, •Improve neurological function | HUCMSC-EVs provide a favorable microenvironment for nerve regeneration to promote functional recovery and nerve regeneration | Ma Y et al. [123] |
Bone Mesenchymal Stem Cells/culture medium /Rat | BMSC-Derived EV | — | TBI/ 1, 3, 7, and 14 days post-injury | •Anti-inflammatory, •Improve neurological function | BMSCs-EVs regulate the polarization of microglia/macrophages to suppress early neuroinflammation in TBI mice, thereby exerting a neuroprotective effect | Ni H et al. [124] |
Mouse and human bone marrow, gingival, and skin MSCs/culture medium /mouse and human | MSC-derived EV | Interleukin-1 receptor antagonist | Cutaneous wound/3,5, 7, 10, and 14 days after wound creation | Cutaneous wound healing | MSCs produce and release sEVs-associated interleukin-1 receptor antagonists to promote gingival wound healing through the Fas/Fap-1/Cav-1 cascade | Kou X et al. [125] |
Microglia/culture medium/mouse | Microglia-EVs | miR-5121 | TBI/1 and 3 days post-injury | •Neuroreparative functions •Improve neurological function | •Overexpression of miR-5121 in EVs improves motor function of TBI mice •miR-5121 may directly target RGMa to promote neurite outgrowth and synaptic recovery | Zhao C et al. [126] |
Mesenchymal stem cells /culture medium/Rat | MSC-Derived miR-133b EV | miR-133b | Spinal Cord Injury/ 12, 24 h, 2, 3, 4, 5, 7,9 and 14 days post-injury | •Neuroprotective function •Neuroreparative functions •Improve neurological function | EVs loaded with miR-133b protect neurons and promote axonal regeneration and recovery of hindlimb motor function in SCI rats | Li D et al. [127] |
Mesenchymal stem cells/culture medium /Human | MSCs-EV | CD63 and CD81 on membrane | TBI/6, 12 h, 28–33 and 35 days post-injury | •Anti-inflammatory •Improve neurological function | CD63+CD81+EVs isolated from mesenchymal stromal cells rescue cognitive impairment after TBI | Kim DK et al. [128] |
Bone marrow mesenchymal stem cells/culture medium/ Rat | BM-MSCs EV | — | Diabetes/1–5 days after treatment | Improve neurological function | Bone marrow-derived mesenchymal stem cells transfer EVs to damaged neurons and astrocytes to improve diabetes-induced cognitive impairment | Nakano M et al. [129] |
Bone marrow mesenchymal stem cells/culture medium/ Rat | BM-MSC-Derived miR-124 EV | miR-124 | TBI/3, 7, 14, 21, and 28 days post-injury | •Anti-inflammatory •Neuroreparative functions •Improve neurological function | EVs carrying miR-124 promote M2 polarization of microglia and improve hippocampal neurogenesis and functional recovery of TBI rats | Yang Y et al. [130] |
Mesenchymal Stromal Cells/Culture medium/ Rat | MSCs-EV | Specific miRNA、messenger RNAs and proteins, etc | Stroke/ 1, 3, 7, 14, 21, and 28 days after surgery | •Neuroreparative functions •Improve neurological function | MSC-EVs enhanced neurite remodeling, neurogenesis, and angiogenesis and improved functional recovery in stroke rats | Xin H et al. [131] |
Bone marrow-derived mesenchymal stem cells/Culture medium/Human | MSCs-EV | — | Status epilepticus/ 24 h after status epilepticus | •Anti-inflammatory •Neuroreparative functions, •Improve neurological function | MSC-derived A1-EVs attenuate inflammation and prevent abnormal neurogenesis and memory dysfunction after status epilepticus | Long Q et al. [132] |
Bone marrow mesenchymal stem cells /Culture medium/Human | MSCs-EV | — | Autism/3 weeks after treatment | Improve neurological function | Mesenchymal stem cell-derived EVs improve autism-like behavior by intranasal administration in BTBR mice | Perets N et al. [133] |
Umbilical cord mesenchymal stem cells /Culture medium /Human | UCMSCs-EV | Vascular endothelial growth factor C, angiopoietin-2, and fibroblast growth factor-2, etc | Nerve injury-induced pain/within 18 days after surgery | •Anti-inflammatory •Neuroreparative functions •Improve neurological function | Umbilical cord MSC-EVs inhibit spinal nerve ligation-induced neuroinflammation and promote the expression of anti-inflammatory cytokines and neurotrophic factors, and may be candidates for the treatment of pain caused by nerve injury | Shiue SJ et al. [134] |
Umbilical cord mesenchymal stem cells/Culture medium /Human | UCMSCs-EV | Specific protein and functional RNAs, etc | Nerve injury-induced pain/within 21 days after surgery | •Anti-inflammatory •Neuroreparative functions •Improve neurological function | UCMSCs-EVs exert analgesic, anti-inflammatory, and neurotrophic effects in a spinal nerve ligation-induced pain model | Hsu JM et al. [135] |
Mesenchymal stem cells/Culture medium /Human | MSCs– EV | — | TBI/ 1, 4,7, 14, 21, 28 and 31–35 days post-injury | •Anti-inflammatory •Neuroreparative functions, •Improve neurological function | MSCs–EVs not only reduced neuroinflammation and hippocampal neuron loss, but also promoted angiogenesis and neurogenesis, significantly improving sensorimotor and cognitive functions in TBI rats | Zhang Y et al. [136] |
Mesenchymal stem cells/Culture medium /Human | MSCs– EV | — | TBI and hemorrhagic Shock/1–7 days post injury | •Anti-inflammatory •Neuroreparative functions, •Improve neurological function | In a large animal model of TBI and hemorrhagic shock, early single-dose MSCs–EV treatment attenuated nerve damage by suppressing inflammation and apoptosis, and promoted neuroplasticity within 7 days | Williams AM et al. [137] |
ESC-derived mesenchymal stem cell /Culture medium /Human | MSCs– EV | Functional proteins and RNA | Heart model of ischemia/24 h after reperfusion | Tissue repair | MSCs–EV reduced infarct size in a mouse model of myocardial ischemia/reperfusion injury | Lai RC et al. [138] |
Multipotent human bone marrow derived mesenchymal stem cells/Culture medium /Human | hMSC-EV | — | TBI/1, 4, 7, 14, 21, 28 and 33–35 days post-injury | •Anti-inflammatory •Neuroreparative functions, •Improve neurological function | hMSC-EV significantly improved functional recovery of TBI rats by promoting endogenous angiogenesis and neurogenesis and reducing neuroinflammation | Zhang Y et al. [139] |
Mesenchymal stem cells/Culture medium /Human | MSCs-EV | — | Skin graft/within 15 days after transplantation | •Anti-inflammatory •Tissue repair | MSCs-EV are immunocompetent and enhance mouse skin allograft survival | Zhang B et al. [140] |
Bone marrow-derived mesenchymal stem cells/Culture medium/Rat | BDNF-induced MSCs-EV | miR-216a-5p | TBI/1, 7, 14, 28 and 31–35 days post-injury | •Anti-inflammatory •Neuroreparative functions, •Improve neurological function | Compared with MSCs-EV, BDNF-mediated MSCs-EVs better promote neurogenesis and inhibit apoptosis after TBI in rats, and the mechanism may be related to the high expression of miR-216a-5p | Xu H et al. [141] |
Mesenchymal stem cells/Culture medium /Human and Mouse | MSCs-EV | Specific miRNA | Hypoxia-induced pulmonary hypertension/ 2, 4, 7 and 11 days in hypoxia, 3 weeks of hypoxic exposure | Protect the lungs | MSCs-EV inhibited the hyperproliferative pathway to suppress pulmonary hypertension and exerted pleiotropic protective effects on the lung | Lee C et al. [142] |
Bone marrow-derived mesenchymal stem cells/Culture medium /Mouse | EV from MSCs of ischemic Preconditioning | miR-22 | Myocardial infarction/4 weeks after treatment | Cardioprotective function | miR-22 in MSCs-EV after ischemic preconditioning targets Mecp2 for cardioprotection | Feng Y et al. [143] |