Table 1.
The role of Exo in the diagnosis, therapy, and improvement of stroke-induced injuries in animal models
| Exosome | miRNA | The role | Mechanism | Reference |
|---|---|---|---|---|
| MSCs Exo | – | Enhancing functional recovery, plasticity, neurite remodeling, neurogenesis, and angiogenesis. in the neurovascular system in the MCAo rat model | Increasing the density of axons and synaptophysin in the ischemic boundary zone of the cortex and striatum | [29] |
| rabies virus glycoprotein (RVG)-decorated exosomes (RVG-Exo) | HMGB1-siRNA | Therapeutic effect for ischemic stroke in the MCAo model | Reducing TNF-α, apoptosis, and infarct size in the brain | [153] |
| MSCs derived Exo | miRNA-17-92 | Promoting neurological recovery after stroke in the neurovascular system in the MCAo rat model | Enhancing oligodendrogenesis, neurogenesis, neurite remodeling/neuronal dendrite plasticity and axonal outgrowth in the ischemic boundary zone (IBZ) by targeting phosphatase and tensin homolog to activate the PI3K/protein kinase B/mechanistic target of rapamycin/glycogen synthase kinase 3β pathway | [30] |
| M2 microglia-derived Exo | miRNA-124 | Reduction of ischemic brain injury and behavioral impairments three days after transient brain ischemia in the MCAo mouse model | Reducing neuronal apoptosis, and infarct volume, and increasing survival of neurons by targeting ubiquitin-specific protease 14 (USP14) | [154] |
| ADSCs Exo | miRNA-30d-5p | The protective effect and cerebral injury prevention after acute ischemic stroke in the rat model of AIS and an in vitro model of oxygen- and glucose-deprived (OGD) | Suppression of autophagy-mediated microglial polarization to M1 | [86] |
| lipopolysaccharide-stimulated macrophage RAW264.7 cell line (LPS-Exo) | – | Neuroprotection effect and functional recovery after ischemic stroke in a rat model of transient focal cerebral ischemia | Reduction of brain infarct size via polarization from the M1 phenotype to the M2 phenotype and suppression of inflammation | [51] |
| Endothelial progenitor cell-derived Exo | miRNA-126 | Functional recovery improvement in the C57BL/6 mice that received moderate treadmill exercise (10 m/min) for 4-wks and then were under MCAO surgery | Reduction of infarct volume, apoptosis, and promoting microvessel density, angiogenesis/neurogenesis, and better sensorimotor functions by targeting BDNF, p-TrkB/TrkB, and p-Akt/Akt signaling pathway | [155] |
| Adipose-derived mesenchymal stem cells-derived Exo | – | Neurological function improvement after acute ischemic stroke in the MCAo rat model | Decreasing ischemic volume, inflammation, and oxidative stress and increasing angiogenesis and return of blood to the ischemic area | [77] |
| Bone marrow-derived mesenchymal stem cells (BMSCs)-derived Exo | microRNA-138-5p | Neuroprotection to astrocytes and reduction of neurological impairment following ischemic stroke in the MCAO mice model | Prevention of astrocytes apoptosis and reduction of inflammatory factors expression through down-regulating neutrophil gelatinase-associated lipocalin (LCN2) | [156] |
| Exo with rabies virus glycoprotein (RVG) | miRNA-124 | Enhancing cortical neural progenitors to obtain neuronal identity and protection against ischemic injury | Promoting neurogenesis, angiogenesis, and neural plasticity | [21] |
| ADSCs Exo | miRNA-126 | Functional recovery improvement after stroke in the MCAo rat model | Enhancing von Willebrand factor (an endothelial cell marker) and doublecortin (a neuroblasts marker) expression, increasing cell proliferation and neurogenesis, inhibiting microglial activation, inflammatory factors expression, and decrease of neural death | [157] |
| Exosomal serum miRNA126 | miRNA-126 | Distinguishing severe permanent ischemia from milder injury after transient ischemia through changes in exosomal serum miRNA-126 in the transient focal cerebral ischemia rat model | Reducing of serum miR-126 at 3 h after permanent ischemia but not transient ischemia and the serum miR-126 levels back the closing to baseline in both permanent and transient ischemia after 24 h | [158] |
| Bone marrow stem cells Exo | – | Neuroprotection and functional recovery in the MCAo rat model | Reduction of infarct volume, diminishing of GFAP positive cells and lipid peroxidation, and downregulating of NLRP1 and NLRP3 genes represent a lower rate of cell death | [159] |
| Exo were extracted from the peri-ischemic striatum | miRNA 146b | Neurological injury improvement after ischemic stroke in the MCAo rat model | Increasing exosomal biomarkers TSG101 and CD81 and enhancing differentiation of neural stem cells into neurons in the peri-ischemic striatum | [160] |
| Human neural stem cells derived Exo | hsa-miRNA-206, hsa-miRNA-133a-3p and hsa-miRNA-3656 | Therapeutic ability and improvement of behavioral and structural outcomes in ischemic stroke in the MCAo rat model | Promoting cell proliferation and cell survival and reducing cell apoptosis in vitro by stimulating interferon-gamma (IFN-γ) | [161] |
| CSF and plasma-derived Exo | miRNA-122-5p and miR-300-3p | Potential blood-based biomarkers for the transient ischemic attack in the MCAo rat model | Downregulating of plasma exosomal rno-miR-122-5p in 10 min ischaemic rats and upregulating of plasma exosomal rno-miR-300-3p in 5 min ischaemic rats | [162] |
| MSCs derived Exo | miRNA 133b | Functional recovery after stroke in the MCAo rat model | Neurite remodeling/brain plasticity in the ischemic boundary zine with a contribution from a stimulated secondary secretion of neurite-enhancing exosomes from astrocytes | [31] |
| Bone marrow-derived MSCs Exo | miRNA-210 | Enhancing angiogenesis, brain tissue repair, and animal survival rat after cerebral ischemia in the transient MCAo mouse model | Increasing integrin β3, vascular endothelial growth factor (VEGF) expression, and upregulating CD34 | [103] |
| Enkephalin delivery using Exo | – | Improving neurological recovery and neurological score after stroke in the transient MCAo rat model | Suppressing neuron apoptosis caused by glutamate, increasing neuron density, and reducing the levels of LDH, p53, caspase-3, and NO | [163] |
| Exo secreted from human umbilical cord blood (HUCB)-derived MSCs under in vitro hypoxic conditions | – | Decreasing the post-stroke brain injury and ameliorating the neurological outcome in the transient MCAo rat model | Diminishing the infarct volume and swelling of the ipsilateral hemisphere | [164] |
| Astrocyte Exo | miRNA-7670-3p | Improving ischemic brain damage in the MCAo mouse model | Upregulating of shuttled circSHOC2astrocyte-derived exosomes, reduction of neuronal apoptosis by regulating neuronal autophagy via the miR-7670-3p/SIRT1 Axis | [89] |
| MSCs Exo | – | Restoring white matter integrity and promoting neurovascular remodeling and functional recovery in adult male rats were subjected to intracerebral hemorrhage (ICH) | Improving lesion size, fiber tract integrity, axonal sprouting, and white matter repair markers | [141] |
| Human umbilical cord mesenchymal stem cells (HUC-MSCs) Exo | – | Improvement of cognition and promoting oligodendrogenesis and remyelination after stroke in the transient MCAo rat model | Overexpression of chemokine receptor type 2 (CCR2) in the HUC-MSCs-derived exosomes, inhibiting activation and migration of CCL2-induced hematogenous macrophage and increasing and microglia/macrophage M2 polarization | [165] |
| Bone mesenchymal stem cell Exo | miRNA-29b-3p | Improving ischemic brain injury, suppressing apoptosis, and enhancing angiogenesis in the MCAo rat model | PTEN negatively regulation and Akt signaling pathway activation | [166] |
| Endothelial progenitor cells (EPCs) Exo | miRNA‐126 | Decreasing acute damage and improving neurological function recovery after ischemic stroke in the MCAo mouse model | Downregulating cleaved caspase‐3, upregulating vascular endothelial growth factor receptor 2 (VEGFR2), diminishing infarct volume. enhancing cerebral blood flow (CBF) and cerebral microvascular density (MVD) ameliorating angiogenesis and neurogenesis | [167] |
| Ischemic cerebral endothelial cell-derived Exo | – | Maintaining vascular and neuronal homeostasis in the normal and ischemic brain in the transient MCAo rat model | Enhancing axonal growth and axonal remodeling in cortical neurons | [168] |
| Bone marrow mesenchymal stem cells Exo harvested from type two diabetes rats | – | Ameliorating of neurological function and restoration of neurons after stroke in type two diabetes rats in the transient MCAo rat model | Decreasing post-stroke weight loss, enhancing tight junction protein ZO-1, promoting the integrity of the blood–brain barrier (BBB), remodeling of the white matter, the density of axon and myelin, oligodendrocytes and oligodendrocyte progenitor cell numbers, primary cortical neuronal axonal outgrowth, expression of miR-9 target ABCA1 (ATP-binding cassette transporter 1) and IGFR1 (Insulin-like growth factor 1 receptor) and diminishing activated microglia, M1 macrophages, inflammatory factors MMP-9 (matrix metalloproteinase-9), MCP-1 (monocyte chemoattractant protein-1) in the ischemic border area of the brain and decreasing of miR-9 expression in serum | [169] |