Table 7.
Summary of therapeutic efficacy and safety of MSC-secretome and EVs in preclinical animal models of AIS.
| Study | Animal model | Therapeutic agent | Route and dosage | Main outcomes |
|---|---|---|---|---|
| Xin et al. [127] | Adult male Wistar rats were subjected to transient MCAO | EVs from rBM-MSCs | Intravenous injection of 100 μg of EVs | Improvement in functional recovery. |
| Increasing in axonal density and synaptophysin-positive areas. | ||||
| Increasing in the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells. | ||||
| Doeppner et al. [128] | C57BL6 mice subjected to transient MCAO | EVs from hBM-MSCs | Intravenous injection | Improvement in neurological impairment. |
| Long-term neuroprotection. | ||||
| Enhancement in angiogenesis and neurogenesis. | ||||
| Cerebral immune cell infiltration was not affected. | ||||
| Chen et al. [129] | Adult male Sprague-Dawley rats subjected to transient MCAO | EVs from mini-pig A-MSCs | Intravenous injection of 100 μg of EVs | Reduction of the brain-infarct zone. |
| Enhancement in neurological recovery. | ||||
| Lee et al. [135] | Male Sprague-Dawley rats subjected to permanent MCAO | EVs from hMSCs primed with normal/ischemic brain extract | Intravenous injection of 0.2 mg of EVs per kg | Enhancement of angiogenesis. |
| Enhancement of neurogenesis. | ||||
| Anti-inflammatory action. | ||||
| Enhancement of behavioral recovery. | ||||
| Reduction of the brain infarct zone. | ||||
| EVs from MSCs primed with normal or ischemic brain extract had significantly greater efficacy. | ||||
| Xin et al. [130] | Adult male Wistar rats subjected to transient MCAO | EVs from rBM-MSCs enriched or not with miR-17-92 | Intravenous injection of 100 μg of EVs | Improvement of functional recovery. |
| Improvement of neurological function. | ||||
| Enhancement of oligodendrogenesis, neurogenesis, and neurite remodeling/neuronal dendrite plasticity in the ischemic boundary zone. This effect was primarily observed for EVs enriched with miR-17-92. | ||||
| Otero-Ortega et al. [137] | Male Sprague-Dawley rats subjected to SCI | EVs from rA-MSCs | Intravenous injection of 100 μg of EVs | Improvement of functional recovery. |
| Enhancement of fiber tract integrity, axonal sprouting and white matter repair markers. | ||||
| Han et al. [138] | Adult male Wistar rats subjected to ICH | EVs from rBM-MSCs | Intravenous injection of 100 μg of EVs | Improvement of neurological function. |
| Improvement of motor recovery. | ||||
| Enhancement of angiogenesis. | ||||
| Enhancement of neurogenesis. | ||||
| Huang et al. [131] | Adult male Sprague-Dawley rats subjected to transient MCAO | EVs from rA-MSCs modified with pigment epithelial-derived factor | Intraventricular injection of 100 μg of EVs per kg | Amelioration of cerebral injury. |
| Activation of autophagy. | ||||
| Suppression of neuronal apoptosis. | ||||
| Jiang et al. [136] | Adult male Sprague-Dawley rats subjected to permanent MCAO | EVs from rA-MSCs enriched with miR-30d-5p | Intravenous injection of 80 μg of EVs | Reduction of the cerebral injury area of infarction. |
| Suppression of autophagy. | ||||
| Promotion of M2 microglia/macrophage polarization. | ||||
| Geng et al. [132] | Sprague-Dawley rats subjected to transient MCAO | EVs from miRNA-126-modified AD-MSCs | Intravenous injection | Improved functional recovery and significant increase of the expression of von Willebrand factor (an endothelial cell marker) and doublecortin (a neuroblasts marker). |
| Decrease of neuron cell death and increase of cell proliferation. | ||||
| Liu et al. [133] | Sprague Dawley rats (8–12 weeks) subjected to transient MCAO | EVs from rBM-MSCs loaded with enkephalin | Intravenous injection | EVs crossed the blood-brain barrier. |
| Reduction of LDH, p53, caspase 3, and NO levels. | ||||
| Improvement of brain neuron density. | ||||
| Improvement of the neurological score. | ||||
| Moon et al. [134] | Sprague-Dawley rats subjected to transient MCAO | EVs from rMSCs | Intravenous injection of 30 μg of EVs | Enhancement of neurogenesis. |
| Enhancement of angiogenesis. | ||||
| Improvement of behavior. |
MCAO = middle cerebral artery occlusion; ICH = intracerebral hemorrhage; SCI = subcortical infarct.
r = rat; h = human.
BM = bone marrow; A = adipose.