Abstract
Aim: To assess the efficacy of 3 doses of exosomes from adipose tissue derived human mesenchymal stem cells to identify the minimal effective dose to enhance brain repair and recovery after subcortical stroke in rats. Methods: Male and female Sprague-Dawley rats (250gr) were injected with endothelin-1 to induce subcortical stroke. 24h after stroke, exosomes were administrated by the tail vein. Study groups were: Sham (n=10): without stroke neither treatment; control: stroke+saline (n=8); stroke+low dose (50μg) (n=10); stroke+intermediate dose (100μg) (n=9); stroke+high dose (200μg) (n=10). We evaluated: motor function (Roger’s, Rotarod and Walking beam test) at 24h, 7 and 28d, lesion volume and tract connectivity were studied by magnetic resonance image at 24h and 28d, brain repair markers: GFAP (Glial Fibrillary Acidic Protein), MOG (Myelin Oligodendrocyte Glycoprotein), MBP (Myelin Basic Protein) by immunofluorescence at 28d. Results: Animals treated with 50μg, 100μg or 200μg of exosomes showed a significant improvement in functional evaluation compared to control (p<0.05). Between treatments, high dose of exosomes demonstrates better functional recovery than low and intermediate doses at 24h and 7d, but without significant differences at 28d (p<0.05). We did not observe reduction of lesion size in treated compared to control groups, however, all doses showed the same significant increase in tract connectivity compared to control group at 28d (p<0.01).All the doses (low, intermediate and high) decrease GFAP expression and increase MOG and MBP expression compared to control group. Also GFAP expression was significantly downregulated in high dose compared to intermediate and low doses (p<0.05).MOG expression was higher in intermediate and high doses compared to low dose (p<0.05). Conclusion: Intravenous administration of different doses of exosomes (50μg, 100μg and 200μg) improves the functional recovery, tract connectivity and expression of brain repair markers. Low dose is as effective as intermediate and high doses. Therefore, 50μg of exosomes is the minimal effective dose to enhance brain repair and recovery in stroke.From a translational point of view, this dose decreases the cost and risk.
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