Neurorestorative therapy of stroke in T2DM mice with exosomes derived from brain endothelial cells.
Chen J, Cui C, Zacharek A, Venkat P, Yu P, and Chopp M. Neurorestorative therapy of stroke in T2DM mice with exosomes derived from brain endothelial cells. Stroke 2017; 48(Suppl 1).
MicroRNA-126 is primarily expressed in endothelial cells (ECs), and is emerging as a key player in the pathogenesis of type two diabetes (T2DM) induced vascular damage. Stroke in T2DM increases vascular and white matter (WM) damage in the ischemic brain, and has a poor prognosis compared to non-DM stroke. In this study, we investigated the neurorestorative effects of exosomes derived from mouse brain ECs (EC-Exo) as a treatment of stroke in T2DM mice. Methods: Adult male BKS.Cg-m+/+Leprdb/J (T2DM) and db/+ (non-DM) control mice (3-4 m) were subjected to right extraluminal permanent distal middle cerebral artery occlusion (dMCAo), and intravenous injection at 3 days after dMCAo with: 1) PBS; 2) Liposome mimic as vehicle control (3X1010); 3): EC-Exo (3x1010); 4) Knockdown of miR-126 in EC-Exo (miR-126-/-EC-Exo, 3X1010); 5) Knock-in miR- 126 in EC-Exo (miR-126+/+EC-Exo, 3X1010). Mice were sacrificed at 28 days after dMCAo.Results: 1) T2DM-dMCAo mice exhibit significantly decreased blood serum, brain tissue and brain-EC miR-126 expression compared to non-DM-dMCAo mice. 2) EC-Exo contain higher levels of miR-126 than exosomes derived from other types of cells (smooth muscle cells, neurons, astrocytes and marrow stromal cells); 3) EC-Exo treatment significantly increases axonal outgrowth and increases capillary tube formation in vitro. Compared to PBS or liposome mimic treatment groups, EC-Exo treatment of stroke in T2DM-dMCAo mice: 4) is safe and does not appear to induce adverse side effects in physiological parameters and does not decrease lesion volume, but significantly improves neurological outcome and cognitive function after dMCAo; 5) significantly increases axon, myelin, vessel density and increases artery diameter in the ischemic boundary zone; 6) significantly increases perfused vessel density measured by FITC-dextran injection. 7) miR-126-/-EC-Exo treatment significantly decreases, but miR- 126+/+EC-Exo increases miR-126 expression compared to EC-Exo control. 8) miR-126+/+EC-Exo treatment significantly improves functional outcomes when compared to miR-126-/-EC-Exo, or PBS control. Conclusion: Treatment of stroke with EC-Exo increases miR-126 expression and promotes neurorestorative effects after stroke in T2DM mice.