Background and Purpose: Roughly 1 in every 3 stroke patients is diabetic and suffers from an increased risk of stroke recurrence, worse prognosis, and exacerbated vascular and white matter (WM) injury that hinders long term recovery. Hence, there is a critical need to develop therapeutic strategies specifically to improve neurological functional outcome after stroke in the diabetic population. We investigated the neurorestorative effects of treatment of stroke in rats with type 2 diabetes mellitus (T2DM) with bone marrow stem cell (MSC) derived exosomes (T2DM-MSC-Exo) and the mechanisms underlying the therapeutic effect.
Methods: Adult male Wistar rats were induced with T2DM using a combination of high fat diet and low dose Streptozotocin and were subjected to transient middle cerebral artery occlusion (MCAo). Three days after MCAo, rats were randomized (n=10/group) and treated via tail-vein injection with: 1) phosphate-buffered-saline (PBS); or 2) T2DM-MSC-Exo (3х1011). A battery of neurological tests was performed and rats were sacrificed at 28 days after stroke for immunohistochemical evaluation.
Results: In T2DM rats, stroke treatment using T2DM-MSC-Exo initiated at a delayed time point (3 days after stroke) significantly (p<0.05 vs. PBS treated T2DM-MCAo rats) improves functional outcome, reduces blood brain barrier (BBB) leakage and hemorrhage, but does not affect blood glucose or lesion volume. Delayed stroke treatment with T2DM-MSC-Exo in T2DM rats, significantly (p<0.05) increases axon and myelin density, increases oligodendrocytes and oligodendrocyte progenitor cell numbers in the ischemic border zone compared to PBS treated T2DM-MCAo rats. Treatment of T2DM stroke rats with T2DM-MSC-Exo significantly (p<0.05) increases the expression of ATP-binding cassette transporter 1 (ABCA1) and Insulin-like growth factor 1 receptor (IGFR1) compared to PBS treated T2DM-MCAo rats.
Conclusion: Delayed treatment of T2DM stroke using T2DM-MSC-Exo significantly promotes long term neurological functional recovery and neurorestorative effects. These beneficial effects may be mediated by a decrease in BBB leakage and hemorrhage, increase in axon and myelin density, and up regulation of the ABCA1-IGFR1 pathway.