MiR-126 Mediates Brain Endothelial Cell Exosome Treatment–Induced Neurorestorative Effects After Stroke in Type 2 Diabetes Mellitus Mice

Abstract

Background and Purpose— Stroke patients with type 2 diabetes mellitus (T2DM) exhibit increased vascular and white matter damage and have worse prognosis compared with nondiabetic stroke patients. We investigated the neurorestorative effects of exosomes derived from mouse brain endothelial cells (EC-Exo) as treatment for stroke in T2DM mice and investigated the role of miR-126 in mediating EC-Exo–derived therapeutic benefits in T2DM-stroke mice. Methods— Adult, male BKS.Cg-m+/+Lepr db /J (T2DM) mice were subjected to photothrombotic stroke model. T2DM mice were intravenously injected at 3 days after stroke with (1) PBS; (2) liposome mimic (vehicle control, 3×10 10 ); (3) EC-Exo (3×10 10 ); (4) knockdown of miR-126 in EC-Exo (miR-126 − /− EC-Exo, 3×10 10 ). Behavioral and cognitive tests were performed, and mice were sacrificed at 28 days after stroke. Results— Compared with non-DM stroke mice, T2DM-stroke mice exhibit significantly decreased serum and brain tissue miR-126 expression. Endothelial cells and EC-Exo contain high levels of miR-126 compared with other cell types or exosomes derived from other types of cells, respectively (smooth muscle cells, astrocytes, and marrow stromal cells). Compared with PBS or liposome mimic treatment, EC-Exo treatment of T2DM-stroke mice significantly improves neurological and cognitive function, increases axon density, myelin density, vascular density, arterial diameter, as well as induces M2 macrophage polarization in the ischemic boundary zone. MiR-126 −/− EC-Exo treatment significantly decreases miR-126 expression in serum and brain, as well as attentuates EC-Exo treatment–induced functional improvement and does not significantly increase axon and myelin density, vascular density, arterial diameter or induce M2 macrophage polarization in T2DM-stroke mice. In vitro, EC-Exo treatment significantly increases primary cortical neuron axonal outgrowth and increases endothelial capillary tube formation whereas miR-126 −/− EC-Exo attentuates EC-Exo induced capillary tube formation and axonal outgrowth. Conclusions— EC-Exo treatment of stroke promotes neurorestorative effects in T2DM mice. MiR-126 may mediate EC-Exo–induced neurorestorative effects in T2DM mice. Visual Overview— An online visual overview is available for this article.

Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI

“…Specifically, the exosomes were intravenously injected via tail vein at a dose of 3 Â 10 10 in 200 mL PBS per mouse. 38 Although the mice did lose body weight during the repetitive impacting procedure, they rapidly regained spontaneous respiration, righting reflex, and the ability to ambulate after each time of injury. The body weight gradually recovered before receiving treatment at 35 DPI, and no difference was observed among the treatment groups after injury ( Figure S1).…”

Strawberry Leaf Extract Treatment Alleviates Cognitive Impairment by Activating Nrf2/HO-1 Signaling in Rats With Streptozotocin-Induced Diabetes

“…Cognitive deficit is a common but underestimated complication of DM that can cause learning and memory dysfunction (Koekkoek et al, 2015 ). The impairment of cognitive function is characterized by a decline in memory, language, and the ability to process complex information, while the decline in the basic attention process, motor reaction time, and transient memory may be relatively small (Venkat et al, 2019 ). The mechanism of diabetes-associated cognitive impairment (DACI) is not entirely clear.…”

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

“…(2) neuronally expressed miR-126-5p regulates angiogenesis by protecting endothelial cells of the developing retinal vasculature from apoptosis [31]; (3) miR-126 is essential for endothelial phenotype expression, promoting endothelial differentiation in autograft adipose-derived stem cells [32] and highlighting that miR-126 from endothelial cells and exosomes from these cells present neurorestorative effects in DMII mice [33]; and, finally, miR-126 presents a protective effect during hypoxia/reoxygenation in endothelial cells mediated by the PI3K/Akt/endothelial nitric oxide synthase (eNOS) signaling pathway [34].…”