Patients with subarachnoid hemorrhage (SAH) often suffer from cognitive function impairments even when they have received proper treatment, such as the clipping or coiling of aneurysms, and this causes problems with returning to work and burdens the family. Increasing attention has been paid to mesenchymal stem cell (MSC)-derived extracellular vesicle (MSC-EV) as promising therapeutic vesicles for stroke management. In this study, we explored the potential role of MSC-EV in a rat model of SAH. We observed that MSC-EV ameliorated early brain injury (EBI) after SAH by reducing the apoptosis of neurons and that SAH induced an increase in the expression level of miR-21 in the prefrontal cortex and hippocampus. In addition, using miRNA profiling and CSF sequencing data from the exRNA Atlas, we demonstrated that EV-derived miR-21 protected neurons from apoptosis and alleviated SAH-induced cognitive dysfunction. The neuroprotective role of MSC-EV was abrogated by miR-21 knockdown or the administration of MK2206, a PTEN/Akt inhibitor. Overall, our results suggest that MSC-EV promotes neuronal survival and alleviates EBI after SAH through transferring miR-21 to recipient neurons.

Peroxisome proliferator‐activated receptors (PPARs) are nuclear receptors which down‐regulate inflammatory signaling pathways. Therefore, we hypothesized that alterations of PPAR functions can contribute to human immunodeficiency virus‐1 (HIV‐1)‐induced dysfunction of brain endothelial cells. Indeed, treatment with HIV‐1 transactivator of transcription (Tat) protein decreased PPAR transactivation in brain endothelial cells. We next stably over‐expressed PPARα and PPARγ in a newly developed cell line of human brain endothelial cells (hCMEC/D3 cells). Tat‐induced up‐regulation of inflammatory mediators, such as interleukin (IL)‐1β, tumor necrosis factor‐α, CCL2, and E‐selectin were markedly attenuated in hCMEC/D3 over‐expressing PPARα or PPARγ. These results were confirmed in CCL2 and E‐selectin promoter activity studies. Similar protective effects were observed in hCMEC/D3 after activation of PPARγ by exogenous PPAR agonists (dPGJ2 and rosiglitazone). PPAR over‐expression also prevented Tat‐induced binding activity and transactivation of nuclear factor‐κB. Importantly, increased PPAR activity attenuated induction of IL‐1β, tumor necrosis factor‐α, CCL2, and E‐selectin in hCMEC/D3 cells co‐cultured with HIV‐1‐infected Jurkat cells. The protective effects of PPAR over‐expression were reversed by the antagonists of PPARα (MK886) or PPARγ (GW9662). The present data suggest that targeting PPAR signaling may provide a novel therapeutic approach to attenuate HIV‐1‐induced local inflammatory responses in brain endothelial cells.

Introduction: Cerebral ischemia-reperfusion injury (CIRI) is the main factor that leads to poor prognosis of cerebral ischemia. Apoptosis has been shown to occur during the process of CIRI. Extracellular vesicles derived from mesenchymal stromal cells (MSCs-EVs) have shown broad potential for treating brain dysfunction and eliciting neuroprotective effects after stroke through neurogenesis and angiogenesis. However, the mechanism of action of extracellular vesicles during CIRI is not well known. Methods: A middle cerebral artery occlusion (MCAO) model was induced by the modified Longa method, and MSCs-EVs were injected via the tail vein. Results: Our results showed that MSCs-EVs significantly alleviated neurological deficits, reduced the volume of cerebral infarction and brain water content, improved pathological lesions in cortical brain tissue, and attenuated neuronal apoptosis in the cortex at 24 h and 48 h after MCAO in rats. Western blotting analysis showed that MSCs-EVs significantly upregulated p-AMPK and downregulated p-JAK2, p-STAT3 and p-NF-κB. In addition, an AMPK pathway blocker reversed the effect of MSCs-EVs on brain damage. Conclusion: These results indicate that MSCs-EVs protected MCAO-injured rats, possibly by regulating the AMPK and JAK2/STAT3/NF-κB signaling pathways. This study supports the use of MSCs-EVs as a potential treatment strategy for MCAO in the future.

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