<p>Neuroprotective Effect of Mesenchymal Stromal Cell-Derived Extracellular Vesicles Against Cerebral Ischemia-Reperfusion-Induced Neural Functional Injury: A Pivotal Role for AMPK and JAK2/STAT3/NF-κB Signaling Pathway Modulation</p>

Abstract

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.

Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

“…MSC-EVs have been shown to regulate the AMPK and JAK2/STAT3/NF-κB signaling pathways [ 164 ]. In a rat stroke model, MSC-EVs significantly alleviated neurological deficits by increasing phosphorylation of AMPK, and reducing phosphorylation of JAK2, STAT3 and NF-κB [ 164 ].…”

“…MSC-EVs have been shown to regulate the AMPK and JAK2/STAT3/NF-κB signaling pathways [ 164 ]. In a rat stroke model, MSC-EVs significantly alleviated neurological deficits by increasing phosphorylation of AMPK, and reducing phosphorylation of JAK2, STAT3 and NF-κB [ 164 ]. Following MCAO and MSC treatment, exosomes containing miR-133b have been detected in neurons where they promote neurite outgrowth via down-regulation of RhoA expression [ 68 ].…”

Mesenchymal Stromal Cells Perspective: New Potential Therapeutic for the Treatment of Neurological Diseases

“…EVs of MSCs have been reported to promote neurite development in middle cerebral artery (MCA) stroke models [ 22 ]. Moreover, MSC-EVs significantly upregulated p-AMPK and downregulated p-JAK2, p-STAT3, and p-NF-κB, which resulted in improvements in pathological lesions in cortical brain tissue and the attenuation of neuronal apoptosis in the cortex of an MCA occlusion rat model [ 23 ]. In addition, anti-inflammatory and immunomodulatory effects of MSC-derived exosomes are reported to be exerted by miR-30d inhibiting autophagy-mediated microglial polarization to M1 [ 24 ].…”

Jak2 Inhibitor AG490 Improved Poststroke Central and Peripheral Inflammation and Metabolic Abnormalities in a Rat Model of Ischemic Stroke

“…Furthermore, either with the reduction of IL-6 levels through anti-inflammatory treatments or the intravenous injection of IL-6 neutralizing antibodies, cerebral ischemic damage can be alleviated [ 24 , 25 , 26 , 27 ]. Besides this, the inhibition of the Jak2/Stat3 pathway that can be activated with excess IL-6 during the acute phase of cerebral ischemia confers neuroprotection in ischemic stroke [ 28 , 29 , 30 , 31 , 32 , 33 ]. Taken altogether, these findings indicated the deleterious effects of IL-6 on neuronal injury after cerebral ischemia.…”