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

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.

Keywords:

• extracellular vesicles
• cerebral ischemia reperfusion
• neuroprotection
• AMPK
• nuclear factor κB
• JAK2/STAT3 signaling pathway

Abbreviations

AMPK, AMP-activated protein kinase; ECA, external carotid artery; EVs, extracellular vesicles; JAK2/STAT3, Janus kinase2/signal transducer and activator of transcription3; HE, hematoxylin and eosin staining; ICA, internal carotid artery; MSCs-EVs, extracellular vesicles derived from mesenchymal stromal cells; MCAO, middle cerebral artery occlusion; NF-κB, nuclear factor kappa B; RT-PCR, reverse transcription-polymerase chain reaction; TEM, transmission electron microscopy; TTC, 2,3,5-triphenyltetrazolium chloride; TUNEL, terminal-deoxynucleotidyl transferase mediated nick end labeling.

Disclosure

No potential conflict of interest was reported by the authors.