What does this research mean for the field?

Extracellular vesicles derived from hypoxia-preconditioned human mesenchymal stem cells significantly reduce infarct size and diminish arrhythmias in ischemia-reperfusion injury by suppressing GSK3β expression via miRNA-26a. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

January 1, 2018Open Access

Extracellular Vesicles Derived from Hypoxic Human Mesenchymal Stem Cells Attenuate GSK3β Expression via miRNA-26a in an Ischemia-Reperfusion Injury Model

Q: What is the clinical evidence from this study?

Study design: Other. Population: Ischemia-reperfusion injury. Intervention: Extracellular vesicles derived from hypoxia-preconditioned human mesenchymal stem cells (EVHM) vs. Phosphate buffered saline (PBS) alone or normoxia-preconditioned EVs (EVNM). Primary outcome: Infarct size (p=<0.001).

Key Result

Extracellular vesicles derived from hypoxia-preconditioned human mesenchymal stem cells significantly reduced infarct size and diminished arrhythmias in a rat ischemia-reperfusion injury model.

Structured PICO

Do extracellular vesicles derived from hypoxia-preconditioned human mesenchymal stem cells reduce infarct size and arrhythmias in a rat ischemia-reperfusion injury model?

Population

Adult male Sprague-Dawley rats (230±10 g) subjected to an ischemia/reperfusion (IR) injury model (left anterior descending artery ligation for 1 h followed by reperfusion for 3 h), and H9C2 cardiomyoblasts for in vitro experiments.

Intervention

Extracellular vesicles derived from hypoxia-preconditioned human mesenchymal stem cells (EV(HM)), 125 μL of 0.4 μg/μL solution in PBS, injected systemically via leg vein immediately after initiation of reperfusion.

Comparator

Phosphate buffered saline (PBS) alone (IR group), extracellular vesicles derived from normoxia-preconditioned MSCs (EV(NM)), and sham-operated controls.

Outcome

Infarct size assessed by TTC staining 3 hours after EV injection.surrogate

Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells protect against ischemia-reperfusion injury and arrhythmias by modulating the Wnt signaling pathway and suppressing GSK3β via miRNA-26a.

Main Result

Absolute Event Rate: 8% vs 24%

p-value: p=<0.001

Limitations

The proteins of the EVs were not assayed in this study.
This study could not demonstrate whether miR-26a targets GSK3β directly.
Dual luciferase assay was not carried out for the evaluation of miRNA binding on 3'UTR of GSK3β.

Abstract

PURPOSE: Bioactive molecules critical to intracellular signaling are contained in extracellular vesicles (EVs) and have cardioprotective effects in ischemia/reperfusion (IR) injured hearts. This study investigated the mechanism of the cardioprotective effects of EVs derived from hypoxia-preconditioned human mesenchymal stem cells (MSCs). MATERIALS AND METHODS: EV solutions (0.4 μg/μL) derived from normoxia-preconditioned MSCs (EV(NM)) and hypoxia-preconditioned MSCs (EV(HM)) were delivered in a rat IR injury model. Successful EV delivery was confirmed by the detection of PKH26 staining in hearts from EV-treated rats. RESULTS: EV(HM) significantly reduced infarct size (24±2% vs. 8±1%, p<0.001), and diminished arrhythmias by recovering electrical conduction, I(Na) current, and Cx43 expression. EV(HM) also reversed reductions in Wnt1 and β-catenin levels and increases in GSK3β induced after IR injury. miRNA-26a was significantly increased in EV(HM), compared with EV(NM), in real-time PCR. Finally, in in vitro experiments, hypoxia-induced increases in GSK3β expression were significantly reduced by the overexpression of miRNA-26a. CONCLUSION: EV(HM) reduced IR injury by suppressing GSK3β expression via miRNA-26a and increased Cx43 expression. These findings suggest that the beneficial effect of EVHM is related with Wnt signaling pathway.

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