Research ArticleBioengineering

Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip

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Science Translational Medicine  14 Oct 2020:
Vol. 12, Issue 565, eaax8005
DOI: 10.1126/scitranslmed.aax8005

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Valuable vesicles

Extracellular vesicles, small membrane-bound particles released from cells, have been shown to have cardioprotective effects. Here, Yadid et al. analyzed the proteins contained in vesicles released from endothelial cells under normoxia and hypoxia and investigated cardioprotective effects on cardiac tissues in vitro. Using a human heart-on-chip composed of cardiomyocytes, the authors showed that endothelial cell–derived vesicles supported metabolic function, tissue contraction, and viability during ischemia-reperfusion injury. This study helps to elucidate the mechanism by which vesicles are cardioprotective in human tissue.

Abstract

Extracellular vesicles (EVs) derived from various stem cell sources induce cardioprotective effects during ischemia-reperfusion injury (IRI). These have been attributed mainly to the antiapoptotic, proangiogenic, microRNA (miRNA) cargo within the stem cell–derived EVs. However, the mechanisms of EV-mediated endothelial signaling to cardiomyocytes, as well as their therapeutic potential toward ischemic myocardial injury, are not clear. EV content beyond miRNA that may contribute to cardioprotection has not been fully illuminated. This study characterized the protein cargo of human vascular endothelial EVs (EEVs) to identify lead cardioactive proteins and assessed the effect of EEVs on human laminar cardiac tissues (hlCTs) exposed to IRI. We mapped the protein content of human vascular EEVs and identified proteins that were previously associated with cellular metabolism, redox state, and calcium handling, among other processes. Analysis of the protein landscape of human cardiomyocytes revealed corresponding modifications induced by EEV treatment. To assess their human-specific cardioprotection in vitro, we developed a human heart-on-a-chip IRI assay using human stem cell–derived, engineered cardiac tissues. We found that EEVs alleviated cardiac cell death as well as the loss in contractile capacity during and after simulated IRI in an uptake- and dose-dependent manner. Moreover, we found that EEVs increased the respiratory capacity of normoxic cardiomyocytes. These results suggest that vascular EEVs rescue hlCTs exposed to IRI possibly by supplementing injured myocytes with cargo that supports multiple metabolic and salvage pathways and therefore may serve as a multitargeted therapy for IRI.

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