Abstract
Myocardial infarction requires urgent reperfusion to salvage viable heart tissue. However, reperfusion increases infarct size further by promoting mitochondrial damage in cardiomyocytes. Exosomes from a wide range of different cell sources have been shown to activate cardioprotective pathways in cardiomyocytes, thereby reducing infarct size. Yet, it is currently challenging to obtain highly pure exosomes in quantities enough for clinical studies. To overcome this problem, we used exosomes isolated from CTX0E03 neuronal stem cells, which are genetically stable, conditionally inducible and can be produced on an industrial scale. However, it is unknown whether exosomes from neuronal stem cells may reduce cardiac ischaemia/reperfusion injury. In this study, we demonstrate that exosomes from differentiating CTX0E03 cells can reduce infarct size in mice. In an in vitro assay, these exosomes delayed cardiomyocyte mitochondrial permeability transition pore opening, which is responsible for cardiomyocyte death after reperfusion. The mechanism of MPTP inhibition was via gp130 signalling and the downstream JAK/STAT pathway. Our results support previous findings that exosomes from non‐cardiomyocyte‐related cells produce exosomes capable of protecting cardiomyocytes from myocardial infarction. We anticipate our findings may encourage scientists to use exosomes obtained from reproducible clinical‐grade stocks of cells for their ischaemia/reperfusion studies.
Highlights
Acute myocardial infarction is typically caused by a coronary artery blockage.[1]
We evaluated the potential of ExoDiff and ExoPr0 exosomes to reduce cardiac ischaemia/reperfusion injury in vivo and delay mitochondrial permeability transition pore (mPTP) opening caused by reactive oxygen species (ROS) in vitro
Because Janus kinases (JAKs)/STAT signalling is commonly activated by type I cytokines acting via the glycoprotein 130 receptor, we investigated a specific inhibitor of gp[130], SC144.46 Inhibition of gp[130] upstream with SC144 produced the same effect as inhibition of JAK, eliminating the protective effect of ExoDiff on mPTP opening (P
Summary
Acute myocardial infarction is typically caused by a coronary artery blockage.[1]. Timely reperfusion is necessary to salvage ischaemic myocardium. The sequential isolation procedure we developed, consisting of tangential flow filtration followed by size exclusion chromatography, is expected to result in highly purified exosomes During this entire isolation process, the exosomes remain in solution in a standard physiological buffer, which avoids the use of harsh and potentially damaging techniques such as ultracentrifugation or precipitation. We first characterized the exosomes to determine their size, appearance and expression of protein exosomal markers, in accordance with recommendations by minimal information for studies of extracellular vesicles 2018 (MISEV2018).[25] We evaluated the potential of ExoDiff and ExoPr0 exosomes to reduce cardiac ischaemia/reperfusion injury in vivo and delay mPTP opening caused by ROS in vitro. We investigated the mechanism of protection by using inhibitors of the RISK pathway and other cardioprotective kinases
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