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1.
Lancet ; 394(10207): 1415-1424, 2019 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-31500849

RESUMO

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.


Assuntos
Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea , Idoso , Terapia Combinada , Morte Súbita Cardíaca/prevenção & controle , Feminino , Insuficiência Cardíaca/etiologia , Hospitalização , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/cirurgia , Estudos Prospectivos , Método Simples-Cego , Resultado do Tratamento , Reino Unido
2.
J Cardiovasc Pharmacol ; 74(3): 194-200, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31356550

RESUMO

Acute occlusion of a coronary artery can result in myocardial infarction-a leading cause of premature death. Prompt restoration of blood flow to the myocardium can prevent excessive death of cardiomyocytes and improve clinical outcome. Although the major mechanism of cell death after reperfusion is necrosis, it is now recognized that many other cell death pathways may be involved in ischemia-reperfusion (I/R) injury. Pyroptosis is one such cell death pathway that is caspase-1-dependent and induced in response to cellular insult. The activated caspase-1 protease cleaves and activates specific cellular targets including gasdermin D and the proinflammatory cytokines interleukin-1ß and interleukin-18. The N-terminal fragment of gasdermin D forms plasma membrane pores resulting in cytosolic leakage and cell rupture, releasing interleukin-1ß and interleukin-18. Evidence suggests that inflammation induced by I/R through the pyroptotic pathway contributes to cardiomyocyte death, excessive scar formation, and poor ventricular remodeling. For this reason, there is growing interest in targeting components of the pyroptotic pathway as a means of reducing I/R injury.

3.
J Mol Cell Cardiol ; 128: 187-197, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30738798

RESUMO

AIMS: The chemokine stromal derived factor-1α (SDF-1α) is known to protect the heart acutely from ischaemia-reperfusion injury via its cognate receptor, CXCR4. However, the timing and cellular location of this effect, remains controversial. METHODS AND RESULTS: Wild type male and female mice were subjected to 40 min LAD territory ischaemia in vivo and injected with either saline (control) or SDF-1α prior to 2 h reperfusion. Infarct size as a proportion of area at risk was assessed histologically using Evans blue and triphenyltetrazolium chloride. Our results confirm the cardioprotective effect of exogenous SDF-1α in mouse ischaemia-reperfusion injury and, for the first time, show protection when SDF-1α is delivered just prior to reperfusion, which has important therapeutic implications. The role of cell type was examined using the same in vivo ischaemia-reperfusion protocol in cardiomyocyte- and endothelial-specific CXCR4-null mice, and by Western blot analysis of endothelial cells treated in vitro. These experiments demonstrated that the acute infarct-sparing effect is mediated by endothelial cells, possibly via the signalling kinases Erk1/2 and PI3K/Akt. Unexpectedly, cardiomyocyte-specific deletion of CXCR4 was found to be cardioprotective per se. RNAseq analysis indicated altered expression of the mitochondrial protein co-enzyme Q10b in these mice. CONCLUSIONS: Administration of SDF-1α is cardioprotective when administered prior to reperfusion and may, therefore, have clinical utility. SDF-1α-CXCR4-mediated cardioprotection from ischaemia-reperfusion injury is contingent on the cellular location of CXCR4 activation. Specifically, cardioprotection is mediated by endothelial signalling, while cardiomyocyte-specific deletion of CXCR4 has an infarct-sparing effect per se.

4.
J Am Coll Cardiol ; 73(1): 89-99, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621955

RESUMO

Many treatments have been identified that confer robust cardioprotection in experimental animal models of acute ischemia and reperfusion injury. However, translation of these cardioprotective therapies into the clinical setting of acute myocardial infarction (AMI) for patient benefit has been disappointing. One important reason might be that AMI is multifactorial, causing cardiomyocyte death via multiple mechanisms, as well as affecting other cell types, including platelets, fibroblasts, endothelial and smooth muscle cells, and immune cells. Many cardioprotective strategies act through common end-effectors and may be suboptimal in patients with comorbidities. In this regard, emerging data suggest that optimal cardioprotection may require the combination of additive or synergistic multitarget therapies. This review will present an overview of the state of cardioprotection today and provide a roadmap for how we might progress towards successful clinical use of cardioprotective therapies following AMI, focusing on the rational combination of judiciously selected, multitarget therapies. This paper emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

6.
Sci Rep ; 8(1): 15885, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367147

RESUMO

Extracellular vesicles (EVs) such as exosomes are nano-sized vesicles that carry proteins and miRNAs and can transmit signals between cells. We hypothesized that exosomes from endothelial cells can transmit protective signals to cardiomyocytes. Co-culture of primary adult rat cardiomyocytes with normoxic HUVEC cells separated by a cell-impermeable membrane reduced the percentage of cardiomyocyte death following simulated ischaemia and reperfusion (sIR) from 80 ± 11% to 51 ± 4% (P < 0.05; N = 5). When EVs were removed from the HUVEC-conditioned medium it was no longer protective. Exosomes were purified from HUVEC-conditioned medium using differential centrifugation and characterized by nanoparticle tracking analysis, electron microscopy, and flow cytometry. Pre-incubation of cardiomyocytes with HUVEC exosomes reduced the percentage of cell death after sIR from 88 ± 4% to 55 ± 3% (P < 0.05; N = 3). This protection required ERK1/2 activity as it was prevented by inhibitors PD98059 and U0126. Ischaemic preconditioning caused about ~3-fold higher rate of exosome production from HUVEC and from isolated, perfused rat hearts. This increase resulted in significantly greater protection against sIR in cardiomyocytes. In conclusion, exosomes released from endothelial cells can confer resistance to sIR injury in cardiomyocytes via the activation of the ERK1/2 MAPK signalling pathway, and may contribute to IPC.

7.
Basic Res Cardiol ; 113(6): 43, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30310998

RESUMO

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury.

9.
Basic Res Cardiol ; 113(4): 25, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29858664

RESUMO

Remote ischaemic conditioning (RIC) is a promising method of cardioprotection, with numerous clinical studies having demonstrated its ability to reduce myocardial infarct size and improve prognosis. On the other hand, there are several clinical trials, in particular those conducted in the setting of elective cardiac surgery, that have failed to show any benefit of RIC. These contradictory data indicate that there is insufficient understanding of the mechanisms underlying RIC. RIC is now known to signal indiscriminately, protecting not only the heart, but also other organs. In particular, experimental studies have demonstrated that it is able to reduce infarct size in an acute ischaemic stroke model. However, the mechanisms underlying RIC-induced neuroprotection are even less well understood than for cardioprotection. The existence of bidirectional feedback interactions between the heart and the brain suggests that the mechanisms of RIC-induced neuroprotection and cardioprotection should be studied as a whole. This review, therefore, addresses the topic of the neural component of the RIC mechanism.

10.
Artigo em Inglês | MEDLINE | ID: mdl-29766336

RESUMO

PURPOSE: Anthracyclines cause chronic irreversible cardiac failure, but the mechanism remains poorly understood. Emerging data indicate that cardiac damage begins early, suggesting protective modalities delivered in the acute stage may confer prolonged benefit. Ischaemic preconditioning (IPC) activates the pro-survival reperfusion injury salvage kinase (RISK) pathway which involves PI3-kinase and MAPK/ERK1/2. METHODS: We investigated whether simulated IPC (sIPC), in the form of a sublethal exposure to a hypoxic buffer simulating ischaemic conditions followed by reoxygenation, protects primary adult rat cardiomyocytes against anthracycline-induced injury. PI3-kinase and MAPK/ERK1/2 were inhibited using LY294002, and PD98059. The role of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm) and mitochondrial permeability transition pore (mPTP) were also investigated in doxorubicin-treated cells. We further examined whether sIPC protected HeLa cancer cells from doxorubicin-induced death. RESULTS: sIPC protected cardiomyocytes against doxorubicin-induced death (35.4 ± 1.7% doxorubicin vs 14.7 ± 1.5% doxorubicin + sIPC; p < 0.01). This protection was abrogated by the PI3-kinase inhibitor, LY294002, but not the MAPK/ERK1/2 inhibitor, PD98059. A ROS scavenger failed to rescue cardiomyocytes from doxorubicin toxicity, and no significant influence on Δψm or mPTP opening was identified after subjecting cells to a doxorubicin insult. Importantly, sIPC did not protect HeLa cancer cells from doxorubicin-induced death. CONCLUSION: sIPC is able to protect cardiomyocytes against anthracycline injury via a pathway involving PI3-kinase. This mechanism appears to be independent of ROS, changes to Δψm, and mPTP. Further investigation of the mechanism of sIPC-induced protection against anthracycline-injury is warranted.

11.
Basic Res Cardiol ; 113(3): 20, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29666943

RESUMO

There remains a significant un-met need to reduce the extent of myocardial injury caused by ischaemia and reperfusion injury in patients experiencing an ST-elevation MI. Although nitric oxide is central to many cardioprotective strategies currently undergoing investigation, cardioprotection from the delivery of nitrates/nitrites has been inconsistently observed. The route of administration appears to be a critical variable. The glyceryl trinitrate (GTN) patch is commonly used as a simple and practical means of delivering nitric oxide to patients with ischaemic heart disease, but whether acute cardioprotection can be achieved by application of a GTN patch has not been investigated before. Here, we use a mouse model to demonstrate that a GTN patch is highly cardioprotective when applied immediately prior to 40 min occlusion of the left anterior coronary artery followed by 2 h reperfusion, reducing infarct size from 54 ± 4% in control mice, to 28 ± 4% (P < 0.001, N = 7). The degree of protection was similar to that achieved with a standard remote ischaemic preconditioning protocol. Furthermore, and of greater potential clinical relevance, a GTN patch was also protective when applied well after the initiation of ischaemia and 15 min prior to reperfusion (28 ± 4 vs 59 ± 4%; P < 0.01, N = 5). Confirmatory experiments verified the expected effect increase in plasma nitrite levels and decrease in blood pressure. The simplicity and rapidity of GTN patch application (easily applied in an ambulance or cardiac catheterization laboratory), and low cost (potentially relevant to low-income countries), make it attractive for further investigation.

12.
Cardiovasc Drugs Ther ; 32(2): 127-133, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29656359

RESUMO

PURPOSE: To accurately estimate the effect size of both local or classic ischaemic preconditioning (IPC) and remote ischaemic preconditioning (RIPC) using a pooling data set of 91 animals. METHODS: We combined all the available mouse data collected from our Institute over the last 3 years regarding (i) local IPC (4 cycles of 5 min of global ischaemia/reperfusion injury, IRI, followed by 35-min ischaemia and 2-h reperfusion) in the Langendorff-isolated perfused mouse heart model and (ii) RIPC (3 cycles of 5 min of limb occlusion followed by 40-min ischaemia and 2-h reperfusion) in the in vivo mouse model. RESULTS: Five independent experiments containing 27 control and 29 IPC mice were used to estimate the overall (i) local IPC effect, which reduced infarct size in the ex-vivo setting by a mean difference of 24.1% (95% CI 19.5, 28.6%) when compared to untreated controls (P < 0.001) and for (ii) RIPC, three independent experiments including data for 16 control and 19 RIPC mice were used to estimate that RIPC diminished infarct size in the in-vivo setting by a mean difference of 20.8% (95% CI 14.7, 26.9%) when compared to controls (P < 0.001). CONCLUSIONS: Using a significant animal dataset, we found that local IPC reduces myocardial infarct size by 24.1% and RIPC by 20.8% in the ex vivo and in vivo mouse models of IRI, respectively. These differences may be used as reference values to either establish positive controls or to determine by how much myocardial infarct size can be reduced by novel cardioprotective interventions following an IRI insult.

13.
Cardiovasc Drugs Ther ; 32(2): 165-168, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29582211

RESUMO

PURPOSE: Protecting the heart from ischaemia-reperfusion (IR) injury is a major goal in patients presenting with an acute myocardial infarction. Pyroptosis is a novel form of cell death in which caspase 1 is activated and cleaves interleukin 1ß. VX-785 is a highly selective, prodrug caspase 1 inhibitor that is also clinically available. It has been shown to be protective against acute IR in vivo rat model, and therefore might be a promising possibility for future cardioprotective therapy. However, it is not known whether protection by VX-765 involves the reperfusion injury salvage kinase (RISK) pathway. We therefore investigated whether VX-765 protects the isolated, perfused rat heart via the PI3K/Akt pathway and whether protection was additive with ischaemic preconditioning (IPC). METHODS: Langendorff-perfused rat hearts were subject to ischaemia and reperfusion injury in the presence of 30 µM VX-765, with precedent IPC, or the combination of VX-765 and IPC. RESULTS: VX-765 reduced infarct size (28 vs 48% control; P < 0.05) to a similar extent as IPC (30%; P < 0.05). The PI3 kinase inhibitor, wortmannin, abolished the protective effect of VX-765. Importantly in the model used, we were unable to show additive protection with VX-765 + IPC. CONCLUSIONS: The caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection.

15.
Mol Aspects Med ; 60: 104-114, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29122678

RESUMO

Exosomes are nano-sized vesicles released by numerous cell types that appear to have diverse beneficial effects on the injured heart. Studies using exosomes from stem cells or from the blood have indicated that they are able to protect the heart both in models of acute ischaemia and reperfusion, and during chronic ischaemia. In addition to decreasing initial infarct size, they are able to stimulate angiogenesis, reduce fibrosis and remodelling, alter immune cell function and improve long-term cardiac contractile function. However, since the technology and techniques used for the study of exosomes is relatively immature and continually evolving, there remain many important caveats to the interpretation of studies. This review presents a critical analysis of the field of exosomes and cardioprotection. We analyse the effects of exosomes from all types of stem cells investigated to date, summarize the major effects observed and their potential mechanism, and offer our perspective on the major outstanding issues.

16.
J Cell Mol Med ; 22(2): 926-935, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29159980

RESUMO

The Reperfusion Injury Salvage Kinase (RISK) pathway is considered the main pro-survival kinase cascade mediating the ischaemic preconditioning (IPC) cardioprotective effect. To assess the role of PI3K-Akt, its negative regulator PTEN and other pro-survival proteins such as ERK and STAT3 in the context of IPC, C57BL/6 mouse hearts were retrogradely perfused in a Langendorff system and subjected to 4 cycles of 5 min. ischaemia and 5 min. reperfusion prior to 35 min. of global ischaemia and 120 min. of reperfusion. Wortmannin, a PI3K inhibitor, was administered either at the stabilization period or during reperfusion. Infarct size was assessed using triphenyl tetrazolium staining, and phosphorylation levels of Akt, PTEN, ERK, GSK3ß and STAT3 were evaluated using Western blot analyses. IPC reduced infarct size in hearts subjected to lethal ischaemia and reperfusion, but this effect was lost in the presence of Wortmannin, whether it was present only during preconditioning or only during early reperfusion. IPC increased the levels of Akt phosphorylation during both phases and this effect was fully abrogated by PI3K, whilst its downstream GSK3ß was phosphorylated only during the trigger phase after IPC. Both PTEN and STAT3 were phosphorylated during both phases after IPC, but this was PI3K independent. IPC increases ERK phosphorylation during both phases, being only PI3K-dependent during the IPC phase. In conclusion, PI3K-Akt plays a major role in IPC-induced cardioprotection. However, PTEN, ERK and STAT3 are also phosphorylated by IPC through a PI3K-independent pathway, suggesting that cardioprotection is mediated through more than one cell signalling cascade.

18.
J Cell Mol Med ; 22(1): 141-151, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28840975

RESUMO

Many patients with ischaemic heart disease also have diabetes. As myocardial infarction is a major cause of mortality and morbidity in these patients, treatments that increase cell survival in response to ischaemia and reperfusion are needed. Exosomes-nano-sized, lipid vesicles released from cells-can protect the hearts of non-diabetic rats. We previously showed that exosomal HSP70 activates a cardioprotective signalling pathway in cardiomyocytes culminating in ERK1/2 and HSP27 phosphorylation. Here, we investigated whether the exosomal cardioprotective pathway remains intact in the setting of type II diabetes. Exosomes were isolated by differential centrifugation from non-diabetic and type II diabetic patients, from non-diabetic and Goto Kakizaki type II diabetic rats, and from normoglycaemic and hyperglycaemic endothelial cells. Exosome size and number were not significantly altered by diabetes. CD81 and HSP70 exosome markers were increased in diabetic rat exosomes. However, exosomes from diabetic rats no longer activated the ERK1/2 and HSP27 cardioprotective pathway and were no longer protective in a primary rat cardiomyocytes model of hypoxia and reoxygenation injury. Hyperglycaemic culture conditions were sufficient to impair protection by endothelial exosomes. Importantly, however, exosomes from non-diabetic rats retained the ability to protect cardiomyocytes from diabetic rats. Exosomes from diabetic plasma have lost the ability to protect cardiomyocytes, but protection can be restored with exosomes from non-diabetic plasma. These results support the concept that exosomes may be used to protect cardiomyocytes against ischaemia and reperfusion injury, even in the setting of type II diabetes.

19.
Cardiovasc Res ; 114(3): 358-367, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040423

RESUMO

Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilize and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium. These effects have beneficial effects on infarct size, and left ventricular remodelling and function. However, the timing of endogenous SDF-1α release and CXCR4 upregulation may not be optimal. Furthermore, current ELISA-based assays cannot distinguish between active SDF-1α, and SDF-1α inactivated by dipeptidyl peptidase 4 (DPP4). Current therapeutic approaches aim to recruit the SDF-1α-CXCR4 pathway or prolong SDF-1α life-time by preventing its cleavage by DPP4. This review assesses the evidence supporting these approaches and proposes SDF-1α as an important confounder in recent studies of DPP4 inhibitors.

20.
J Extracell Vesicles ; 6(1): 1388731, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29184625

RESUMO

Small extracellular vesicles (sEVs) such as exosomes are nanocarriers of proteins, RNAs and DNAs. Isolation of pure sEV populations remains challenging, with reports of protein and lipoprotein contaminants in the isolates. Cellular uptake - a cornerstone for understanding exosome and sEV function - is frequently examined using lipophilic dyes such as PKH67 or CellMask to label the vesicles. In this study, we investigated whether contaminants can confound the outcomes from sEV and exosomes uptake experiments. sEVs were isolated from blood plasma of fasted or non-fasted rats as well as from serum-supplemented or serum-free conditioned cell culture medium using size-exclusion chromatography (SEC). Eluent fractions were characterized using nanoparticle tracking, protein and triglyceride assays and immunoassays. SEC fractions were labelled with different lipophilic dyes and cellular uptake was quantified using endothelial cells or primary cardiomyocytes. We report co-isolation of sEVs with apolipoprotein B-containing lipoproteins. Cellular dye transfer did not correspond to sEV content of the SEC fractions, but was severely affected by lipoprotein and protein content. Overnight fasting of rats decreased lipoprotein content and also decreased dye transfer, while late, sEV-poor/protein-rich fractions demonstrated even greater dye transfer. The potential for dye transfer to occur in the complete absence of sEVs was clearly shown by experiments using staining of sEV-depleted serum or pure protein sample. In conclusion, proteins and lipoproteins can make a substantial contribution to transfer of lipophilic dyes to recipient cells. Considering the likelihood of contamination of sEV and exosome isolates, lipophilic dye staining experiments should be carefully controlled, and conclusions interpreted with caution.

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