Comprehensive Phenotyping of Extracellular Vesicles in Blood of Healthy Humans – Insights into Cellular Origin and Biological Variability
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Abstract
Despite immense interest in biomarker applications of extracellular vesicles (EVs) from blood, our understanding of their physiological population in healthy humans remains limited. Using imaging and multiplex bead-based flow cytometry, we comprehensively quantified circulating EVs with respect to their cellular origin in a large cohort of healthy blood donors. We assessed coefficients of variations to characterise their biological variability and explored demographic, clinical, and lifestyle factors contributing to this variability. Cell-specific circulating EV subsets show a wide range of concentrations, which do not directly reflect concentrations of blood cells, indicating diverse patterns of EV subset release and/or uptake, even for EVs originating from the same cell type. Interestingly, tetraspanin+ circulating EVs largely originate from platelets and to a lesser extent from lymphocytes. PCA and association analyses demonstrate high biological inter-individual variability in circulating EVs across healthy humans, which can be only partly explained by the influence of sex, menopausal status, age and smoking on specific circulating EV and/or tetraspanin+ circulating EV subsets. No global influence of the explored subject’s factors on circulating EVs was detected. Our findings provide the first comprehensive, quantitative data towards the cell-origin atlas of blood EVs, with important implications in the clinical use of EVs as biomarkers of disease.
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Circulating EVs show high inter-individual biological variability in a healthy human cohort
Given that circulating EVs show high inter-individual variability, does this limit their utility as biomarkers? With the information currently available, what specific EV level or composition data do you consider most promising for further biomarker investigation?
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granulocyte-derived CD66b+ EVs
Do granulocytes release EVs during degranulation, or are they participating in a separate process entirely from their canonical function?
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EV subset concentrations did not directly reflect concentrations of blood cells, indicating diverse patterns of EV subset release and/or uptake, even for EVs originating from the same cell type
Clearly, the factors that control steady-state EV levels are distinct from those that control steady-state blood cell levels. What follow-up studies would you propose to begin investigating some of these factors that regulate EV levels?
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To further explore possible patterns among EV subsets, we assessed correlations among all 25 EV subset concentrations (Figure 2c). We identified only four moderate associations (ρ > 0.6, marked with a red cross in Figure 2c), suggesting diverse patterns of EV subset release and/or uptake, even from the same cell type.
In Figure 2c, if I understand correctly, it seems like EV levels from different cell types are mostly positively correlated, even if loosely (i.e. there don’t seem to be many instances where high levels of EVs from one cell type result in low EV secretion from another). Does this indicate the possibility of (a) more cell type-agnostic factor(s) that contribute to EV secretion?
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activated platelet EVs emerged as the most abundant among circulating EVs
It makes sense to me that platelet EVs would be quite abundant, given the membrane and cytoskeletal dynamics that occur during their development from megakaryocytes. Are platelet EVs related to their hemostatic function? It would be interesting to see how platelet EV levels or compositions change in patients with bleeding or clotting disorders.
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To identify the cellular origins of circulating EVs in healthy adults
How much is known about how the functions of EVs differ given their cell type of origin?
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