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Multi-omics discovery of hallmark protein and lipid features of circulating small extracellular vesicles in humans

ABSTRACT: Extracellular vesicles (EVs) are now being increasingly recognized as an essential signalling entity in human plasma, linking them to health and various diseases. Still, their core protein and lipid componentry, which epicentres EV form and function, remains poorly defined. Achieving this unmet milestone remains greatly hindered by abundant non-vesicular extracellular plasma components (non-EVs) in mass spectrometry-based analyses. Here, we performed high-resolution density gradient fractionation of over 80 human plasma samples to isolate circulating EVs, and systematically construct their quantitative proteome (4500 proteins) and lipidome (829 lipids) landscapes. This led to the discovery of a highly conserved panel of 182 proteins (ADAM10, STEAP23, STX7) and 52 lipids (PS, PIPs, Hex2Cer, PAs), providing a deep survey of hallmark molecular features and biological pathways intrinsic to circulating EVs. Our efforts also mapped the surfaceome diversity, identifying 126 proteins on EV surface. We further establish a set of 42 proteins and 114 lipids features that served as hallmark features of non-EV particles in plasma. We submit ADAM10 and PS(36:1) as conserved EV biological markers that enable precise differentiation between EV and non-EV particles. Our findings, which can be explored via open-source Shiny web tool will serve as a valuable repository to the research community for a clearer understanding of circulating EV biology.

INSTRUMENT(S): Q Exactive HF-X, 6495C Triple Quadrupole LC/MS

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: David Greening

PROVIDER: MSV000094307 | MassIVE | Wed Mar 13 04:54:00 GMT 2024

REPOSITORIES: MassIVE

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Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.

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Multi-omics discovery of hallmark protein and lipid features of circulating small extracellular vesicles in humans

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