Dissecting the biochemical architecture and morphological release pathways of the human platelet extracellular vesiculome |
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| Authors: | Silvia H De Paoli Tseday Z Tegegn Oumsalama K Elhelu Michael B Strader Mehulkumar Patel Lukas L Diduch Ivan D Tarandovskiy Yong Wu Jiwen Zheng Mikhail V Ovanesov Abdu Alayash Jan Simak |
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| Institution: | 1.Laboratory of Cellular Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research,U.S. Food and Drug Administration,Silver Spring,USA;2.Laboratory of Biochemistry and Vascular Biology, Office of Blood Research and Review, Center for Biologics Evaluation and Research,U.S. Food and Drug Administration,Silver Spring,USA;3.Dakota Consulting, Inc.,Silver Spring,USA;4.Division of Biology, Chemistry and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health,U.S. Food and Drug Administration,Silver Spring,USA;5.Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research,U.S. Food and Drug Administration,Silver Spring,USA |
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| Abstract: | Platelet extracellular vesicles (PEVs) have emerged as potential mediators in intercellular communication. PEVs exhibit several activities with pathophysiological importance and may serve as diagnostic biomarkers. Here, imaging and analytical techniques were employed to unveil morphological pathways of the release, structure, composition, and surface properties of PEVs derived from human platelets (PLTs) activated with the thrombin receptor activating peptide (TRAP). Based on extensive electron microscopy analysis, we propose four morphological pathways for PEVs release from TRAP-activated PLTs: (1) plasma membrane budding, (2) extrusion of multivesicular α-granules and cytoplasmic vacuoles, (3) plasma membrane blistering and (4) “pearling” of PLT pseudopodia. The PLT extracellular vesiculome encompasses ectosomes, exosomes, free mitochondria, mitochondria-containing vesicles, “podiasomes” and PLT “ghosts”. Interestingly, a flow cytometry showed a population of TOM20+LC3+ PEVs, likely products of platelet mitophagy. We found that lipidomic and proteomic profiles were different between the small PEV (S-PEVs; mean diameter 103 nm) and the large vesicle (L-PEVs; mean diameter 350 nm) fractions separated by differential centrifugation. In addition, the majority of PEVs released by activated PLTs was composed of S-PEVs which have markedly higher thrombin generation activity per unit of PEV surface area compared to L-PEVs, and contribute approximately 60% of the PLT vesiculome procoagulant potency. |
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