Abstract
Although extracellular vesicle (EV) surface electrostatic properties (measured as zeta potential, ζ-potential) have been reported by many investigators, the biophysical implications of charge and EV origin remains uncertain. Here, we compared the ζ-potential of human blood EVs (BEVs) and semen EVs (SEVs) from 26 donors that were HIV-infected (HIV+, n = 13) or HIV uninfected (HIV-, n = 13). We found that, compared to BEVs that bear neutral surface charge, SEVs were significantly more negatively charged, even when BEVs and SEVs were from the same individual. Comparison of BEVs and SEVs from HIV- and HIV+ groups revealed subtle HIV-induced alteration in the ζ-potential of EVs, with the effect being more significant in SEVs (∆ζ-potential = −8.82 mV, p-value = 0.0062) than BEVs (∆ζ-potential = −1.4 mV, p-value = 0.0462). These observations were validated by differences in the isoelectric point (IEP) of EVs, which was in the order of HIV + SEV ≤ HIV-SEV ≪ HIV + BEV ≤ HIV-BEV. Functionally, the rate and efficiency of SEV internalization by the human cervical epithelial cell line, primary peripheral blood lymphocytes, and primary blood-derived monocytes were significantly higher than those of BEVs. Mechanistically, removal of sialic acids from the surface of EVs using neuraminidase treatment significantly decreased SEV’s surface charge, concomitant with a substantial reduction in SEV’s internalization. The neuraminidase effect was independent of HIV infection and insignificant for BEVs. Finally, these results were corroborated by enrichment of glycoproteins in SEVs versus BEVs. Taken together, these findings uncover fundamental tissue-specific differences in surface electrostatic properties of EVs and highlight the critical role of surface charge in EV/target cell interactions.
Highlights
Cell membrane surface charge is the net sum of the charges of its components and determines the electrostatic surface properties of a cell
The results show that extracellular vesicle (EV) entered the cells in the first three hours, with semen EVs (SEVs) being more efficiently internalized compared to blood EVs (BEVs) both in Peripheral blood lymphocytes (PBLs) (Figure 4a) and monocytes (Figure 4b), suggesting cell-type independency in EV internalization rate and efficiency
We showed differences in BEV and SEV sialylation and desialylation, which correlated with their internalization efficiency by target cells
Summary
Cell membrane surface charge is the net sum of the charges of its components and determines the electrostatic surface properties of a cell. Sialylation, which is the covalent addition of negatively charged sialic acid residues to the terminal ends of N and O-linked glycoproteins, and glycosphingolipids [22,23], is a major determinant of cell and EV membrane surface charge. The biological characteristics and functions of EVs are becoming increasingly clear, major physical properties such as membrane surface charge, which may contribute to the behavior and function of EVs, remain unexplored This is especially important because EVs carry markers of the producer cells. BEV surface charge and internalization were largely unaffected by desialylation
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