Minimizing Isotropic And Deviatoric Membrane Energy - An Unifying Formation Mechanism Of Different Cellular Membrane Nanovesicle Types

Tiny membrane-enclosed cellular fragments that can mediate interactions between cells and organisms have recently become a subject of increasing attention. In this work the mechanism of formation of cell membrane nanovesicles (CNVs) was studied experimentally and theoretically. CNVs were isolated by centrifugation and washing of blood cells and observed by optical microscopy and scanning electron microscopy. The shape of the biological membrane in the budding process, as observed in phospholipid vesicles, in erythrocytes and in CNVs, was described by an unifying model. Taking the mean curvature h and the curvature deviator d of the membrane surface as the relevant parameters, the shape and the distribution of membrane constituents were determined theoretically by minimization of membrane free energy. Considering these results and previous results on vesiculation of red blood cells it was interpreted that the budding processes may lead to formation of different types of CNVs as regards the compartment (exo/endovesicles), shape (spherical/tubular/torocytic) and composition (enriched/depleted in particular kinds of molecules). It was concluded that the specificity of pinched off nanovesicles derives from the shape of the membrane constituents and not primarily from their chemical identity, which explains evidences on great heterogeneity of isolated extracellular vesicles with respect to composition.Author summaryOne of the amazing properties of a biological membrane is the ability to undergo dramatic changes of its shape. It may exhibit very high curvature and thereby enclose nano-sized compartments that pinch off from the mother membrane and become freely moving cellular nanovesicles (CNVs). CNVs externalize the pieces of the cell and make them available to other cells within the same organism or other organisms. Therefore they have been acknowledged as mediators of communication between microorganisms, plants, animals and human. Furthernore, they dwell on the border between living and non-living things. Recent findings report on heterogeneity of the size and composition of CNVs found in isolates from different biological samples. As communication between cells is involved in many physiological and patophysiological processes, it is of importance to understand the mechanisms of CNVs formation and recognize the natural laws that mainly govern them. We point to an unifying mechanism that explains stability of differently shaped and composed CNVs by taking into account that the biological membrane tends to attain the minimum of its relevant energy. Conveniently, the procedure can be described by a mathematical model which allows for transparent comparison between experimentally induced shapes of membrane-enclosed vesicular structures and numerical calculations.