Biophysical modeling of extracellular vesicle formation

Formation of extracellular vesicles is critical for long-range intercellular communication. While many mechanical models have focused on membrane curvature generation, how cells release extracellular vesicles is less investigated. Here, we focus on the role of the glycocalyx and the actin cortex on extracellular vesicle formation. The glycocalyx is a dense layer of glycosylated transmembrane proteins and lipids distributed on the extracellular surface of eukaryotic cells. It is known to mediate cell–cell interactions and protect cells from invasion by pathogens. We developed a polymer brush theory-based model, which suggests that the interplay between glycocalyx polymers and membrane bending captures the wide variety of membrane shapes from spherical buds to elongated pearl-like shapes found in previously published experiments. We predicted that the physical properties of glycocalyx polymers and membrane properties play significant roles in regulating membrane morphologies. We then extended the model to consider the energy of a glycocalyx-membrane-actin cortex composite to investigate the effects of glycocalyx and membrane-cortex adhesion on the formation of outward budding extracellular vesicles. We showed that modulating the mechanical feedback among the glycocalyx, membrane-cortex attachment, and membrane curvature can give rise to two types of instabilities: a conserved Turing-type instability and a Cahn-Hilliard-type instability. Next, we identified the critical conditions for the formation of extracellular: an initial detachment of the membrane from the underlying cortex and then a sufficient driving force to induce membrane deformation. Finally, we used our model to predict that a heterogeneous size distribution of these veiscles can be generated through the regulation of glycocalyx properties, shedding insight into how extracellular vesicles of different radii may be generated.