Vesiculation of healthy and defective red blood cells

Abstract

Vesiculation of mature red blood cells (RBCs) contributes to removal of defective patches of the erythrocyte membrane. In blood disorders, which are related to defects in proteins of the RBC membrane, vesiculation of the plasma membrane is intensified. Several hypotheses have been proposed to explain RBC vesiculation but the exact underlying mechanisms and what determines the sizes of the vesicles are still not completely understood. In this work, we apply a twocomponent coarse-grained molecular dynamics (CGMD) RBC membrane model to study how RBC vesiculation is controlled by the membrane spontaneous curvature and by lateral compression of the membrane. Our simulation results show that the formation of small homogeneous vesicles with a diameter less than 40 nm can be attributed to a large spontaneous curvature of membrane domains. On the other hand, compression on the membrane can cause the formation of vesicles with heterogeneous composition and with sizes comparable with the size of the cytoskeleton corral. When spontaneous curvature and lateral compression are simultaneously considered, the compression on the membrane tends to facilitate formation of vesicles originated from curved membrane domains. We also simulate vesiculation of RBCs with membrane defects connected to hereditary elliptocytosis (HE) and to hereditary spherocytosis (HS). When the vertical connectivity between the lipid bilayer and the membrane skeleton is elevated, as is in normal RBCs, multiple vesicles are shed from the compressed membrane with diameters similar to the cytoskeleton corral size. In HS RBC, where the connectivity between the lipid bilayer and the cytoskeleton is reduced, larger size vesicles are released under the same compression ratio as in normal RBCs. Lastly, we find that vesicles released from HE RBCs can contain cytoskeletal filaments due to fragmentation of the membrane skeleton while vesicles released from the HS RBCs are depleted of cytoskeletal filaments.

The Fluid Membrane determines Mechanics of Red Blood Cell Extracellular Vesicles and is Softened in Hereditary Spherocytosis

“…Suggested mechanisms for membrane shedding by RBCs are related to clustering of membrane proteins driving curvature generation 46,47,58 and to the balance between membrane bending and stretching of the spectrin cytoskeleton. [58][59][60] The weaker linkage of the membrane with the underlying cytoskeleton in HS likely causes loss of organization in the membrane. This is supported by the observation that diffusion of membrane proteins is faster in RBCs from patients with HS.…”

Tuning of Differential Lipid Order Between Submicrometric Domains and Surrounding Membrane Upon Erythrocyte Reshaping

“…Indeed, it has been hypothesized several years ago that upon RBC aging the larger compressive forces on the cell membrane due to cytoskeleton stiffness and density increase could be accommodated by increased membrane curvature and vesicle detachment from the membrane [39,41]. Accordingly, based on a two-component coarsegrained molecular dynamics RBC membrane model, Li and Lykotrafitis have revealed that lateral compression generates large vesicles with heterogeneous composition, similar in size to the cytoskeleton corral [59]. The lower vesiculation we observed here in elliptocytosis is also in agreement with the role of the cytoskeleton, since a lower compression is expected to occur in elliptocytotic RBCs.…”

MD/DPD Multiscale Framework for Predicting Morphology and Stresses of Red Blood Cells in Health and Disease

“…For example, a two-component composite model of RBC membrane with explicit descriptions of lipid bilayer, cytoskeleton, and transmembrane proteins has been developed and implemented using coarse-grained molecular dynamics (CGMD) [10, 41, 42]. This CGMD membrane model has been successfully applied to study the membrane-related problems in RBCs such as protein diffusion and vesiculation in defective RBC membrane [43, 44], and the stiffening effects of knobs on Pf -RBCs [10]. Although changes on the biomechanics of RBC membrane, including bending rigidity and shear modulus, in certain diseases can be evaluated by modeling a small piece of cell membrane with the two-component composite model, the whole-cell characteristics strongly related to RBC biomechanics and biorheology are not efficiently depicted by modeling only a portion of the RBC membrane.…”