Prospects for Human Erythrocyte Skeleton-Bilayer Dissociation during Splenic Flow

Abstract

Prospects of vesiculation occurring during splenic flow of erythrocytes are addressed via model simulations of RBC flow through the venous slits of the human spleen. Our model is multiscale and contains a thermally activated rate-dependent description of the entropic elasticity of the RBC spectrin cytoskeleton, including domain unfolding/refolding. Our model also includes detail of the skeleton attachment to the fluidlike lipid bilayer membrane, including a specific accounting for the expansion/contraction of the skeleton that may occur via anchor protein diffusive motion, that is, band 3 and glycophorin, through the membrane. This ability allows us to follow the change in anchor density and thereby the strength of the skeleton/membrane attachment. We define a negative pressure between the skeleton/membrane connection that promotes separation; critical levels for this are estimated using published data on the work of adhesion of this connection. By following the maximum range of negative pressure, along with the observed slight decrease in skeletal density, we conclude that there must be biochemical influences that probably include binding of degraded hemoglobin, among other things, that significantly reduce effective attachment density. These findings are consistent with reported trends in vesiculation that are believed to occur in cases of various hereditary anemias and during blood storage. Our findings also suggest pathways for further study of erythrocyte vesiculation that point to the criticality of understanding the biochemical phenomena involved with cytoskeleton/membrane attachment.

Red Blood Cell Homeostasis: Mechanisms and Effects of Microvesicle Generation in Health and Disease

“…The molecular mechanism underlying vesiculation in the spleen is unknown, but may involve a combination of biochemical and biophysical stress. Recent model simulations support the involvement of degraded hemoglobin in reducing the cytoskeleton/membrane connection, thereby promoting microvesicle shedding during splenic flow ( Zhu et al, 2017 ). Thus, the mechanical and biochemical circumstances in the spleen, together with the presence of specialized macrophages, may make the spleen a microvesicle-based quality control and repair system.…”

Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding?

“…Accumulation of Band3 and actin, which contrasts with the absence of spectrin in MVs generated upon RBC aging and blood storage, supports the hypothesis that partial membrane:cytoskeleton uncoupling, due to the breakage of ankyrin:Band3 binding, could contribute to the vesiculation process [ 21 ]. Accordingly, a simulation study highlighted that a significant reduction of the local anchorage density is required for vesiculation [ 119 ]. Furthermore, it has been shown that cytoskeleton stiffness and density both increase upon RBC senescence, leading to larger compressive forces on the cell membrane.…”

Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders

“…The function of spleen in sensing and clearing RBCs with alterations in their size, shape, and deformability has been elucidated through in vivo ( 13 , 14 ), ex vivo ( 3 – 5 ), and in vitro ( 15 – 17 ) experiments and computational modeling ( 18 – 21 ). However, the role of IES in filtering RBCs with significant membrane protein defects, as seen in HS and HE, has not been investigated in sufficient detail.…”