Cytoskeletal dynamics of human erythrocyte

Abstract

The human erythrocyte (red blood cell, RBC) demonstrates extraordinary ability to undergo reversible large deformation and fluidity. Such mechanical response cannot be consistently rationalized on the basis of fixed connectivity of the cell cytoskeleton that comprises the spectrin molecular network tethered to phospholipid membrane. Active topological remodeling of spectrin network has been postulated, although detailed models of such dynamic reorganization are presently unavailable. Here we present a coarsegrained cytoskeletal dynamics simulation with breakable protein associations to elucidate the roles of shear stress, specific chemical agents, and thermal fluctuations in cytoskeleton remodeling. We demonstrate a clear solid-to-fluid transition depending on the metabolic energy influx. The solid network's plastic deformation also manifests creep and yield regimes depending on the strain rate. This cytoskeletal dynamics model offers a means to resolve long-standing questions regarding the reference state used in RBC elasticity theory for determining the equilibrium shape and deformation response. In addition, the simulations offer mechanistic insights into the onset of plasticity and void percolation in cytoskeleton. These phenomena may have implication for RBC membrane loss and shape change in the context of hereditary hemolytic disorders such as spherocytosis and elliptocytosis.cytoskeleton remodeling ͉ computer simulation ͉ fluidization ͉ plasticity ͉ spectrin-actin dissociation D uring its 120-day life span, a red blood cell (RBC) circulates a million times in human body, often squeezing through narrow capillaries. The erythrocyte's remarkable mechanical properties originate from the unique architecture of its cell wall, which is the main load bearing component as there are no stress fibers inside the cell. The cell wall comprises a spectrin tetramer network tethered to a phospholipid bilayer (1, 2). It is very flexible, and yet resilient enough to recover the biconcave shape whenever the cell is quiescent (see Fig. 1). It has been proposed that the spectrin network connectivity is not fixed and can experience extensive remodeling as the RBC undergoes large deformation. Experiments show that, under physiological conditions, the spectrin tetramers in an unstressed intact cell wall exist in rapid dynamic equilibrium with the dimers, and that shear-induced cell wall deformation displaces the balance in favor of the dimers (3). Here, the cell wall behaves as a weak elastic solid at low strain levels, whereas it can be fluidized beyond a certain level of shear deformation, similar to soft matter such as emulsions and colloidal pastes (4, 5). Upon unloading, the dynamic stability is shifted toward tetramers and the stiffness of the cell wall increases. Experiments also suggest that cytoskeleton remodeling can be regulated by biochemical factors such as Ca 2ϩ and ATP (adenosine 5Ј-triphosphate) concentrations (6, 7). It has been postulated that phosphorylation affects spectrin-actin binding and produces changes i...

Metabolic remodeling of the human red blood cell membrane

“…Theoretically, RBC membrane fluctuations were traditionally studied by using models of thermally-driven equilibrium systems (2, 3). A recent theoretical model (15,17), validated by simulation (18,19), showed that local breaking and reforming of the spectrin network can result in enhanced fluctuations. Our results here showed that the depletion of ATP decreased the fluctuations in RBC membranes that can be reversed when ATP is reintroduced.…”

Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles

“…Melting of this layer resulted in a suspension of hydrogel particles. in fundamental structure: RBCs are fluid-filled sacs contained by a complex membrane that has extreme flexibility originating from the membrane structure (28,29), whereas the RBCMs are uninterrupted hydrogel discs. These two disparate structures should have different behaviors and mechanisms of deformation in constricted flow (13) though further studies are needed to elucidate these details for the RBCMs.…”

Measurement Techniques for Red Blood Cell Deformability: Recent Advances

“…Microfludic device was used to induce large deformation of RBCs and its mechanical behavior was studied (Fig. 10) (Li, Lykotrafitis et al,2007) . For the study of sickle cell disease, microfluidic device has been used to measure the resistance change rate of blood flow under the sudden change of oxygen concentration (Wang, Ding et al,2011).…”