The Double-Edged Sword of Erythrocytes in Health and Disease via Their Adhesiveness.

Their widespread presence throughout the vasculature, coupled with their reactivity, and thereby to their potential to release reactive oxidative species, or to utilize their anti-oxidative capacities, has promoted much discussion of the role(s) of red blood cells (RBCs) in the progression of health or, alternatively, a wide range of disease states. Moreover, these role(s) have been linked to the development of adhesiveness and, in fact, thereby to the essential pathway to their eventual clearance, e.g.

Red Blood Cells: Tethering, Vesiculation, and Disease in Micro-Vascular Flow.

The red blood cell has become implicated in the progression of a range of diseases; mechanisms by which red cells are involved appear to include the transport of inflammatory species via red cell-derived vesicles. We review this role of RBCs in diseases such as diabetes mellitus, sickle cell anemia, polycythemia vera, central retinal vein occlusion, Gaucher disease, atherosclerosis, and myeloproliferative neoplasms. We propose a possibly unifying, and novel, paradigm for the inducement of RBC vesiculation during vascular flow of red cells adhered to the vascular endothelium as well as to the red pulp of the spleen.

RRx-001 Increases Erythrocyte Preferential Adhesion to the Tumor Vasculature.

Red blood cells (RBCs) serve a variety of functions beyond mere oxygen transport both in health and pathology. Notably, RRx-001, a minimally toxic pleiotropic anticancer agent with macrophage activating and vascular normalization properties currently in Phase III trials, induces modification to RBCs which could promote vascular adhesion similar to sickle cells. This study assessed whether RBCs exposed to RRx-001 adhere to the tumor microvasculature and whether this adhesion alters tumor viability.

Tethering, evagination, and vesiculation via cell-cell interactions in microvascular flow.

Vesiculation is a ubiquitous process undergone by most cell types and serves a variety of vital cell functions; vesiculation from erythrocytes, in particular, is a well-known example and constitutes a self-protection mechanism against premature clearance, inter alia. Herein, we explore a paradigm that red blood cell derived vesicles may form within the microvascular, in intense shear flow, where cells become adhered to either other cells or the extracellular matrix, by forming tethers or an evagination. Adherence may be enhanced, or caused, by diseased states or chemical anomalies as are discussed herein.

Vital erythrocyte phenomena: what can theory, modeling, and simulation offer?

We overview recent advances in the theoretical modeling, in particular via numerical simulation, of various vital human erythrocyte phenomena. The review is novel in how it interconnects a range of analysis within a coherent framework and focuses on extracting from them specific suggestions for experimental studies focused on, either validation of the analysis' mechanistic basis, or uncovering heretofore unrecognized effects and mechanistic understanding. In some cases, new analysis is described to fill in gaps and expand on previously published findings.

Mechanosensitivity Occurs along the Adhesome's Force Train and Affects Traction Stress.

Herein, we consider the process of force development along the adhesome within cell focal adhesions. Our model adhesome consists of the actin cytoskeleton-vinculin-talin-integrin-ligand-extracellular matrix-substrate force train. We specifically consider the effects of substrate stiffness on the force levels expected along the train and on the traction stresses they create at the substrate.

Erythrocyte Aging, Protection via Vesiculation: An Analysis Methodology via Oscillatory Flow.

We demonstrate that erythrocyte deformations, specifically of a type as occur in splenic flow (Zhu et al., 2017), and of the type that promote vesiculation can be caused by simple, yet tailored, oscillatory shear flow. We show that such oscillatory shear flow provides an ideal environment to explore a wide variety of metabolic and biochemical effects that promote erythrocyte vesiculation.

Diffusion-advection within dynamic biological gaps driven by structural motion.

To study the significance of advection in the transport of solutes, or particles, within thin biological gaps (channels), we examine theoretically the process driven by stochastic fluid flow caused by random thermal structural motion, and we compare it with transport via diffusion. The model geometry chosen resembles the synaptic cleft; this choice is motivated by the cleft's readily modeled structure, which allows for well-defined mechanical and physical features that control the advection process. Our analysis defines a Péclet-like number, A^{D}, that quantifies the ratio of time scales of advection versus diffusion.

Do Skeletal Dynamics Mediate Sugar Uptake and Transport in Human Erythrocytes?

We explore, herein, the hypothesis that transport of molecules or ions into erythrocytes may be affected and directly stimulated by the dynamics of the spectrin/actin skeleton. Skeleton/actin motions are driven by thermal fluctuations that may be influenced by ATP hydrolysis as well as by structural alterations of the junctional complexes that connect the skeleton to the cell's lipid membrane. Specifically, we focus on the uptake of glucose into erythrocytes via glucose transporter 1 and on the kinetics of glucose disassociation at the endofacial side of glucose transporter 1.

Prospects for Human Erythrocyte Skeleton-Bilayer Dissociation during Splenic Flow.

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.

Multiscale simulation of erythrocyte membranes.

To quantitatively predict the mechanical response and mechanically induced remodeling of red blood cells, we developed a multiscale method to correlate distributions of internal stress with overall cell deformation. This method consists of three models at different length scales: in the complete cell level the membrane is modeled as two distinct layers of continuum shells using finite element method (Level III), in which the skeleton-bilayer interactions are depicted as a slide in the lateral (i.e.

Macromolecular structure of the organic framework of nacre in Haliotis rufescens: implications for mechanical response.

Direct experimental probes of the mechanical response of the biopolymer framework of nacre extracted from the shell of the gastropod Haliotis rufescens have been performed. Both monotonic tensile, and time dependent relaxation, tests revealed that the tissue comprising the interlamellar layers within nacre obeyed a simple constitutive model conforming to the visco-elastic standard linear solid, with time constants in the range tau=140+/-4s. We conclude that the behavior is essentially that imparted by the chitin core of these layers.

Macromolecular structure of the organic framework of nacre in Haliotis rufescens: implications for growth and mechanical behavior.

We have performed a macromolecular structural analysis of the interlamellar and intertabular parts of the organic framework of the nacreous part of the shell of Haliotis rufescens, including the identification of structural chitin. Using histochemical optical microscopy we have mapped the locations of carboxylates and sulfates of proteins and chitin on the surfaces and within the core of the interlamellar layers and the intertabular matrix that together form the external organic matrix of composite nacre. This extends the earlier work of Nudelmann et al.

Spectrin folding versus unfolding reactions and RBC membrane stiffness.

Spectrin (Sp), a key component of the erythrocyte membrane, is routinely stretched to near its fully folded contour length during cell deformations. Such dynamic loading may induce domain unfolding as suggested by recent experiments. Herein we develop a model to describe the folding/unfolding of spectrin during equilibrium or nonequilibrium extensions.

A hybrid model for erythrocyte membrane: a single unit of protein network coupled with lipid bilayer.

To investigate the nanomechanics of the erythrocyte membrane we developed a hybrid model that couples the actin-spectrin network to the lipid bilayer. This model features a Fourier space Brownian dynamics model of the bilayer, a Brownian dynamics model of the actin protofilament, and a modified wormlike-chain model of the spectrin (including a cable-dynamics model to predict the oscillation in tension). This model enables us to predict the nanomechanics of single or multiple units of the protein network, the lipid bilayer, and the effect of their interactions.