Role of Band 3 in the Erythrocyte Membrane Structural Changes Under Isotonic and Hypotonic Conditions

An attempt was made to discuss and connect various modeling approaches which have been proposed in the literature in order to shed further light on the erythrocyte membrane relaxation under isotonic and hypotonic conditions. Roles of the main membrane constituents: (1) the actin‐spectrin cortex, (2) the lipid bilayer, and (3) the transmembrane protein band 3 and its course‐consequence relations were considered to estimate the membrane relaxation phenomena. Cell response to loading conditions includes the successive sub‐bioprocesses: (1) erythrocyte local or global deformation, (2) the cortex‐bilayer coupling, and (3) the rearrangements of band 3. The results indicate that the membrane structural changes include: (1) the spectrin flexibility distribution and (2) the rate of its changes influenced by the number of band 3 molecules attached to spectrin filaments, and phosphorylation of the actin‐spectrin junctions. Band 3 rearrangement also influences: (1) the effective bending modulus and (2) the band 3‐bilayer interaction energy and on that base the bilayer bending state. The erythrocyte swelling under hypotonic conditions influences the bilayer integrity which leads to the hemolytic hole formation. The hemolytic hole represents the excited cluster of band 3 molecules

Cell jamming and unjamming in development: physical aspects

Collective cell migration is essential for a wide range of biological processes such as: morphogenesis, wound healing, and cancer spreading. However, it is well known that migrating epithelial collectives frequently undergo jamming, stay trapped some period of time, and then start migration again. Consequently, only a part of epithelial cells actively contributes to the tissue development. In contrast to epithelial cells, migrating mesenchymal collectives successfully avoid the jamming. It has been confirmed that the epithelial unjamming cannot be treated as the epithelial-to-mesenchymal transition. Some other mechanism is responsible for the epithelial jamming/unjamming. Despite extensive research devoted to study the cell jamming/unjamming, we still do not understand the origin of this phenomenon. The origin is connected to physical factors such as: the cell compressive residual stress accumulation and surface characteristics of migrating (unjamming) and resting (jamming) epithelial clusters which depend primarily on the strength of cell-cell adhesion contacts and cell contractility. The main goal of this theoretical consideration is to clarify these cause-consequence relations.Comment: 18 pages, 4 figure

Physics of cancer spreading through epithelium

Many cancers spread across the epithelium and physics is needed to describe the process. Cell dynamics at the normal epithelium/cancer biointerface play a crucial role in the progression of the disease. An altered arrangement of epithelial cells significantly impacts progression, so that a detailed understanding of the biological and physical mechanisms governing the interface dynamics provides a promising basis for cancer prevention. The biological mechanisms involve cell signalling and gene expression, while the physical mechanisms are associated with the interplay between physical properties such as the epithelium-cancer interfacial tension, the epithelial surface tension, and the compressive stress within the epithelium. Despite extensive in vitro research on epithelium/cancer co-cultured cell systems, the influence of these physical parameters on cell reorganization remains incomplete. This review provides an account of what is known about the physical processes involved in cell reorganization within epithelium/cancer cell clusters and the dissemination of cancer within co-cultured systems

Epithelial cell-cell interactions in an overcrowded environment: jamming or live cell extrusion

Epithelial tissues respond strongly to the mechanical stress caused by collective cell migration and are able to regulate it, which is important for biological processes such as morphogenesis, wound healing, and suppression of the spread of cancer. Compressive, tensional, and shear stress components are produced in cells when epithelial monolayers on substrate matrices are actively or passively wetted or de-wetted. Increased compressive stress on cells leads to enhanced cell-cell interactions by increasing the frequency of change the cell-cell distances, triggering various signalling pathways within the cells. This can ultimately lead either to cell jamming or to the extrusion of live cells. Despite extensive research in this field, it remains unclear how cells decide whether to jam, or to extrude a cell or cells, and how cells can reduce the compressive mechanical stress. Live cell extrusion from the overcrowded regions of the monolayers is associated with the presence of topological defects of cell alignment, induced by an interplay between the cell compressive and shear stress components. These topological defects stimulate cell re-alignment, as a part of the cells’ tendency to re-establish an ordered trend of cell migration, by intensifying the glancing interactions in overcrowded regions. In addition to individual cell extrusion, collective cell extrusion has also been documented during monolayer active de-wetting, depending on the cell type, matrix stiffness, and boundary conditions. Cell jamming has been discussed in the context of the cells’ contact inhibition of locomotion caused by cell head-on interactions. Since cell-cell interactions play a crucial role in cell rearrangement in an overcrowded environment, this review is focused on physical aspects of these interactions in order to stimulate further biological research in the field

Physical aspects of epithelial cell-cell interactions : hidden system complexities

The maintenance of homeostasis and the retention of ordered epithelial cell self-organization are essential for morphogenesis, wound healing, and the spread of cancer across the epithelium. However, cell-cell interactions in an overcrowded environment introduce a diversity of complications. Such interactions arise from an interplay between the cell compressive and shear stress components that accompany increased cell packing density. They can lead to various kinds of cell rearrangement such as: the epithelial-to-mesenchymal cell state transition; live cell extrusion; and cell jamming. All of these scenarios of cell rearrangement under mechanical stress relate to changes in the strengths of the cell-cell and cell-matrix adhesion contacts. The objective of this review study is twofold: first, to provide a comprehensive summary of the biological and physical factors influencing the effects of cell mechanical stress on cell-cell interactions, and the consequences of these interactions for the status of cell-cell and cell-matrix adhesion contacts; and secondly, to offer a bio-physical/mathematical analysis of the aforementioned biological aspects. By presenting these two approaches in conjunction, we seek to highlight the intricate nature of biological systems, which manifests in the form of complex bio-physical/mathematical equations. Furthermore, the juxtaposition of these apparently disparate approaches underscores the importance of conducting experiments to determine the multitude of parameters that contribute to the development of these intricate bio-physical/mathematical models

Marangoni effect and cell spreading

Cells are very sensitive to the shear stress (SS). However, undesirable SS is generated during physiological process such as collective cell migration (CCM) and influences the biological processes such as morphogenesis, wound healing and cancer invasion. Despite extensive research devoted to study the SS generation caused by CCM, we still do not fully understand the main cause of SS appearance. An attempt is made here to offer some answers to these questions by considering the rearrangement of cell monolayers. The SS generation represents a consequence of natural and forced convection. While forced convection is dependent on cell speed, the natural convection is induced by the gradient of tissue surface tension. The phenomenon is known as the Marangoni effect. The gradient of tissue surface tension induces directed cell spreading from the regions of lower tissue surface tension to the regions of higher tissue surface tension and leads to the cell sorting. This directional cell migration is described by the Marangoni flux. The phenomenon has been recognized during the rearrangement of (1) epithelial cell monolayers and (2) mixed cell monolayers made by epithelial and mesenchymal cells. The consequence of the Marangoni effect is an intensive spreading of cancer cells through an epithelium. In this work, a review of existing literature about SS generation caused by CCM is given along with the assortment of published experimental findings, to invite experimentalists to test given theoretical considerations in multicellular systems

Role of viscoelasticity in the appearance of low-Reynolds turbulence: Considerations for modelling

Inertial effects caused by perturbations of dynamical equilibrium during the flow of soft matter constitute a hallmark of turbulence. Such perturbations are attributable to an imbalance between energy storage and energy dissipation. During the flow of Newtonian fluids, kinetic energy can be both stored and dissipated, while the flow of viscoelastic soft matter systems, such as polymer fluids, induces the accumulation of both kinetic and elastic energies. The accumulation of elastic energy causes local stiffening of stretched polymer chains, which can destabilise the flow. Migrating multicellular systems are hugely complex and are capable of self-regulating their viscoelasticity and mechanical stress generation, as well as controlling their energy storage and energy dissipation. Since the flow perturbation of viscoelastic systems is caused by the inhomogeneous accumulation of elastic energy, rather than of kinetic energy, turbulence can occur at low Reynolds numbers. This theoretical review is focused on clarifying the role of viscoelasticity in the appearance of low-Reynolds turbulence. Three types of system are considered and compared: (1) high-Reynolds turbulent flow of Newtonian fluids, (2) low and moderate-Reynolds flow of polymer solutions, and (3) migration of epithelial collectives, discussed in terms of two model systems. The models considered involve the fusion of two epithelial aggregates, and the free expansion of epithelial monolayers on a substrate matrix

Viscoelasticity of multicellular surfaces

Various modeling approaches have been applied to describe viscoelasticity of multicellular surfaces. The viscoelasticity is considered within three time regimes: (1) short time regime for milliseconds to seconds time scale which corresponds to sub-cellular level; (2) middle time regime for several tens of seconds to several minutes time scale which corresponds to cellular level; and (3) long time regime for several tens of minutes to several hours time scale which corresponds to supra-celltilar level. Short and middle time regimes have been successfully elaborated in the literature, whereas long time viscoelasticity remains unclear. Long time regime accounts for collective cell migration. Collective cell migration could induce uncorrelated motility which has an impact to energy storage and dissipation during cell surface rearrangement. Uncorrelated motility influences: (1) volume fraction of migrating cells, (2) distribution of migrating cells, (3) shapes of migrating cell groups. These parameters influence mechanical coupling between migrating and resting subpopulations and consequently the constitutive model for long time regime. This modeling consideration indicates that additional experimental work is needed to confirm the feasibility of constitutive models which have been applied in literature for long time regime as: (1) relaxation of stress and strain, (2) storage and loss moduli as the function of time, (3) distribution of migrating cells

Red Blood Cell Deformability Is Expressed by a Set of Interrelated Membrane Proteins

Red blood cell (RBC) deformability, expressing their ability to change their shape, allows them to minimize their resistance to flow and optimize oxygen delivery to the tissues. RBC with reduced deformability may lead to increased vascular resistance, capillary occlusion, and impaired perfusion and oxygen delivery. A reduction in deformability, as occurs during RBC physiological aging and under blood storage, is implicated in the pathophysiology of diverse conditions with circulatory disorders and anemias. The change in RBC deformability is associated with metabolic and structural alterations, mostly uncharacterized. To bridge this gap, we analyzed the membrane protein levels, using mass spectroscopy, of RBC with varying deformability determined by image analysis. In total, 752 membrane proteins were identified. However, deformability was positively correlated with the level of only fourteen proteins, with a highly significant inter-correlation between them. These proteins are involved in membrane rafting and/or the membrane–cytoskeleton linkage. These findings suggest that the reduction of deformability is a programmed (not arbitrary) process of remodeling and shedding of membrane fragments, possibly mirroring the formation of extracellular vesicles. The highly significant inter-correlation between the deformability-expressing proteins infers that the cell deformability can be assessed by determining the level of a few, possibly one, of them