A Theoretical Analysis for the Effect of Substrate Elasticity on Cellular Adhesion

2010 ◽  
Author(s):  
Alireza Sarvestani
Keyword(s):  
Cell Adhesion ◽  
Thermodynamic Model ◽  
Intracellular Signaling ◽  
Mechanistic Model ◽  
Cellular Adhesion ◽  
Mechanical Stiffness ◽  
Ligand Density ◽  
Spread Area ◽  
Adhesive Proteins ◽  
Substrate Elasticity

Cell behavior is mediated by variety of physiochemical properties of extracellular matrix (ECM). Material composition, surface chemistry, roughness, and distribution pattern of cell adhesive proteins are among the ECM properties which are known to modulate various cellular physiological functions. Mechanical stiffness of ECM in particular is found to be a major regulator for multiple aspects of cellular function. Experiments show that cells in general, exhibit an apparent adhesion preference for stiffer substrates with a larger projected spread area with increasing the substrate stiffness. In addition, it seems that the effect of substrates elasticity is strongly coupled with adhesivity of the substrate; on relatively stiff substrates the spread area of the cells exhibits strong biphasic dependence to the changes in ligand density, whereas on soft substrates their limited spreading is much less sensitive to the density of surface ligands. This study aims to propose a theoretical basis for the interplay between substrate elasticity and cellular adhesion, using an equilibrium thermodynamic model. Within this framework, the equilibrium contact area is assumed to ensure minimization of the free energy contributed by interfacial adhesive and repulsive interactions between the membrane and substrate as well as the deformation of cell and substrate. Hence, this thermodynamic model overlooks the contribution of intracellular signaling or actively regulated cytoskeleton and assumes that cell adhesion is solely a result of the balance between the membrane-substrate repulsive potentials, stored elastic energy, binding enthalpy, and mixing entropy of mobile receptors. The predictions of this purely mechanistic model for cell adhesion qualitatively follow the experimental results featuring the variation of cell spread area on compliant bio-adhesive substrates. This suggests that the mechanistic pathways inherent to membrane-substrate interactions may be equally important as intracellular signaling pathways to mediate the cellular adhesion.

Kinetics of Membrane Spreading on Compliant Bio-Adhesive Substrates

2010 ◽  
Author(s):  
Alireza Sarvestani
Keyword(s):  
Focal Adhesion ◽  
Early Stage ◽  
Thermodynamic Force ◽  
Mechanical Stiffness ◽  
Compliant Substrates ◽  
Wide Range ◽  
Adhesion Zone ◽  
Spread Area ◽  
Substrate Elasticity ◽  
Kinetics Of

The contact formation between cell membrane and a bio-adhesive substrate is driven by binding between transmembrane mobile receptors (e.g., integrin) and complementary ligand molecules on the substrate (fibronectin, collagen, etc.) This short range specific adhesion is alleviated by a phalanx of interfacial non-specific forces. In addition to cell-substrate interfacial interactions, cell adhesion can be mediated by a wide range of substrate physiochemical properties. In particular, mechanical stiffness of the substrate has been recognized as one of the major regulators for bio-adhesion. Cells in general, exhibit an apparent adhesion preference for stiffer substrates and switch from a round to spread morphology as the substrate stiffness increases. Understanding the mechano-chemical pathways mediating the interplay between the substrate properties and cell behavior could be critical for effective performance of synthetic biomaterials in tissue engineering applications. In this study, we consider the effect of substrate elasticity on the dynamics of membrane spreading and growth of focal adhesion zone. The formation and growth of the focal adhesion points during the early stage of adhesion process is a result of spontaneous spreading of membrane on the substrate. This can be considered as a non-equilibrium kinetic process which is controlled by the diffusibility of receptor molecules. In order to study the effect of substrate elasticity on the kinetics of membrane-substrate association, receptors are assumed as ideal solute particles laterally diffusing within the plane of the membrane until they are stabilized through association with their complementary ligands which are immobilized on the surface of a compliant substrate. Considering different mechanical stiffness for the substrates, the displacement and speed of spreading at the edge of adhesion zone are predicted as a function of time. Results show that decreasing the stiffness of bio-adhesive substrates reduces the rate of membrane spreading, due to a weaker thermodynamic force which drives the membrane-substrate association. This mechanism restrains the growth of focal adhesion zones on compliant substrates and can be considered as a reason for smaller spread area of the cells after stabilization of adhesion.

scholarly journals Perinatal Inflammation: Could Partial Blocking of Cell Adhesion Molecule Function Be a Solution?

Children ◽  
2021 ◽  
Vol 8 (5) ◽  
pp. 380
Author(s):  
Nikolaos Vrachnis ◽  
Dimitrios Zygouris ◽  
Dionysios Vrachnis ◽  
Nikolaos Roussos ◽  
Nikolaos Loukas ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Cell Adhesion Molecules ◽  
Clinical Symptoms ◽  
Leukocyte Adhesion ◽  
Cellular Adhesion ◽  
Functional Impairments ◽  
Perinatal Medicine ◽  
Term Infants ◽  
Scientific Advance

In spite of the great advances made in recent years in prenatal and perinatal medicine, inflammation can still frequently result in injury to vital organs and often constitutes a major cause of morbidity. It is today well established that in neonates—though vulnerability to infection among neonates is triggered by functional impairments in leukocyte adhesion—the decreased expression of cell adhesion molecules also decreases the inflammatory response. It is also clear that the cell adhesion molecules, namely, the integrins, selectins, and the immunoglobulin (Ig) gene super family, all play a crucial role in the inflammatory cascade. Thus, by consolidating our knowledge concerning the actions of these vital cell adhesion molecules during the prenatal period as well as regarding the genetic deficiencies of these molecules, notably leukocyte adhesion deficiency (LAD) I, II, and III, which can provoke severe clinical symptoms throughout the first year of life, it is anticipated that intervention involving blocking the function of cell adhesion molecules in neonatal leukocytes has the potential to constitute an effective therapeutic approach for inflammation. A promising perspective is the potential use of antibody therapy in preterm and term infants with perinatal inflammation and infection focusing on cases in which LAD is involved, while a further important scientific advance related to this issue could be the combination of small peptides aimed at the inhibition of cellular adhesion.

scholarly journals Neural Cell Adhesion Molecule Induces Intracellular Signaling via Multiple Mechanisms of Ca2+ Homeostasis

2006 ◽  
Vol 17 (5) ◽  
pp. 2278-2286 ◽  
Author(s):  
Darya Kiryushko ◽  
Irina Korshunova ◽  
Vladimir Berezin ◽  
Elisabeth Bock
Keyword(s):  
Cell Adhesion ◽  
Neuronal Differentiation ◽  
Adhesion Molecule ◽  
Intracellular Signaling ◽  
Hippocampal Neurons ◽  
Cell Adhesion Molecule ◽  
Neural Cell Adhesion Molecule ◽  
Neural Cell ◽  
Src Family Kinases ◽  
Neural Cell Adhesion

The neural cell adhesion molecule (NCAM) plays a pivotal role in the development of the nervous system, promoting neuronal differentiation via homophilic (NCAM–NCAM) as well as heterophilic (NCAM-fibroblast growth factor receptor [FGFR]) interactions. NCAM-induced intracellular signaling has been shown to affect and be dependent on the cytoplasmic Ca2+ concentration ([Ca2+]i). However, the molecular basis of this remains unclear. In this study, we determined [Ca2+]i regulating mechanisms involved in intracellular signaling induced by NCAM. To mimic the effect of homophilic NCAM interaction on [Ca2+]i in vitro, we used a peptide derived from a homophilic binding site of NCAM, termed P2, which triggers signaling cascades similar to those activated by NCAM–NCAM interaction. We found that P2 increased [Ca2+]i in primary hippocampal neurons. This effect depended on two signaling pathways. The first pathway was associated with activation of FGFR, phospholipase Cγ, and production of diacylglycerol, and the second pathway involved Src-family kinases. Moreover, NCAM-mediated Ca2+ entry required activation of nonselective cation and T-type voltage-gated Ca2+ channels. These channels, together with the Src-family kinases, were also involved in neuritogenesis induced by physiological, homophilic NCAM interactions. Thus, unanticipated mechanisms of Ca2+ homeostasis are shown to be activated by NCAM and to contribute to neuronal differentiation.

scholarly journals Glioma Pathogenesis-Related 1-Like 1 Is Testis Enriched, Dynamically Modified, and Redistributed during Male Germ Cell Maturation and Has a Potential Role in Sperm-Oocyte Binding

Endocrinology ◽  
2010 ◽  
Vol 151 (5) ◽  
pp. 2331-2342 ◽  
Author(s):  
Gerard M. Gibbs ◽  
Jennifer Chi Yi Lo ◽  
Brett Nixon ◽  
Duangporn Jamsai ◽  
Anne E. O'Connor ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Zona Pellucida ◽  
Secretory Protein ◽  
Cellular Adhesion ◽  
Binding Assays ◽  
Distinct Subgroup ◽  
Functional Studies ◽  
Pathogenesis Related ◽  
Antigen 5

The glioma pathogenesis-related 1 (GLIPR1) family consists of three genes [GLIPR1, GLIPR1-like 1 (GLIPR1L1), and GLIPR1-like 2 (GLIPR1L2)] and forms a distinct subgroup within the cysteine-rich secretory protein (CRISP), antigen 5, and pathogenesis-related 1 (CAP) superfamily. CAP superfamily proteins are found in phyla ranging from plants to humans and, based largely on expression and limited functional studies, are hypothesized to have roles in carcinogenesis, immunity, cell adhesion, and male fertility. Specifically data from a number of systems suggests that sequences within the C-terminal CAP domain of CAP proteins have the ability to promote cell-cell adhesion. Herein we cloned mouse Glipr1l1 and have shown it has a testis-enriched expression profile. GLIPR1L1 is posttranslationally modified by N-linked glycosylation during spermatogenesis and ultimately becomes localized to the connecting piece of elongated spermatids and sperm. After sperm capacitation, however, GLIPR1L1 is also localized to the anterior regions of the sperm head. Zona pellucida binding assays indicate that GLIPR1L1 has a role in the binding of sperm to the zona pellucida surrounding the oocyte. These data suggest that, along with other members of the CAP superfamily and several other proteins, GLIPR1L1 is involved in the binding of sperm to the oocyte complex. Collectively these data further strengthen the role of CAP domain-containing proteins in cellular adhesion and propose a mechanism whereby CAP proteins show overlapping functional significance during fertilization.

scholarly journals Separable portions of the CD2 cytoplasmic domain involved in signaling and ligand avidity regulation.

1993 ◽  
Vol 178 (5) ◽  
pp. 1831-1836 ◽  
Author(s):  
W C Hahn ◽  
B E Bierer
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Cell Receptor ◽  
Cytoplasmic Domain ◽  
Cellular Adhesion ◽  
Transmembrane Signaling ◽  
Tcr Signaling ◽  
T Cell Immune Responses

Effective T cell immune responses require the molecular interplay between adhesive and signaling events mediated by the T cell receptor for antigen (TCR) and other cell surface coreceptor molecules. In this report, we have distinguished between the role of regulated adhesion and transmembrane signaling in coreceptor function using the T cell glycoprotein CD2. By binding its ligands on antigen-presenting cell (APC), CD2 serves both to initiate signal transduction events and to promote cellular adhesion. Furthermore, the avidity of CD2 for one ligand, CD58 (LFA-3), is regulated by TCR signaling. We have expressed wild type CD2 and a series of mutated CD2 molecules in an antigen-specific murine T cell hybridoma. Structure-function studies using these stably transfected cell lines identify two structurally and functionally distinct regions of the 116 amino acid (aa) cytoplasmic domain. One region is required for CD2-mediated signal transduction, and a separate COOH-terminal 21 aa portion is required for CD2 activity regulation. Cell lines expressing CD2 molecules lacking the cytoplasmic segment required for CD2-initiated IL-2 production retain the ability to upregulate CD2 avidity. Conversely, cell lines expressing CD2 mutants lacking the cytoplasmic segment required for avidity regulation retain the ability to initiate CD2-specific signaling. In antigen-specific T cell responses, basal binding of CD2 to its ligands enhances antigen responsiveness only minimally, whereas regulated avidity and transmembrane signaling are both required for optimal coreceptor function. Taken together, these studies demonstrate the independent contributions of regulated adhesion and intracellular signaling in CD2 coreceptor function.

scholarly journals Enhancing network activation in natural killer cells: predictions from in silico modeling

2020 ◽  
Vol 12 (5) ◽  
pp. 109-121
Author(s):  
Sahak Z Makaryan ◽  
Stacey D Finley
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
In Silico ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Nk Cell ◽  
Mechanistic Model ◽  
Cell Killing ◽  
Published Data ◽  
Network Activation

Abstract Natural killer (NK) cells are part of the innate immune system and are capable of killing diseased cells. As a result, NK cells are being used for adoptive cell therapies for cancer patients. The activation of NK cell stimulatory receptors leads to a cascade of intracellular phosphorylation reactions, which activates key signaling species that facilitate the secretion of cytolytic molecules required for cell killing. Strategies that maximize the activation of such intracellular species can increase the likelihood of NK cell killing upon contact with a cancer cell and thereby improve efficacy of NK cell-based therapies. However, due to the complexity of intracellular signaling, it is difficult to deduce a priori which strategies can enhance species activation. Therefore, we constructed a mechanistic model of the CD16, 2B4 and NKG2D signaling pathways in NK cells to simulate strategies that enhance signaling. The model predictions were fit to published data and validated with a separate dataset. Model simulations demonstrate strong network activation when the CD16 pathway is stimulated. The magnitude of species activation is most sensitive to the receptor’s initial concentration and the rate at which the receptor is activated. Co-stimulation of CD16 and NKG2D in silico required fewer ligands to achieve half-maximal activation than other combinations, suggesting co-stimulating these pathways is most effective in activating the species. We applied the model to predict the effects of perturbing the signaling network and found two strategies that can potently enhance network activation. When the availability of ligands is low, it is more influential to engineer NK cell receptors that are resistant to proteolytic cleavage. In contrast, for high ligand concentrations, inhibiting phosphatase activity leads to sustained species activation. The work presented here establishes a framework for understanding the complex, nonlinear aspects of NK cell signaling and provides detailed strategies for enhancing NK cell activation.

STRUCTURAL DIVERSITY AMONG CELLULAR ADHESION RECEPTORS: FIBRINOGEN BINDING IS A NOVEL BIOLOGICAL PROPERTY OF THE MONOCYTE DIFFERENTIATION ANTIGEN OKM1

1987 ◽  
Author(s):  
Dario C Altieri ◽  
Rossella Bader ◽  
Pier M Mannucci
Keyword(s):  
Molecular Size ◽  
Structural Diversity ◽  
Cellular Adhesion ◽  
Differentiation Antigen ◽  
Cell Surface Antigens ◽  
Monocyte Differentiation ◽  
Fibrinogen Receptor ◽  
Biological Adhesion ◽  
Fibrinogen Binding ◽  
Adhesive Proteins

A family of related glycoproteins (GP) mediate the interaction between the circulating adhesive proteins and a variety of cells (cytyoadhesins). In this study we have compared two cell-surface antigens which share the property to bind fibrinogen: the platelet GP IIb/IIIa, prototype of the cytoadhesins, and the receptor for fibrinogen costitutively synthesized by monocytes. Two anti-GP IIb/IIIa monoclonal antibodies (Mabs) (LJP9, LJP5), recognizing functionally distinct epitopes of the GP IIb/IIIa did not react with monocytes nor inhibited 125I-fibrinogen binding to monocytes. Similarly, an Arg-Gly-Asp containing peptide which completely abolished platelet-fibrinogen interaction, had no effect on monocytes. Structurally, the monocyte fibrinogen receptor was dimeric and composed of two subunits with molecular weight (Mr) of 155,000 and 95,000. This structural organization was different from that of the GP IIb/IIIa (Mr= 116,000), but in close analogy with the family of leukocyte differentiation antigens OKM1, LFA-1. Therefore, this possible relationship was investigated. A Mab to OKM1 antigen (10 μg/ml) completely suppressed fibrinogen binding to monocytes while it was ineffective on plateles. Iodinated monocyte lysate subjected to immunoprecipitation with OKM1 Mab (60 μg/ml) showed a dimeric antigen with the same molecular size of the monocyte fibrinogen receptor. Moreover, preclearing of the monocyte lysate with OKM1 Mab removed the immunoprecipitate corresponding to the monocyte fibrinogen receptor. These data indicate that the immunologic differentiation antigen OKM1, in addition to function as a complement receptor, displays also the novel biological adhesion property to mediate the binding of fibrinogen to monocytes.

scholarly journals Electric Fields and Inflammation: May the Force be with You

2008 ◽  
Vol 8 ◽  
pp. 1280-1294 ◽  
Author(s):  
Simon B. Brown ◽  
Ian Dransfield
Keyword(s):  
Cell Adhesion ◽  
Electric Fields ◽  
Conformational Changes ◽  
Intracellular Signaling ◽  
Tissue Injury ◽  
Potassium Efflux ◽  
Ample Evidence ◽  
Surface Receptors ◽  
Signaling Events ◽  
A Site

Integrins are a family of ubiquitous cell surface receptors comprising heterodimers of β and α chains that are required for cell adhesion and motility. Integrin-dependent adhesion and signaling is associated with major conformational changes in the ectodomain as it shifts from a low-affinity “bent” to a high-affinity “extended” structure. The ability of a cell to regulate dynamically the affinity or activation state of an integrin, and hence its binding to extracellular matrix or cell adhesion molecules, is assumed to be driven by intracellular signaling events transmitted by protein binding to the cytoplasmic tail. The binding of an integrin to its ligand can then transmit signals back into the cell to regulate the formation of a macromolecular focal adhesion complex that effectively anchors the cytoskeleton to the adhesion site. Many proteins have been reported to associate physically and functionally with integrins, leading to altered signaling events. A particularly intriguing molecular association exists between integrins and transmembrane proteins that gate the movement of charge, especially voltage-gated potassium channels, although the significance of this interaction is not understood. Although ample evidence indicates that the engagement of integrins can promote potassium efflux by both excitable and nonexcitable cells, we speculate the converse, that the activation state of integrins is dynamically regulated by changes in a transmembrane potential. In this way, direct-current electric fields generated at a site of tissue injury can promote the galvanotaxis or directed migration of cells involved in tissue repair and inflammation.

scholarly journals Differential modulation of cell adhesion by interaction between adhesive and counter-adhesive proteins: characterization of the binding of vitronectin to osteonectin (BM40, SPARC)

1997 ◽  
Vol 324 (1) ◽  
pp. 311-319 ◽  
Author(s):  
Sylvia ROSENBLATT ◽  
James A. BASSUK ◽  
Charles E. ALPERS ◽  
Helene E. SAGE ◽  
Rupert TIMPL ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Heparan Sulphate ◽  
The Body ◽  
Dependent Manner ◽  
Heparin Binding ◽  
Endothelial Cell Function ◽  
Cultured Endothelial Cells ◽  
Adhesive Proteins ◽  
Pai 1

Heparin-binding forms of vitronectin, a multifunctional adhesive glycoprotein, are associated with the extracellular matrix (ECM) at different locations in the body and serve to promote cell adhesion and the regulation of pericellular proteolysis at sites of angiogenesis. In the present study we characterized the interactions of vitronectin with the counter-adhesive protein osteonectin (also termed SPARC or BM40). Osteonectin and vitronectin were both found associated with the ECM of cultured endothelial cells and were localized in vessel wall sections of kidney tissue. In vitro, the heparin-binding multimeric isoform of vitronectin bound to immobilized osteonectin in a saturable manner with half-maximal binding at 30–40 nM. Preincubation of plasma vitronectin with plasminogen activator inhibitor 1 (PAI-1), which provoked multimer formation, induced the binding of vitronectin to osteonectin. Binding was optimal at physiological ionic strength, and binary complexes were stabilized by tissue transglutaminase-mediated cross-linking. In a concentration-dependent fashion, PAI-1, CaCl2, heparin and heparan sulphate, but not other glycosaminoglycans, interfered with the binding of vitronectin to osteonectin. Using vitronectin-derived synthetic peptides as well as mutant forms of recombinant osteonectin, we found that the heparin-binding region of vitronectin interacted with the C-terminal region of osteonectin that contains a high-affinity Ca2+-binding site with counter-adhesive properties. Adhesion of cultured endothelial cells was partly abrogated by osteonectin and was correspondingly reversed by vitronectin in a concentration-dependent manner. These results indicate that specific interactions between vitronectin and osteonectin modulate cell adhesion and might thereby regulate endothelial cell function during angiogenesis.

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