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A semianalytical model to study the effect of cortical tension on cell rolling.

ABSTRACT: Cell rolling on the vascular endothelium plays an important role in trafficking of leukocytes, stem cells, and cancer cells. We describe a semianalytical model of cell rolling that focuses on the microvillus as the unit of cell-substrate interaction and integrates microvillus mechanics, receptor clustering, force-dependent receptor-ligand kinetics, and cortical tension that enables incorporation of cell body deformation. Using parameters obtained from independent experiments, the model showed excellent agreement with experimental studies of neutrophil rolling on P-selectin and predicted different regimes of cell rolling, including spreading of the cells on the substrate under high shear. The cortical tension affected the cell-surface contact area and influenced the rolling velocity, and modulated the dependence of rolling velocity on microvillus stiffness. Moreover, at the same shear stress, microvilli of cells with higher cortical tension carried a greater load compared to those with lower cortical tension. We also used the model to obtain a scaling dependence of the contact radius and cell rolling velocity under different conditions of shear stress, cortical tension, and ligand density. This model advances theoretical understanding of cell rolling by incorporating cortical tension and microvillus extension into a versatile, semianalytical framework.

SUBMITTER: Bose S

PROVIDER: S-EPMC3000478 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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A semianalytical model to study the effect of cortical tension on cell rolling.

Bose Suman S Das Sarit K SK Karp Jeffrey M JM Karnik Rohit R

Biophysical journal 20101201 12

Cell rolling on the vascular endothelium plays an important role in trafficking of leukocytes, stem cells, and cancer cells. We describe a semianalytical model of cell rolling that focuses on the microvillus as the unit of cell-substrate interaction and integrates microvillus mechanics, receptor clustering, force-dependent receptor-ligand kinetics, and cortical tension that enables incorporation of cell body deformation. Using parameters obtained from independent experiments, the model showed ex ...[more]

PMID: 21156128

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Project description:Throughout the body, epithelial tissues contain curved features (e.g. cysts, ducts and crypts) that influence cell behaviors. These structures have varied curvature, with flat structures having zero curvature and structures such as crypts having large curvature. In the ovary, cortical inclusion cysts (CICs) of varying curvatures are found, and fallopian tube epithelial (FTE) cells have been found trapped within these cysts. FTE are the precursor for ovarian cancer, and the CIC niche has been proposed to play a role in ovarian cancer progression. We hypothesized that variations in ovarian CIC curvature that occur during cyst resolution impact the ability of trapped FTE cells to invade into the surrounding stroma. Using a lumen model in collagen gels, we determined that increased curvature resulted in more invasions of mouse FTE cells. To isolate curvature as a system parameter, we developed a novel technique to pattern concave curvatures into collagen gels. When FTE cells were seeded to confluency on curved substrates, increases in curvature increased the number of invading FTE cells and the invasion distance. FTE invasion into collagen substrates with higher curvature depended on matrix metalloproteinases (MMPs), but expression of collagen I degrading Mmps was not different on curved and flat regions. A finite-element model predicted that contractility and cell-cell connections were essential for increased invasion on substrates with higher curvature, while cell-substrate interactions had minimal effect. Experiments supported these predictions, with invasion decreased by blebbistatin, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) or N-cadherin-blocking antibody, but with no effect from a focal adhesion kinase inhibitor. Finally, experimental evidence supports that cell invasion on curved substrates occurs in two phases-a cell-cell-dependent initiation phase where individual cells break away from the monolayer and an MMP-dependent phase as cells migrate further into the collagen matrix.

Project description:Mechanical stability is a fundamental and essential property of epithelial cell sheets. It is in large part determined by cell-cell adhesion sites that are tightly integrated by the cortical cytoskeleton. An intimate crosstalk between the adherens junction-associated contractile actomyosin system and the desmosome-anchored keratin intermediate filament system is decisive for dynamic regulation of epithelial mechanics. A major question in the field is whether and in which way mechanical stress affects junctional plasticity. This is especially true for the desmosome-keratin scaffold whose role in force-sensing is virtually unknown. To examine this question, we inactivated the actomyosin system in human keratinocytes (HaCaT) and canine kidney cells (MDCK) and monitored changes in desmosomal protein turnover. Partial inhibition of myosin II by para-nitro-blebbistatin led to a decrease of the cells' elastic modulus and to reduced desmosomal protein turnover in regions where nascent desmosomes are formed and, to a lower degree, in regions where larger, more mature desmosomes are present. Interestingly, desmosomal proteins are affected differently: a significant decrease in turnover was observed for the desmosomal plaque protein desmoplakin I (DspI), which links keratin filaments to the desmosomal core, and the transmembrane cadherin desmoglein 2 (Dsg2). On the other hand, the turnover of another type of desmosomal cadherin, desmocollin 2 (Dsc2), was not significantly altered under the tested conditions. Similarly, the turnover of the adherens junction-associated E-cadherin was not affected by the low doses of para-nitro-blebbistatin. Inhibition of actin polymerization by low dose latrunculin B treatment and of ROCK-driven actomyosin contractility by Y-27632 treatment also induced a significant decrease in desmosomal DspI turnover. Taken together, we conclude that changes in the cortical force balance affect desmosome formation and growth. Furthermore, they differentially modulate desmosomal protein turnover resulting in changes of desmosome composition. We take the observations as evidence for a hitherto unknown desmosomal mechanosensing and mechanoresponse pathway responding to an altered force balance.

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A semianalytical model to study the effect of cortical tension on cell rolling.

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A semianalytical model to study the effect of cortical tension on cell rolling.

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