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TECHNICAL PAPERS: Cell

Finite-Element Analysis of the Adhesion-Cytoskeleton-Nucleus Mechanotransduction Pathway During Endothelial Cell Rounding: Axisymmetric Model

[+] Author and Article Information
Ronald P. Jean, Christopher S. Chen

Department of Biomedical Engineering,  The Johns Hopkins University, Baltimore, Maryland 21205

Alexander A. Spector1

Department of Biomedical Engineering,  The Johns Hopkins University, Baltimore, Maryland 21205aspector@bme.jhu.edu

1

Corresponding author.

J Biomech Eng 127(4), 594-600 (Jan 20, 2005) (7 pages) doi:10.1115/1.1933997 History: Received July 26, 2004; Revised January 20, 2005

Endothelial cells possess a mechanical network connecting adhesions on the basal surface, the cytoskeleton, and the nucleus. Transmission of force at adhesions via this pathway can deform the nucleus, ultimately resulting in an alteration of gene expression and other cellular changes (mechanotransduction). Previously, we measured cell adhesion area and apparent nuclear stretch during endothelial cell rounding. Here, we reconstruct the stress map of the nucleus from the observed strains using finite-element modeling. To simulate the disruption of adhesions, we prescribe displacement boundary conditions at the basal surface of the axisymmetric model cell. We consider different scenarios of the cytoskeletal arrangement, and represent the cytoskeleton as either discrete fibers or as an effective homogeneous layer. When the nucleus is in the initial (spread) state, cytoskeletal tension holds the nucleus in an elongated, ellipsoidal configuration. Loss of cytoskeletal tension during cell rounding is represented by reactive forces acting on the nucleus in the model. In our simulations of cell rounding, we found that, for both representations of the cytoskeleton, the loss of cytoskeletal tension contributed more to the observed nuclear deformation than passive properties. Since the simulations make no assumption about the heterogeneity of the nucleus, the stress components both within and on the surface of the nucleus were calculated. The nuclear stress map showed that the nucleus experiences stress on the order of magnitude that can be significant for the function of DNA molecules and chromatin fibers. This study of endothelial cell mechanobiology suggests the possibility that mechanotransduction could result, in part, from nuclear deformation, and may be relevant to angiogenesis, wound healing, and endothelial barrier dysfunction.

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Copyright © 2005 by American Society of Mechanical Engineers
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Figures

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Figure 1

The boundary condition to simulate detachment of the cell surface from the substrate during cell rounding. The case of an adhesion area fraction=0.4 is considered, and the jump in the radial component of the cell displacement as a function of the cell radius is prescribed.

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Figure 2

Concept of the active forces associated with a loss of cytoskeletal tension in the cytoskeletal fibers due to loss of adhesion area: (a) reference spread state where the solid lines represent the originally stressed fibers connecting the nucleus to the adhesion sites, (b) intermediate state where a portion of the fibers is detached and associated with the reactive stresses (dashed lines); and, the rest of the fibers (solid lines) is still attached to the adhesion sites, and (c) preround state where all the fibers are associated with the reactive stresses.

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Figure 3

Arrangement of cytoskeletal fibers in the computational cell model using (a) discrete fiber, and (b) effective layer representations

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Figure 4

Computational simulation of cell rounding for different states and different cytoskeletal configurations. Adhesion area fractions of (a) 1.0, (b) 0.9, (c) 0.7, and (d) 0.4 correspond to simulations with discrete cytoskeletal fibers. Simulations incorporating an effective layer representation of the cytoskeleton are shown for adhesion area fractions of (e) 1.0, (f) 0.9, (g) 0.7, and (h) 0.4.

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Figure 5

Undeformed (dark) and deformed (light) states of the nucleus with prescribed reactive forces for different states and different cytoskeletal configurations. Adhesion area fractions of (a) 0.9, (b) 0.7, and (c) 0.4 correspond to simulations with discrete cytoskeletal fibers. Simulations incorporating an effective layer representation of the cytoskeleton are shown for adhesion area fractions of (d) 0.9, (e) 0.7, and (f) 0.4.

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Figure 6

Nuclear stress field of Cauchy stress component, S11, corresponding to an adhesion area fraction=0.4 for (a) discrete fiber and (b) effective layer representations of the cytoskeleton

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Figure 7

Nuclear stress field of Cauchy stress component, S22, corresponding to an adhesion area fraction=0.4 for (a) discrete fiber and (b) effective layer representations of the cytoskeleton

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Figure 8

Nuclear stress field of Cauchy shear stress component, S12, corresponding to an adhesion area fraction=0.4 for (a) discrete fiber and (b) effect layer representations of the cytoskeleton

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