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doi: 10.1242/10.1242/jcs.00360

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Tensegrity II. How structural networks influence cellular information processing networks

Departments of Surgery and Pathology, Children's Hospital and Harvard Medical School, Enders 1007, 300 Longwood Avenue, Boston, MA 02115, USA

View larger version (40K): [in a new window]   Fig. 1. A schematic diagram of how forces applied via the ECM (A) or directly to the cell surface (B) travel to integrin-anchored focal adhesions through matrix attachments or cytoskeletal filaments, respectively. Internally generated tension and forces transmitted via cell-cell contact similarly reach focal adhesions through the cytoskeleton. Forces concentrated within the focal adhesion (magnified at bottom of the figure) can stimulate clustering of dimeric (,ß) integrin receptors and induce recruitment of focal adhesion proteins [e.g. Vinculin (Vin), Paxillin (Pax), Talin (Tal)] that connect directly to microfilaments and indirectly to microtubules and intermediate filaments (certain integrins can also connect directly to intermediate filaments, for example, within hemidesmosomes). Forces applied to this specialized cytoskeletal adhesion complex activate integrin-associated signaling cascades, which among others, include such protein as focal adhesion kinase (FAK), extracellular signal-regulated protein kinase (ERK), Shc, Rho, mDia1, caveolin-1 (cav-1), CD47, heterotrimeric G-proteins, adenylate cyclase (AC) and protein kinase A (PKA).

View larger version (47K): [in a new window]   Fig. 2. Cell distortion-dependent switching between distinct cell fates. (Top) Phase contrast microscopic images of capillary endothelial cells whose shape, size and orientation were controlled using the corresponding micropatterned adhesive substrate designs (20 or 50 µm circles or 10 µm wide lines) shown above in gray that were coated with a constant fibronectin density. Although cells were cultured in the same growth-factor-containing medium, well spread cells on large circles proliferated, retracted cells on the small circles underwent apoptosis, and cells on linear patterns that exhibited an intermediate degree of spreading differentiated into hollow capillary tubes (for details, see Chen et al., 1997; Dike et al., 1999). (Bottom) A schematic summary of cell-distortion-dependent switching between growth, differentiation and apoptosis that has been demonstrated using micropatterned substrates of different size in various cell types, as described in the text.

View larger version (37K): [in a new window]   Fig. 3. Contribution of cellular tensegrity to mechanochemical transduction. (Top) A schematic diagram of the tensegrity-based complementary force balance between tensed microfilaments, compressed microtubules and transmembrane integrin receptors (gray oval dimer) in living cells (intermediate filaments are not shown for simplicity) (for details, see Ingber, 2003). Black forms indicate regulatory proteins and enzymes that are physically immobilized on load-bearing cytoskeletal filaments; red oval represents a transmembrane protein that does not link to the internal cytoskeletal lattice. (Bottom) When force is applied to integrins, thermodynamic and kinetic parameters change locally for cytoskeleton-associated molecules that physically experience the mechanical load; when force is applied to non-adhesion receptors that do not link to the cytoskeleton, stress dissipates locally at the cell surface, and the biochemical response is muted. In this diagram, new tubulin monomers add onto the end of a microtubule (yellow symbols) when tension is applied to integrins, and the microtubule is decompressed as a result of a change in the critical concentration of tubulin. The blue form indicates a molecule that is physically distorted by stress transferred from integrins to the cytoskeleton and, as a result, changes its kinetics (increases its rate constant for chemical conversion of substrate 1 into product 2). In this manner, both cytoskeletal structure (architecture) and prestress (tension) in the cytoskeleton may modulate the cellular response to mechanical stress.

View larger version (35K): [in a new window]   Fig. 4. A schematic showing how local changes in ECM mechanics may guide tissue patterning. The local thinning in the ECM produced by accelerated ECM turnover will increase ECM compliance and result in local cell distortion through the action of tractional forces exerted by surrounding cells. Increased tension transfer across cell surface ECM receptors (integrins) will result in coordinated changes in cell and cytoskeletal form and, thereby, produce changes in cellular biochemistry that result in the localized growth and motility that drive tissue morphogenesis. Thus, in this view, cell growth and migration are constrained to the small group of cells (red) that is underlined by the thinned region of the basement membrane (green). Outward budding results when red cells extend and grow because neighboring cells along the same basement membrane do not experience the stress and, hence, remain quiescent (white cells).

View larger version (55K): [in a new window]   Fig. 5. Attractor landscape representation of cell fate determination. A hypothetical `potential landscape' that represents the n-dimensional state space compressed into two dimensions (XY) for visualization purposes. Every position in the XY plane would correspond to a network state (e.g. expression profile of gene and protein activities). The vertical axis (Z) represents a potential function, an `energy equivalent', representing some distance measure of a network state to the attractor state. Lowest points in the valleys correspond to attractor states that represent cell fates. Yellow arrows indicate a path that takes the cell from growth to apoptosis.

View larger version (140K): [in a new window]   Fig. 6. Cell fate switching in an epigenetic landscape, as portrayed by Waddington (Waddington, 1956). In this view of embryonic regulation, cell fate regulation is based on selection between pre-existing, intrinsically robust fates. The dynamics of this developmental selection is represented as a landscape with hills and valleys. The phenotypic state of a cell at any time is indicated by the position of a marble on that landscape. The marble will spontaneously roll down the valleys (stable developmental paths) leading to a distinct phenotype. The lowest points in the valleys correspond to the distinct, stable phenotypes within a given repertoire of fates that the cell may experience.

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