Biomedical subjects

Ulrich S Schwarz

Publications and source records attributed to Ulrich S Schwarz.

8 recordsLinked to original sources

PubMed2006

Bistability of cell-matrix adhesions resulting from nonlinear receptor-ligand dynamics.

Bistability is a major mechanism for cellular decision making and usually results from positive feedback in biochemical control systems. Here we show theoretically that bistability between unbound and bound states of adhesion clusters results from positive feedback mediated by structural rather than biochemical processes, namely by receptor-ligand dissociation and association dynamics that depend nonlinearly on mechanical force and receptor-ligand separation. For small cell-matrix adhesions, we find rapid switching between unbound and bound states, which in the initial stages of adhesion allows the cell to explore its environment through many transient adhesions.

Cell-Matrix Junctions↗

PubMed2006

Collective effects in cellular structure formation mediated by compliant environments: a Monte Carlo study.

Compliant environments can mediate interactions between mechanically active cells like fibroblasts. Starting with a phenomenological model for the behavior of single cells, we use extensive Monte Carlo simulations to predict non-trivial structure formation for cell communities on soft elastic substrates as a function of elastic moduli, cell density, noise and cell position geometry. In general, we find a disordered structure as well as ordered string-like and ring-like structures. The transition between ordered and disordered structures is controlled both by cell density and noise level, while the transition between string- and ring-like ordered structures is controlled by the Poisson ratio. Similar effects are observed in three dimensions. Our results suggest that in regard to elastic effects, healthy connective tissue usually is in a macroscopically disordered state, but can be switched to a macroscopically ordered state by appropriate parameter variations, in a way that is reminiscent of wound contraction or diseased states like contracture.

Biomechanical Phenomena↗

PubMed2005

Focal adhesions as mechanosensors: the two-spring model.

Adhesion-dependent cells actively sense the mechanical properties of their environment through mechanotransductory processes at focal adhesions, which are integrin-based contacts connecting the extracellular matrix to the cytoskeleton. Here we present first steps towards a quantitative understanding of focal adhesions as mechanosensors. It has been shown experimentally that high levels of force are related to growth of and signaling at focal adhesions. In particular, activation of the small GTPase Rho through focal adhesions leads to the formation of stress fibers. Here we discuss one way in which force might regulate the internal state of focal adhesions, namely by modulating the internal rupture dynamics of focal adhesions. A simple two-spring model shows that the stiffer the environment, the more efficient cellular force is built up at focal adhesions by molecular motors interacting with the actin filaments.

Animals↗

PubMed2005

Physical determinants of cell organization in soft media.

Cell adhesion is an integral part of many physiological processes in tissues, including development, tissue maintenance, angiogenesis, and wound healing. Recent advances in materials science (including microcontact printing, soft lithography, microfluidics, and nanotechnology) have led to strongly improved control of extracellular ligand distribution and of the properties of the micromechanical environment. As a result, the investigation of cellular response to the physical properties of adhesive surfaces has become a very active area of research. Sophisticated use of elastic substrates has revealed that cell organization in soft media is determined by active mechanosensing at cell-matrix adhesions. In order to determine the underlying mechanisms, quantification and biophysical modelling are essential. In tissue engineering, theory might help to design new environments for cells.

Animals↗

PubMed2004

Stochastic dynamics of adhesion clusters under shared constant force and with rebinding.

Single receptor-ligand bonds have finite lifetimes, so that biological systems can dynamically react to changes in their environment. In cell adhesion, adhesion bonds usually act cooperatively in adhesion clusters. Outside the cellular context, adhesion clusters can be probed quantitatively by attaching receptors and ligands to opposing surfaces. Here we present a detailed theoretical analysis of the stochastic dynamics of a cluster of parallel bonds under shared constant loading and with rebinding. Analytical solutions for the appropriate one-step master equation are presented for special cases, while the general case is treated with exact stochastic simulations. If the completely dissociated state is modeled as an absorbing boundary, mean cluster lifetime is finite and can be calculated exactly. We also present a detailed analysis of fluctuation effects and discuss various approximations to the full stochastic description.

Journal Article↗

PubMed2004

L-selectin-mediated leukocyte tethering in shear flow is controlled by multiple contacts and cytoskeletal anchorage facilitating fast rebinding events.

L-selectin-mediated tethers result in leukocyte rolling only above a threshold in shear. Here we present biophysical modeling based on recently published data from flow chamber experiments, which supports the interpretation that L-selectin-mediated tethers below the shear threshold correspond to single L-selectin carbohydrate bonds dissociating on the time scale of milliseconds, whereas L-selectin-mediated tethers above the shear threshold are stabilized by multiple bonds and fast rebinding of broken bonds, resulting in tether lifetimes on the time scale of 10(-1) seconds. Our calculations for cluster dissociation suggest that the single molecule rebinding rate is of the order of 10(4) Hz. A similar estimate results if increased tether dissociation for tail-truncated L-selectin mutants above the shear threshold is modeled as diffusive escape of single receptors from the rebinding region due to increased mobility. Using computer simulations, we show that our model yields first-order dissociation kinetics and exponential dependence of tether dissociation rates on shear stress. Our results suggest that multiple contacts, cytoskeletal anchorage of L-selectin, and local rebinding of ligand play important roles in L-selectin tether stabilization and progression of tethers into persistent rolling on endothelial surfaces.

Cell Movement↗

PubMed2003

Avidity enhancement of L-selectin bonds by flow: shear-promoted rotation of leukocytes turn labile bonds into functional tethers.

L-selectin is a key lectin essential for leukocyte capture and rolling on vessel walls. Functional adhesion of L-selectin requires a minimal threshold of hydrodynamic shear. Using high temporal resolution videomicroscopy, we now report that L-selectin engages its ligands through exceptionally labile adhesive bonds (tethers) even below this shear threshold. These tethers share a lifetime of 4 ms on distinct physiological ligands, two orders of magnitude shorter than the lifetime of the P-selectin-PSGL-1 bond. Below threshold shear, tether duration is not shortened by elevated shear stresses. However, above the shear threshold, selectin tethers undergo 14-fold stabilization by shear-driven leukocyte transport. Notably, the cytoplasmic tail of L-selectin contributes to this stabilization only above the shear threshold. These properties are not shared by P-selectin- or VLA-4-mediated tethers. L-selectin tethers appear adapted to undergo rapid avidity enhancement by cellular transport, a specialized mechanism not used by any other known adhesion receptor.

Binding Sites↗

PubMed2002

L-selectin dimerization enhances tether formation to properly spaced ligand.

Selectin counterreceptors are glycoprotein scaffolds bearing multiple carbohydrate ligands with exceptional ability to tether flowing cells under disruptive shear forces. Bond clusters may facilitate formation and stabilization of selectin tethers. L-selectin ligation has been shown to enhance L-selectin rolling on endothelial surfaces. We now report that monoclonal antibodies-induced L-selectin dimerization enhances L-selectin leukocyte tethering to purified physiological L-selectin ligands and glycopeptides. Microkinetic analysis of individual tethers suggests that leukocyte rolling is enhanced through the dimerization-induced increase in tether formation, rather than by tether stabilization. Notably, L-selectin dimerization failed to augment L-selectin-mediated adhesion below a threshold ligand density, suggesting that L-selectin dimerization enhanced adhesiveness only to properly clustered ligand. In contrast, an epidermal growth factor domain substitution of L-selectin enhanced tether formation to L-selectin ligands irrespective of ligand density, suggesting that this domain controls intrinsic ligand binding properties of L-selectin without inducing L-selectin dimerization. Strikingly, at low ligand densities, where L-selectin tethering was not responsive to dimerization, elevated shear stress restored sensitivity of tethering to selectin dimerization. This is the first indication that shear stress augments effective selectin ligand density at local contact sites by promoting L-selectin encounter of immobilized ligand.

Animals↗