Biomedical subjects

R T Tranquillo

Publications and source records attributed to R T Tranquillo.

42 records · Page 3Linked to original sources

PubMed1988

A stochastic model for leukocyte random motility and chemotaxis based on receptor binding fluctuations.

Two central features of polymorphonuclear leukocyte chemosensory movement behavior demand fundamental theoretical understanding. In uniform concentrations of chemoattractant, these cells exhibit a persistent random walk, with a characteristic "persistence time" between significant changes in direction. In chemoattractant concentration gradients, they demonstrate a biased random walk, with an "orientation bias" characterizing the fraction of cells moving up the gradient. A coherent picture of cell movement responses to chemoattractant requires that both the persistence time and the orientation bias be explained within a unifying framework. In this paper, we offer the possibility that "noise" in the cellular signal perception/response mechanism can simultaneously account for these two key phenomena. In particular, we develop a stochastic mathematical model for cell locomotion based on kinetic fluctuations in chemoattractant/receptor binding. This model can simulate cell paths similar to those observed experimentally, under conditions of uniform chemoattractant concentrations as well as chemoattractant concentration gradients. Furthermore, this model can quantitatively predict both cell persistence time and dependence of orientation bias on gradient size. Thus, the concept of signal "noise" can quantitatively unify the major characteristics of leukocyte random motility and chemotaxis. The same level of noise large enough to account for the observed frequency of turning in uniform environments is simultaneously small enough to allow for the observed degree of directional bias in gradients.

Cell Movement↗

PubMed1987

Stochastic model of leukocyte chemosensory movement.

We propose a hypothesis for a unified understanding of the persistent and biased random walk behavior of leukocytes exhibiting random motility and chemotaxis, respectively. This hypothesis is based on a description of the leukocyte as an integrated system sensing and responding to a "noisy" receptor signal: random fluctuations inherent in receptor-sensing of chemo-attractant concentrations underlie the random walk behavior. Noise arises from real fluctuations in the receptor binding process, which translate into perceived fluctuations in receptor-measured concentration. The unbiased random walk characteristic of random motility arises from perceived fluctuating gradients without a mean reference direction and the biased random walk in chemotaxis arises due to the occurrence of perceived concentration fluctuations around the mean gradient. Analysis of a stochastic model based on this hypothesis yields an objective index of directional randomness in random motility, the directional persistence time, in terms of model parameters associated with receptor binding, receptor signal transduction, and the cell turning response. Simulation of the model equations yields cell paths from which the orientation behavior in a chemoattractant gradient is characterized in terms of the same model parameters. Our results provide a theoretical relationship between directional persistence and orientation bias and suggest quantitative answers to the questions: Is there an optimal level of persistence with respect to maximizing orientation bias? Do directional persistence and orientation bias both display the same parametric sensitivity? How does this sensitivity depend on the sensing, transduction, and response components of the cell system?

Cell Membrane↗

PubMed1986

Consequences of chemosensory phenomena for leukocyte chemotactic orientation.

The stochastic nature of cell surface receptor-ligand binding is known to limit the accuracy of detection of chemoattractant gradients by leukocytes, thus limiting the orientation ability that is crucial to the chemotactic response in host defense. The probabilistic cell orientation model of Lauffenburger is extended here to assess the consequences of recently discovered receptor phenomena: "down-regulation" of total surface receptor number, spatial asymmetry of surface receptors, and existence of a higher-affinity receptor subpopulation. In general, a reduction in orientation accuracy is predicted by inclusion of these phenomena. An orientation signal based on a simple model of chemosensory adaptation (i.e., a spatial difference in relative receptor occupancy) is found to be functionally different from the signal suggested by an experimental correlation (i.e., a spatial difference in absolute receptor occupancy). However, in the context of receptor "signal noise," the signal based on adaptation yields predictions in better qualitative agreement with the experimental orientation data of Zigmond. From this cell orientation model we can estimate the effective time-averaging period required for noise diminution to a level allowing orientation predictions to match observed levels. This time-averaging period presumably reflects the time constant for receptor signal transduction and locomotory response.

Animals↗

PubMedDate not supplied

Biased cell migration of fibroblasts exhibiting contact guidance in oriented collagen gels.

We present here the first quantitative correlation for cell contact guidance in an oriented fibrillar network in terms of biased cell migration. The correlation is between the anisotropic cell diffusion parameter, DA = Dx/Dy, and the collagen gel birefringence, delta n, a measure of axially biased collagen fibril orientation in the x-direction. The cell diffusion coefficients, Dx and Dy, measure the dispersal of cells in the directions coincident with and normal to the axis of fibril orientation, respectively. Three essential methodological components are involved: (i) exploiting the orienting effect of a magnetic field on collagen fibrils during fibrillogenesis to systematically prepare uniform axially oriented collagen gels; (ii) using a microscope/image analysis workstation with precise, computer-controlled rotating and translating stages to automate birefringence measurement and, along with rapid "coarse optical sectioning" via digital image processing, to enable 3-D cell tracking of many cells in multiple samples simultaneously; and (iii) employing a rigorous statistical analysis of the cell tracks to estimate the magnitude and precision of the direction-dependent cell diffusion coefficients, Dx and Dy, that define DA. We find that this measure of biased migration in contact guidance (DA) increases with increasing collagen fibril orientation (delta n) due mainly to a rapid enhancement of migration along the axis of fibril orientation at low levels of fibril orientation, and to a continued suppression of migration normal to the axis of fibril orientation at high levels of fibril orientation.

Anisotropy↗

PubMedDate not supplied

Quantitative characterization of cell invasion in vitro: formulation and validation of a mathematical model of the collagen gel invasion assay.

An in vitro assay proposed to systematically characterize and compare cell invasion under different conditions is the collagen gel invasion assay where cells, initially seeded onto the surface of a type I collagen gel, penetrate the surface and migrate within the gel over time. Using simplifying assumptions about cell transport across the gel surface and migration within the gel, we formulate and solve a mathematical model of this assay which predicts the resulting cell distribution based on three phenomenological parameters characterizing the ability of cells to penetrate the gel surface interface, migrate randomly within the gel, and return to the gel surface. An index of cell invasiveness is defined based on these parameters that reflects the overall ability of cells to transport across the gel surface interface, that is, invade the gel. Cell concentration profiles predicted by the model correspond well to measured profiles for murine melanoma cells invading gels supplemented with extracellular matrix proteins fibronectin and type IV collagen as well as unsupplemented gels, allowing these parameters to be estimated by a nonlinear regression fit of the model solution to the measured profiles. Our analysis suggests that type IV collagen and fibronectin primarily modulate cell transport across the gel surface interface rather than migration within the gel. Further, we validate the key model assumptions and obtain independent, direct estimates of model parameters by time-lapse video microscopy and digital image analysis of cell penetration of the gel surface and migration within the gel during the assay.

Algorithms↗

PubMedDate not supplied

Stochasticity in membrane-localized "ligand-receptor-G protein" binding: consequences for leukocyte movement behavior.

The signal that governs the chemotactic response of mammalian white blood cells and tissue cells arises from membrane-localized binding events involving chemotactic factor ligands and receptors and G proteins. Fluctuations in this signal have been traditionally attributed to significant "noise" in receptor-ligand binding owing to a limited number of receptors. This paper examines the validity and consequences of a new hypothesis which states that the noise could be associated with a limited number of G proteins as well as receptors. This work characterizes via stochastic analysis and simulation the effects of the relative sizes of G protein and receptor populations on the variance of fluctuations of receptor states and consequently on the directional persistence behavior of cells in uniform chemotactic factor concentrations under the assumptions of the model used to link a G protein-mediated receptor signal to cell turning. Our results suggest that there may exist an optimal number of G proteins through which chemotactic receptors can signal that maximizes cell orientation accuracy in a chemotactic factor gradient.

Animals↗