In multicellular organisms and complex ecosystems, cells migrate in a social context. Whereas this is essential for the basic processes of life, the influence of neighboring cells on the individual remains poorly understood. Previous work on isolated cells has observed a stereotypical migratory behavior characterized by short-time directional persistence with long-time random movement. We discovered a much richer dynamic in the social context, with significant variations in directionality, displacement, and speed, which are all modulated by local cell density. We developed a mathematical model based on the experimentally identified "cellular traffic rules" and basic physics that revealed that these emergent behaviors are caused by the interplay of single-cell properties and intercellular interactions, the latter being dominated by a pseudopod formation bias mediated by secreted chemicals and pseudopod collapse following collisions. The model demonstrates how aspects of complex biology can be explained by simple rules of physics and constitutes a rapid test bed for future studies of collective migration of individual cells.cell migration | single-cell analysis | physical modeling | microfluidics C ollective migration, from migrating cells in tissue (1-3) to swarming insects (4) to flocks of birds (5) and pedestrians in heavy traffic (6), constitutes one of the most fascinating spectacles in nature. In addition to its aesthetic qualities, social cell migration is involved in embryonic development (7), wound healing (8), and immune response (9), and unregulated migration leads to disease, including cancer metastasis (10). Previous work on single-cell migration has focused on isolated (11)(12)(13)(14)(15)(16)(17)(18)(19)(20) or strongly polarized and aligning (21, 22) cell types, mostly using population-averaged bulk assays (23) or simple observations in a social context (2, 3). However, strongly cross-correlated cell motion and collective substrate deformation has been found to arise in mechanically interlinked cells transmitting forces through both cell-cell linkages and the substrate (24-29). These studies revealed useful information on cell migration, but because in general the relevant interactions in a social context and their relative importance are not established, migratory behavior of cells in a social context remains as one of the major unresolved problems in biology (30). Furthermore, striking social effects such as highly sensitive collective responses in a number of sensing systems [e.g., quorum sensing (31, 32) and onset of collective behavior in Dictyostelium discoideum (33)] mediated by increased levels of cell-secreted signals in higher cell density indicate that mechanical links are not necessary for collective behavior. At the subcellular level, many types of nonswimming motile cells involved in multicellular biology [e.g., fibroblasts, Dictyostelium, and neutrophils (13,14,(16)(17)(18)] have been found to transmit traction force to the substrate by intracellularly polymerizing their cytoskeleton...

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Taylor-Aris dispersion, the shear-induced enhancement of solute diffusion in the flow direction of the solvent, has been studied intensely in the past half century for the case of steady flow and single-frequency pulsating flows. Here, combining Aris's method of moments with Dirac's bra-ket formalism, we derive an expression for the effective solute diffusivity valid for transient Taylor-Aris dispersion in any given time-dependent, multi-frequency solvent flow through straight channels. Our theory shows that the solute dispersion may be greatly enhanced by the time-dependent parts of the flow, and it explicitly reveals how the dispersion coefficient depends on the external driving frequencies of the velocity field and the internal relaxation rates for mass and momentum diffusion. Although applicable to any type of fluid, we restrict the examples of our theory to Newtonian fluids, for which we both recover the known results for steady and single-frequency pulsating flows, and find new, richer structure of the dispersion as function of system parameters in multi-frequency systems. We show that the effective diffusivity is enhanced significantly by those parts of the time-dependent velocity field that have frequencies smaller than the fluid momentum diffusion rate and the solute diffusion rate.

IntroductionHigh cell density is known to enhance adipogenic differentiation of mesenchymal stem cells, suggesting secretion of signaling factors or cell-contact-mediated signaling. By employing microfluidic biochip technology, we have been able to separate these two processes and study the secretion pathways.Methods and resultsAdipogenic differentiation of human adipose-derived stem cells (ASCs) cultured in a microfluidic system was investigated under perfusion conditions with an adipogenic medium or an adipogenic medium supplemented with supernatant from differentiating ASCs (conditioned medium). Conditioned medium increased adipogenic differentiation compared to adipogenic medium with respect to accumulation of lipid-filled vacuoles and gene expression of key adipogenic markers (C/EBPα, C/EBPβ, C/EBPδ, PPARγ, LPL and adiponectin). The positive effects of conditioned medium were observed early in the differentiation process.ConclusionsUsing different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s) were shown to act in the recruitment phase of the differentiation process.