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WIREs Syst Biol Med
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Endothelial cell motility, coordination and pattern formation during vasculogenesis

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How vascular networks assemble is a fundamental problem of developmental biology that also has medical importance. To explain the organizational principles behind vascular patterning, we must understand how can tissue level structures be controlled through cell behavior patterns like motility and adhesion that, in turn, are determined by biochemical signal transduction processes? We discuss the various ideas that have been proposed as mechanisms for vascular network assembly: cell motility guided by extracellular matrix alignment (contact guidance), chemotaxis guided by paracrine and autocrine morphogens, and multicellular sprouting guided by cell–cell contacts. All of these processes yield emergent patterns, thus endothelial cells can form an interconnected structure autonomously, without guidance from an external pre‐pattern. WIREs Syst Biol Med 2013, 5:587–602. doi: 10.1002/wsbm.1233 This article is categorized under: Models of Systems Properties and Processes > Cellular Models Developmental Biology > Developmental Processes in Health and Disease Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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Vasculogenesis in an avian embryo. Endothelial cells are visualized by a cell surface epitope QH1 (red), the ECM is labeled by an antibody against Fibronectin (green). The earliest vascular network is a transient structure, built up from multicellular sprouts—linear segments consisting of 3–10 cells.
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Mullins–Sekerka instability develops when the dynamics of a diffusive field is fast and a stronger gradient accelerates the movement of the interface. In such systems the tip of a ‘sprout’ senses larger gradients in the ‘updated’ concentration field, i.e., in the field that is adapted to the altered shape of interface. Hence the sprout elongates as long as it can effectively reduce the concentration of the chemoattractant at the tip. The symbols are the same as in Figure .
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Mechanism for patterning instability in the autocrine chemotaxis model. If the diffusion length of the chemoattractant is small (concentration is indicated by orange color, and selected concentrations by black contour lines), then the strongest gradient (red arrows) develops at the surface of the aggregate (gray). Cells, however, cannot follow this gradient due to the finite compressibility of the cells within the aggregate (green arrows). If a cell, however, leaves the aggregate and the adaptation of the concentration field is slow, then the sprout‐forming cell encounters progressively smaller gradients and diminishing chemotactic bias to return.
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Irreversible alteration of the ECM together with adhesivity increases the persistence of cell movements. In the absence of ECM (a), formation of a protrusion increases the length of free cell surface. Hence such a protrusion has a high probability to collapse. If cells can degrade the ECM (b), the collapse of the protrusion would result a free cell surface instead of the cell‐ECM interface that was originally present. Moreover, depending on the parameters, the longer cell‐ECM boundary can be preferred to the shorter free boundary. Hence, the stability of the protrusion is greatly increased. Arrows represent transitions between the depicted states. The size of the arrow indicates the likelihood of the transition.
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Schematic representations of the various mechanisms suggested for vascular pattern formation during vasculogenesis. Arrows represent causal links: changes in one component are directly influenced by the factors indicated by arrows. (a) Conventional description of vascular pattern formation. Cells arrive to well‐defined spatial structures following extracellular guidance cues. (b) Vascular patterning by ECM mechanics. Cells exert traction forces that are balanced by mechanical stresses arising in the surrounding ECM microenvironment due to its deformation. The deformed ECM convects cells and also guides active cell motility. These processes alter the spatial distribution (density) of cells. (c) Pattern formation utilizing ECM ‘memory’. Cells irreversibly alter the state of the surrounding ECM, e.g., by creating micro‐channels or by changes in ECM bundling or crosslinking. The altered ECM states persist even after the cells leave and thus are able to guide the motility of cells visiting the area at a later time point. The interplay between adhesion to and degradation of the ECM also has a profound influence on cell motion persistence. Most models also take into account that cell motility is restricted by the presence of other cells (dashed line). (d) Schematic representation of autocrine chemoattractant signaling. Cells secrete a diffusing chemoattractant, which in turn guides their movements. Cell motility or chemotactic response is restricted by contact with adjacent cells (dashed line). (e) Schematic representation of chemoattractant signaling modulated by a secreted inhibitor. Cells secrete a diffusing chemoattractant inhibitor, such as sVEGFR1, which sequesters the VEGF available in the ECM microenvironment. The resulting concentration gradient of functional VEGF guides cell motility. (f) Schematic representation of multicellular sprouts guided by cell–cell contacts. In these models cells are explicitly represented, and the shape and/or contact properties of adjacent cells serve as migration targets and also restrict the possible cell movements. Such cellular scale mechanisms can help to recruit additional cells into the expanding sprouts.
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Morphology diagram of the equilibrium cellular Potts model (CPM) (w = 0) where cells are within a cavity lined by immutable ECM‐containing sites. Morphologies are shown as a function of the costs associated with free (β) and ECM‐bound (γ) cell boundaries. These values are compared to α, the cost associated with intercellular boundaries. Configurations shown were obtained in the steady‐state regime, with parameters marked by the blue dots and with α = 1 and λ = 1. For each set of parameters, two configurations are shown—one with high and the other with low cell density. The red line divides the parameter space into two domains where cells are either adhesive (right) or nonadhesive (left). The green line indicates neutral ECM. Above and below this line the matrix is repulsive and attractive, respectively. The blue line demarcates an area where cells spread along the ECM, i.e., where an increase in cell perimeter is offset by the low expense associated with cell‐ECM adhesion sites.
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Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
Models of Systems Properties and Processes > Cellular Models
Developmental Biology > Developmental Processes in Health and Disease

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