Ion of the maximum cell elongation, elong, versus thermotaxis, chemotaxis and electrotaxis stimuli. doi:10.1371/journal.pone.0122094.gFig 16. Variation of the maximum CMI versus thermotaxis, chemotaxis and electrotaxis stimuli. doi:10.1371/journal.pone.0122094.gPLOS ONE | DOI:10.1371/journal.pone.0122094 March 30,25 /3D Num. Model of Cell Morphology during Mig. in Multi-Signaling Sub.[67, 69]. This causes a decrease in the cell elongation and CMI once the cell centroid is around IEP. The overall cell behavior and cell shape may be changed by activation of other signals in the cell environment. For instance, by adding chemotaxis and/or thermotaxis to the micro-environment, the maximum cell elongation and CMI increase and the location of the cell centroid moves towards the end of the RG1662 custom synthesis substrate despite of the unconstrained boundary surface. As the cell migrate along chemical gradient, the cell elongates in gradient direction but when it is near the end of the substrate, the cell elongation and CMI decrease. Once the cell reaches the surface of maximum chemoattractant concentration, it extends pseudopods in the vertical direction of chemical gradient. Afterward, because the cell extends pseudopods in the vertical direction of chemical gradient, the cell elongation and CMI slightly increases, which is more obvious for greater chemical effective factor (Fig 12). The ultimate location of the cell centroid is sensitive to the chemotactic effective factors whereas employing of a higher chemoattractant effective factor causes that the cell centroid moves further to the end of the substrate. In other words, a greater chemoattractant effective factor dominates mechanotaxis signal and drives the cell towards the chemoattractant source. The cell movement to the end of the substrate is more ICG-001 biological activity critical in presence of electrotaxis. Since our study focuses on a typical cell migrating towards the cathode, EF significantly reorientates the cell towards the cathodal pole. This reorientation can be even considerably affected by increase of EF strength, in agreement with experimental observations [26]. So, generally, the stronger signal imposes a greater cell elongation and CMI that is because of directional cell polarisation towards the more effective stimulus. Because adding any new stimulus to the cell substrate will affect the cell polarization direction by increase of directional motility of the cell so that all signals directionally guide the cell towards the source of stimuli (warmer position, chemoattractant source, cathodal pole), diminishing the cell random movement (see Fig 8). In particular, in presence of the saturated EF there is a considerable increase in cell elongation and CMI due to exposing the cell to a greater electrostatic force. As a general remark, consistent with experimental observations, our findings indicate that electrotaxis effect is a dominant cue (see Figs 15 and 16). Because, for both the thermotactic and chemotactic signals, the variation of th and ch parameters has trivial effect on the magnitude of effective force (Equation 16), however it may considerably change the cell polarisation direction [67]. Therefore, changes of thermotaxis and chemotaxis slightly affect the magnitude of drag force in contrast to electrotaxis, which is an independent force from others, its magnitude can be directly controlled by the EF strength. Consequently, according to Equation 17 electrotaxis can affect both magnitude and direction of drag force.Ion of the maximum cell elongation, elong, versus thermotaxis, chemotaxis and electrotaxis stimuli. doi:10.1371/journal.pone.0122094.gFig 16. Variation of the maximum CMI versus thermotaxis, chemotaxis and electrotaxis stimuli. doi:10.1371/journal.pone.0122094.gPLOS ONE | DOI:10.1371/journal.pone.0122094 March 30,25 /3D Num. Model of Cell Morphology during Mig. in Multi-Signaling Sub.[67, 69]. This causes a decrease in the cell elongation and CMI once the cell centroid is around IEP. The overall cell behavior and cell shape may be changed by activation of other signals in the cell environment. For instance, by adding chemotaxis and/or thermotaxis to the micro-environment, the maximum cell elongation and CMI increase and the location of the cell centroid moves towards the end of the substrate despite of the unconstrained boundary surface. As the cell migrate along chemical gradient, the cell elongates in gradient direction but when it is near the end of the substrate, the cell elongation and CMI decrease. Once the cell reaches the surface of maximum chemoattractant concentration, it extends pseudopods in the vertical direction of chemical gradient. Afterward, because the cell extends pseudopods in the vertical direction of chemical gradient, the cell elongation and CMI slightly increases, which is more obvious for greater chemical effective factor (Fig 12). The ultimate location of the cell centroid is sensitive to the chemotactic effective factors whereas employing of a higher chemoattractant effective factor causes that the cell centroid moves further to the end of the substrate. In other words, a greater chemoattractant effective factor dominates mechanotaxis signal and drives the cell towards the chemoattractant source. The cell movement to the end of the substrate is more critical in presence of electrotaxis. Since our study focuses on a typical cell migrating towards the cathode, EF significantly reorientates the cell towards the cathodal pole. This reorientation can be even considerably affected by increase of EF strength, in agreement with experimental observations [26]. So, generally, the stronger signal imposes a greater cell elongation and CMI that is because of directional cell polarisation towards the more effective stimulus. Because adding any new stimulus to the cell substrate will affect the cell polarization direction by increase of directional motility of the cell so that all signals directionally guide the cell towards the source of stimuli (warmer position, chemoattractant source, cathodal pole), diminishing the cell random movement (see Fig 8). In particular, in presence of the saturated EF there is a considerable increase in cell elongation and CMI due to exposing the cell to a greater electrostatic force. As a general remark, consistent with experimental observations, our findings indicate that electrotaxis effect is a dominant cue (see Figs 15 and 16). Because, for both the thermotactic and chemotactic signals, the variation of th and ch parameters has trivial effect on the magnitude of effective force (Equation 16), however it may considerably change the cell polarisation direction [67]. Therefore, changes of thermotaxis and chemotaxis slightly affect the magnitude of drag force in contrast to electrotaxis, which is an independent force from others, its magnitude can be directly controlled by the EF strength. Consequently, according to Equation 17 electrotaxis can affect both magnitude and direction of drag force.