R direction to the imposed chemical gradient, which is considerable in case of greater chemotaxis effective factor (see Figs 11d and 12a). Because of the higher chemotaxis effective factor, the cell receives stronger chemotactic signal to spread more on the surface with chemoattractant source. Besides, the cell random movement relatively decreases for both cases in comparison with either mechanotaxis or thermotaxis example (Fig 8). Cell migration towards chemoattractant source is qualitatively consistent with many experimental [20, 105, 106] and numerical [17, 51, 107] studies. Besides, cell elongation and shape change ABT-737 supplement during migration is consistent with finding of Maeda et al. [108] implying that gradient sensing and polarization direction of the cell are linked to the cell shape changes and accompanied with motility length of pseudopods.Cell behavior in presence of electrotaxisAs mentioned above, endogenous EF is developed around wounds during tissues injury, causing cell migration towards wound cites. Experiments show that in a Guinea pig skin injury just 3 mm away from wound, lateral potential drops to 0 from 140 mV/mm at the wound edge [6, 109?11]. Besides, in cornea ulcer, an EF equal to 42 mV/mm is measured [6, 112]. The cell movement can be also directed and accelerated via exposing it to an exogenous dcEF depending on cell phenotype. In this process, both calcium ion release from and influx into intracellular are generally associated with cell polarisation direction. For instance, human granulocytes [85], SP600125 site rabbit corneal endothelial cells [113], metastatic human breast cancer cells [84] are attracted by anode. Unlike metastatic rat prostate cancer cells [114], embryo fibroblasts [27], human keratinocytes [86], fish epidermal cells [40], human retinal pigment epithelial cells [87], epidermal and human skin cells [30] that move towards cathode. Therefore, altogether, different cell phenotypes may present different electrotactic behavior. To consider the influence of the electrotaxis on cell behavior, it is considered that the cell is exposed to a dcEF through which the anode is located at x = 0 m and the cathode at x = 400 m. It is assumed that the cell phenotype is such that to be attracted by the cathode, such as human keratinocytes [86] or embryo fibroblasts [27]. First, the cell is located near the anode at x = 0. To demonstrate effect of dcEF strength on cell behavior the simulation is repeated for two different dcEF strength, E = 10 mV/mm and E = 10 100 mV/mm. Cell migration and shape change in the presence of both weak and strong EF are presented in Fig 13. In response of an EF, the cell re-organizes its side that is facing the cathode, and migrates directionally towards the cathode. The presence of the EF can dominate mechanotaxis effect and move the cell to the end of the substrate even more than previous cases where the cell centroid locates around IEP at x = 379 ?3 m and x = 383 ?2 m for the weak and strong EF strengths, respectively, (Fig 6 and Fig 8). Besides, the presence of the EF decreases considerably the random movementPLOS ONE | DOI:10.1371/journal.pone.0122094 March 30,20 /3D Num. Model of Cell Morphology during Mig. in Multi-Signaling Sub.Fig 12. Cell elongation, elong (left axis), and CMI (right axis) versus the cell centroid translocation in the presence of chemotaxis as well as mechanotaxis. a- ch = 0.35 and b- ch = 0.40. For both cases, the cell elongation and CMI are maximum in the intermediate regions of.R direction to the imposed chemical gradient, which is considerable in case of greater chemotaxis effective factor (see Figs 11d and 12a). Because of the higher chemotaxis effective factor, the cell receives stronger chemotactic signal to spread more on the surface with chemoattractant source. Besides, the cell random movement relatively decreases for both cases in comparison with either mechanotaxis or thermotaxis example (Fig 8). Cell migration towards chemoattractant source is qualitatively consistent with many experimental [20, 105, 106] and numerical [17, 51, 107] studies. Besides, cell elongation and shape change during migration is consistent with finding of Maeda et al. [108] implying that gradient sensing and polarization direction of the cell are linked to the cell shape changes and accompanied with motility length of pseudopods.Cell behavior in presence of electrotaxisAs mentioned above, endogenous EF is developed around wounds during tissues injury, causing cell migration towards wound cites. Experiments show that in a Guinea pig skin injury just 3 mm away from wound, lateral potential drops to 0 from 140 mV/mm at the wound edge [6, 109?11]. Besides, in cornea ulcer, an EF equal to 42 mV/mm is measured [6, 112]. The cell movement can be also directed and accelerated via exposing it to an exogenous dcEF depending on cell phenotype. In this process, both calcium ion release from and influx into intracellular are generally associated with cell polarisation direction. For instance, human granulocytes [85], rabbit corneal endothelial cells [113], metastatic human breast cancer cells [84] are attracted by anode. Unlike metastatic rat prostate cancer cells [114], embryo fibroblasts [27], human keratinocytes [86], fish epidermal cells [40], human retinal pigment epithelial cells [87], epidermal and human skin cells [30] that move towards cathode. Therefore, altogether, different cell phenotypes may present different electrotactic behavior. To consider the influence of the electrotaxis on cell behavior, it is considered that the cell is exposed to a dcEF through which the anode is located at x = 0 m and the cathode at x = 400 m. It is assumed that the cell phenotype is such that to be attracted by the cathode, such as human keratinocytes [86] or embryo fibroblasts [27]. First, the cell is located near the anode at x = 0. To demonstrate effect of dcEF strength on cell behavior the simulation is repeated for two different dcEF strength, E = 10 mV/mm and E = 10 100 mV/mm. Cell migration and shape change in the presence of both weak and strong EF are presented in Fig 13. In response of an EF, the cell re-organizes its side that is facing the cathode, and migrates directionally towards the cathode. The presence of the EF can dominate mechanotaxis effect and move the cell to the end of the substrate even more than previous cases where the cell centroid locates around IEP at x = 379 ?3 m and x = 383 ?2 m for the weak and strong EF strengths, respectively, (Fig 6 and Fig 8). Besides, the presence of the EF decreases considerably the random movementPLOS ONE | DOI:10.1371/journal.pone.0122094 March 30,20 /3D Num. Model of Cell Morphology during Mig. in Multi-Signaling Sub.Fig 12. Cell elongation, elong (left axis), and CMI (right axis) versus the cell centroid translocation in the presence of chemotaxis as well as mechanotaxis. a- ch = 0.35 and b- ch = 0.40. For both cases, the cell elongation and CMI are maximum in the intermediate regions of.