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• W2046589586 abstract "En masse cell migration is more relevant compared with single-cell migration in physiological processes of tissue formation, such as embryogenesis, morphogenesis, and wound healing. In these situations, cells are influenced by the proximity of other cells including interactions facilitated by substrate mechanics. Here, we found that when fibroblasts migrated en masse over a hydrogel, they established a well-defined deformation field by traction forces and migrated along a trajectory defined by field gradients. The mechanics of the hydrogel determined the magnitude of the gradient. For materials stiff enough to withstand deformation related to cellular traction forces, such patterns did not form. Furthermore, migration patterns functioned poorly on very soft matrices where only a minimal traction gradient could be established. The largest degree of alignment and migration velocity occurred on the gels with the largest gradients. Granulation tissue formation in punch wounds of juvenile pigs was correlated strongly with the modulus of the implanted gel, in agreement with in vitro en masse cell migration studies. These findings provide basic insight into the biomechanical influences on fibroblast movement in early wounds and relevant design criteria for the development of tissue-engineered constructs that aim to stimulate en masse cell recruitment for rapid wound healing. En masse cell migration is more relevant compared with single-cell migration in physiological processes of tissue formation, such as embryogenesis, morphogenesis, and wound healing. In these situations, cells are influenced by the proximity of other cells including interactions facilitated by substrate mechanics. Here, we found that when fibroblasts migrated en masse over a hydrogel, they established a well-defined deformation field by traction forces and migrated along a trajectory defined by field gradients. The mechanics of the hydrogel determined the magnitude of the gradient. For materials stiff enough to withstand deformation related to cellular traction forces, such patterns did not form. Furthermore, migration patterns functioned poorly on very soft matrices where only a minimal traction gradient could be established. The largest degree of alignment and migration velocity occurred on the gels with the largest gradients. Granulation tissue formation in punch wounds of juvenile pigs was correlated strongly with the modulus of the implanted gel, in agreement with in vitro en masse cell migration studies. These findings provide basic insight into the biomechanical influences on fibroblast movement in early wounds and relevant design criteria for the development of tissue-engineered constructs that aim to stimulate en masse cell recruitment for rapid wound healing. adult human dermal fibroblast digital image speckle correlation extracellular matrix fibronectin functional domain poly(ethylene glycol) diacrylate Tissue cell migration is the sine qua non of wound repair and regeneration (Singer and Clark, 1999Singer A.J. Clark R.A.F. Mechanisms of disease—cutaneous wound healing.N Engl J Med. 1999; 341: 738-746Crossref PubMed Scopus (4641) Google Scholar). During the inflammatory phase of wound healing, blood leukocytes sense chemical gradients emanating from the wound to which they respond by directed migration (chemotaxis) as single cells. In contrast, tissue cells often move en masse rather than as single cells. For example, in skin, epidermal cells quickly move across the wound space as a sheet in a tractor-tread manner associated with dynamic formation and dissolution of cell junctions (Vespa et al., 2005Vespa A. D'Souza S.J.A. Dagnino L. A novel role for integrin-linked kinase in epithelial sheet morphogenesis.Mol Biol Cell. 2005; 16: 4084-4095Crossref PubMed Scopus (37) Google Scholar; Chometon et al., 2006Chometon G. Zhang Z.G. Rubinstein E. et al.Dissociation of the complex between CD151 and laminin-binding integrins permits migration of epithelial cells.Exp Cell Res. 2006; 312: 983-995Crossref PubMed Scopus (43) Google Scholar). Fibroblasts, which can respond to haptotactic (Carter, 1967Carter S.B. Haptotaxis and methods of motility.Nature. 1967; 213: 256-260Crossref PubMed Scopus (365) Google Scholar; Raeber et al., 2008Raeber G.P. Lutolf M.P. Hubbell J.A. Part II: fibroblasts preferentially migrate in the direction of principal strain.Biomech Model Mechanobiol. 2008; 7: 215-225Crossref PubMed Scopus (37) Google Scholar), as well as chemotactic signals, also move into the wound space en masse rather than as single cells during rapid granulation tissue formation (McClain et al., 1996McClain S.A. Simon M. Jones E. et al.Mesenchymal cell activation is the rate-limiting step of granulation tissue induction.Am J Pathol. 1996; 149: 1257-1270PubMed Google Scholar). However, fibroblasts form relatively fewer cell junctions compared with epithelial and endothelial structures and these were only recently described (Morris et al., 2006Morris A.P. Tawil A. Berkova Z. et al.Junctional adhesion molecules (JAMs) are differentially expressed in fibroblasts and co-localize with ZO-1 to adherens-like junctions.Cell Commun Adhes. 2006; 13: 233-247Crossref PubMed Scopus (51) Google Scholar). In addition to biochemical signals (Palecek et al., 1997Palecek S.P. Loftus J.C. Ginsberg M.H. et al.Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness.Nature. 1997; 385: 537-540Crossref PubMed Scopus (1185) Google Scholar), it has become increasingly clear that substrate mechanics is another key attribute that modulates tissue cell dynamics (Choquet et al., 1997Choquet D. Felsenfeld D.P. Sheetz M.P. Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages.Cell. 1997; 88: 39Abstract Full Text Full Text PDF PubMed Scopus (1064) Google Scholar; Pelham and Wang, 1997Pelham R.J. Wang Y.L. Cell locomotion and focal adhesions are regulated by substrate flexibility.Proc Natl Acad Sci USA. 1997; 94: 13661Crossref PubMed Scopus (2446) Google Scholar; Lo et al., 2000Lo C.M. Wang H.B. Dembo M. et al.Cell movement is guided by the rigidity of the substrate.Biophys J. 2000; 79: 144Abstract Full Text Full Text PDF PubMed Scopus (2528) Google Scholar; Discher et al., 2005Discher D.E. Janmey P. Wang Y.-I. Tissue cells feel and respond to the stiffness of their substrate.Science. 2005; 310: 1139-1143Crossref PubMed Scopus (4800) Google Scholar; Georges and Janmey, 2005Georges P.C. Janmey P.A. Cell type-specific response to growth on soft materials.J Appl Physiol. 2005; 98: 1547-1553Crossref PubMed Scopus (414) Google Scholar; Ghosh and Ingber, 2007Ghosh K. Ingber D.E. Micromechanical control of cell and tissue development: Implications for tissue engineering.Adv Drug Deliv Rev. 2007; 59: 1306-1318Crossref PubMed Scopus (169) Google Scholar). Many groups have shown that cells can sense substrate stiffness through their adhesions to the extracellular matrix (ECM) and respond by altering their cytoskeletal organization and tension accordingly (Galbraith and Sheetz, 1998Galbraith C.G. Sheetz M.P. Forces on adhesive contacts affect cell function.Curr Opin Cell Biol. 1998; 10: 566-571Crossref PubMed Scopus (245) Google Scholar; Sheetz et al., 1998Sheetz M.P. Felsenfeld D.P. Galbraith C.G. Cell migration: Regulation of force on extracellular-matrix-integrin complexes.Trends Cell Biol. 1998; 8: 51-54Abstract Full Text PDF PubMed Scopus (360) Google Scholar; Lo et al., 2000Lo C.M. Wang H.B. Dembo M. et al.Cell movement is guided by the rigidity of the substrate.Biophys J. 2000; 79: 144Abstract Full Text Full Text PDF PubMed Scopus (2528) Google Scholar; Beningo and Wang, 2002Beningo K.A. Wang Y.L. Flexible substrata for the detection of cellular traction forces.Trends Cell Biol. 2002; 12: 79Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar; Geiger and Bershadsky, 2002Geiger B. Bershadsky A. Exploring the neighborhood: adhesion-coupled cell mechanosensors.Cell. 2002; 110: 139Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar; Ingber, 2003Ingber D.E. Mechanosensation through integrins: cells act locally but think globally.Proc Natl Acad Sci USA. 2003; 100: 1472Crossref PubMed Scopus (171) Google Scholar). The tension exerted onto the substrate through adhesion sites, called cellular traction forces, has been known as the mechanical reason for the movement of a single cell (Schmidt et al., 1993Schmidt C.E. Horwitz A.F. Lauffenburger D.A. et al.Integrin cytoskeletal interactions in migrating fibroblasts are dynamic, asymmetric, and regulated.J Cell Biol. 1993; 123: 977-991Crossref PubMed Scopus (295) Google Scholar; Oliver et al., 1999Oliver T. Dembo M. Jacobson K. Separation of propulsive and adhesive traction stresses in locomoting keratocytes.J Cell Biol. 1999; 145: 589-604Crossref PubMed Scopus (139) Google Scholar; Pan et al., 2009Pan Z. Ghosh K. Liu Y.J. et al.Traction stresses and translational distortion of the nucleus during fibroblast migration on a physiologically relevant ECM mimic.Biophys J. 2009; 96: 4286-4298Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). More interestingly, because these traction forces can cause deformation on flexible substrates for distances larger compared with the size of the cell, a mechanical means of communication between cells may occur over large distances and influence their en masse behavior. The recent study by Reinhart-King et al., 2008Reinhart-King C.A. Dembo M. Hammer D.A. Cell-cell mechanical communication through compliant substrates.Biophys J. 2008; 95: 6044-6051Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar on paired endothelial cells on substrates with varying stiffness has clearly demonstrated that with appropriate substrate stiffness, cells can detect and respond to substrate strains created by neighboring cells), and Sen et al., 2009Sen S. Engler A.J. Discher D.E. Matrix strains induced by cells: computing how far cells can feel.Cell Mol Bioeng. 2009; 2: 39-48Crossref PubMed Scopus (153) Google Scholar applied a finite element analysis to study the length scale of the deformation at the interface of isolated cells and a gel substrate. However, in most physiological processes, such as embryonic development, morphogenesis, and wound healing, en masse behavior of a large number of cells becomes more relevant (Clark, 1996Clark R.A.F. The Molecular and Celluar Biology of Wound Repair. 2nd edn. Plenum Press, New York, London1996Google Scholar; Rorth, 2007Rorth P. Collective guidance of collective cell migration.Trends Cell Biol. 2007; 17: 575-579Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, Rorth, 2009Rorth P. Collective cell migration.Annu Rev Cell Dev Biol. 2009; 25: 407-429Crossref PubMed Scopus (391) Google Scholar; Friedl and Gilmour, 2009Friedl P. Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer.Nat Rev Mol Cell Biol. 2009; 10: 445-457Crossref PubMed Scopus (1727) Google Scholar). In these situations, where the cell density is high, the mechanism of communication between cells is more complicated, and can result in different migration behavior than for either single cells or a small cluster of cells. In this report, we studied the dynamics of cells, plated at low density with those at high density, but placed on identical substrates and cultured in the same growth media. In this way, we could directly compare the effect of substrate mechanics on the migration behavior of single cells with those subjected to influence from their neighbors. In contrast to the previous in vivo studies (McClain et al., 1996McClain S.A. Simon M. Jones E. et al.Mesenchymal cell activation is the rate-limiting step of granulation tissue induction.Am J Pathol. 1996; 149: 1257-1270PubMed Google Scholar), where “en masse” migration was defined in terms of the migration of multiple cell types within an ECM, here, we focused on the en masse migration of one cell type out of an agarose droplet placed on a hydrogel substrate composed of cross-linked hyaluronic acid (HA) and fibronectin functional domains (FNfds). By changing cross-link ratios, we varied the stiffness of substrates and studied their effects on en masse cell migration. As the same substrates have been previously used to establish the correlation between substrate modulus and single-cell migration (Ghosh et al., 2007Ghosh K. Pan Z. Guan E. et al.Cell adaptation to a physiologically relevant ECM mimic with different viscoelastic properties.Biomaterials. 2007; 28: 671-679Crossref PubMed Scopus (302) Google Scholar), we could readily quantify the difference between en masse and single-cell migration response to substrate stiffness. We then used an optimized version of the digital image speckle correlation (DISC) technique (Guan et al., 2004Guan E. Smilow S. Rafailovich M. et al.Determining the mechanical properties of rat skin with digital image speckle correlation.Dermatology. 2004; 208: 112-119Crossref PubMed Scopus (20) Google Scholar; Pan et al., 2009Pan Z. Ghosh K. Liu Y.J. et al.Traction stresses and translational distortion of the nucleus during fibroblast migration on a physiologically relevant ECM mimic.Biophys J. 2009; 96: 4286-4298Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar) to quantify displacement fields of cell ensembles as a function of substrate modulus and demonstrated that a direct correlation could be established between en masse cell motion and the displacement field topology. As the HA/FNfd hydrogels used in vitro are biofunctional, biodegradable, and have moduli that could be varied in a range relevant to an early-wound environment (Hinz, 2007Hinz Boris Formation and function of the myofibroblast during tissue repair.J Invest Dermatol. 2007; 127: 526-537Abstract Full Text Full Text PDF PubMed Scopus (1161) Google Scholar), they were used in a porcine excisional wound model, where en masse fibroblast migration into wound site is critical for granulation tissue formation and subsequent healing (McClain et al., 1996McClain S.A. Simon M. Jones E. et al.Mesenchymal cell activation is the rate-limiting step of granulation tissue induction.Am J Pathol. 1996; 149: 1257-1270PubMed Google Scholar). In agreement with in vitro findings, the percentage of granulation formed within a 4-day porcine full-thickness excisional wound correlated positively with increasing modulus of the implant. An agarose droplet loaded with adult human dermal fibroblasts (AHDFs) was placed on a HA hydrogel functionalized with FNfds and cross-linked with poly(ethylene glycol) diacrylate (PEGDA) and incubated as shown in Figure 1a to allow cell attachment to the substrate. The outward migration of AHDF cells that emerged completely from the agarose and migrated on the hydrogel substrate was then monitored at 6, 15, and 24hours and the distance between the migration fronts, delineated by circular contours from the edge of the agarose droplet (Figure 1b), was recorded for each time. The shear modulus for this substrate was G’=4,270Pa, which was previously shown to support cell adhesion and actin stress fiber organization (Ghosh et al., 2007Ghosh K. Pan Z. Guan E. et al.Cell adaptation to a physiologically relevant ECM mimic with different viscoelastic properties.Biomaterials. 2007; 28: 671-679Crossref PubMed Scopus (302) Google Scholar). As can be seen from the phase contrast images in Figure 1a, the AHDFs migrated en masse from the cell-laden agarose droplet in a radially outward manner that resulted in a continuous decrease in cell density with increasing distance from the droplet. Using time-lapse photography, we recorded the cell movement at 15-minute intervals over periods of 1 hour after 6, 15, and 24hours incubations. Thus, we were able to obtain both cell velocity and regional cell density. To obtain single-cell-migration velocity, without interference from extraneous traction forces, cells were plated in the absence of agarose, at a very low density of ∼500cellscm−2 on HA hydrogel functionalized with FNfd hydrogels with the same stiffness (G’=4,270Pa) and observed following the same protocols. In the lower panel of Figure 1a, we show high-magnification phase contrast images corresponding to one quadrant of the outward migration pattern at the three incubation times. From the figures, we see that the local cell density in the outermost ring of migrating cells at the leading edge is decreasing with increasing incubation time (Figure 1a). The average migration distance (S) from the droplet edge to the nucleus of a given cell at the migration front (Figure 1b schematic) was plotted as a function of incubation time, together with the derivative of the curve, which is the radial velocity function (Figure 1b graph). Single-cell velocity was measured from the time-lapse images, as a function of incubation time (Figure 1b), and it was found that the velocity of leading cells during en masse outmigration decreased exponentially, approaching the single-cell-migration speeds that did not change significantly during the 15-hour incubation period. The local velocity of the leading cells was also measured as a function of the distance to the nearest neighbor cells along the edge (Figure 1c). The rx and ry show the distances from the nucleus of one cell to the nuclei of its neighboring cells along the radial directions and the circumference, respectively (Figure 1b schematic). The local density can then be approximately one cell per rxry unit area (1/rxry) and was plotted as a function of incubation time. The three panels of Figure 1c together showed that with longer incubation time, leading cells migrated slower with decreasing cell density. From these results it appears that local cell density is a primary driver controlling migration speed on the hydrogel surface. In addition to cell density, substrate stiffness also has an important role in migration dynamics. It has previously been shown that the migration speed of single cells negatively correlates with the distribution and magnitude of substrate stiffness–dependent cell traction forces (Dembo et al., 1996Dembo M. Oliver T. Ishihara A. et al.Imaging the traction stresses exerted by locomoting cells with the elastic substratum method.Biophys J. 1996; 70: 2008-2022Abstract Full Text PDF PubMed Scopus (235) Google Scholar; Dembo and Wang, 1999Dembo M. Wang Y.L. Stresses at the cell-to-substrate interface during locomotion of fibroblasts.Biophys J. 1999; 76: 2307Abstract Full Text Full Text PDF PubMed Scopus (1037) Google Scholar; Oliver et al., 1999Oliver T. Dembo M. Jacobson K. Separation of propulsive and adhesive traction stresses in locomoting keratocytes.J Cell Biol. 1999; 145: 589-604Crossref PubMed Scopus (139) Google Scholar; Pan et al., 2009Pan Z. Ghosh K. Liu Y.J. et al.Traction stresses and translational distortion of the nucleus during fibroblast migration on a physiologically relevant ECM mimic.Biophys J. 2009; 96: 4286-4298Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Here, we show that, like single cells, en masse migrating cells also sense and respond to substrate elasticity, although, contrary to single cells (Ghosh et al., 2007Ghosh K. Pan Z. Guan E. et al.Cell adaptation to a physiologically relevant ECM mimic with different viscoelastic properties.Biomaterials. 2007; 28: 671-679Crossref PubMed Scopus (302) Google Scholar), en masse cell migration becomes faster on hydrogels of increasing stiffness (Figure 2a). When the average cell migration area and the number of migrating cell from the radius and area of the corona around the droplet were measured as functions of shear moduli, G’ of the gels, it was confirmed quantitatively that en masse cell migration increased with increasing hydrogel moduli. A 5- to 10-fold increase in substrate shear modulus (G’) produced a 2- to 3-fold increase in both the number of cells, which migrated out of the droplet, and the area that they covered during the observation time. This result indicated that substrate mechanics alone can markedly regulate en masse cell behavior in a different manner from single cells. Previously we have shown that isolated AHDFs, which were adherent to FNfds tethered to HA hydrogel, exerted traction forces whose magnitudes were related to substrate moduli. The substrate stiffness through the reactive cellular traction forces affected cell functions that were dependent on cellular adhesions, such as spreading, migration, and proliferation (Ghosh et al., 2007Ghosh K. Pan Z. Guan E. et al.Cell adaptation to a physiologically relevant ECM mimic with different viscoelastic properties.Biomaterials. 2007; 28: 671-679Crossref PubMed Scopus (302) Google Scholar). However, substrate deformation extended distances that were much larger compared with the area occupied by individual cells. Thus, in addition to the more classical cell–cell communication systems, such as cell–cell contact or paracrine gradients, local cell traction forces can create extended regions of substrate deformation that permit cells to communicate with each other by sensing the deformation gradients. This is especially relevant in understanding the influence of the substrate stiffness on the en masse cell migration where large deformation gradients are generated within the hydrogels and are in turn sensed by the cells, thereby altering both the direction and magnitude of resultant outward migration (Figure 3). In our system, the leading edge of cells migrating out of the droplet, cell–cell adhesions are not apparent, even though they may be present inside the agarose droplet where the cells are at very high density. Furthermore, the migration speed decreases as the cells move further away from the droplet and their density decreases making cell contacts even less probable. In Figure 3a, fibroblasts migrating out of an agarose droplet placed on a fibronectin-coated glass coverslip are shown together with cells migrating outward from an agarose droplet placed on the stiffest hydrogel (G’=4,270Pa). Compared with migration on gels, cell migration on glass was more disordered as cells did not follow each other in a radial pattern. Instead, cells appeared to leave the droplet, become physically isolated, and migrate in random directions. Furthermore, after some time, they triangulated and ceased to migrate presumably secondary to strong adherence. In contrast, during en masse cell migration on hydrogels, the cells were elongated and appeared to follow each other. Although the migration patterns decrease cell density, only the distance between cells along the ry direction increased continuously. The distance along the rx direction remained fairly constant, with no significant change in the contacts between adjacent cells, even at the largest distances from the droplet. Random cell migration may explain the initial outward migration from the droplet, but it cannot account for the ray pattern formation. Rather, the radial arrays might result directly from the hydrogel deformation fields around the edge of agarose droplets as measured by DISC (Figure 3b). In fact, cell migration rays appeared to follow deformation gradients and form trajectories of cells in the direction of decreasing deformation gradients. Furthermore, the orderly progression of the cells out of the agarose droplet along rays appeared responsible for the larger number of cells that migrated out of the droplet on the gel surface relative to those on glass, i.e., directed migration versus random migration. Hence, deformation, in addition to modulus, becomes a key element in the migration pattern. As the deformation patterns as well as the cellular response that create them are both a function of the hydrogel moduli, a system of dynamic reciprocity between cell traction forces and substrate mechanical properties is established. This interpretation does not rule out the possibility that the cells are also depositing ECM “tracks”, causing cells to emerge in interconnected streams, as previously proposed (Miron-Mendoza et al., 2012Miron-Mendoza M. Lin X. Ma L. et al.Individual versus collective fibroblast spreading and migration: regulation by matrix composition in 3D culture.Exp Eye Res. 2012; 99: 36-44Crossref PubMed Scopus (27) Google Scholar) for corneal fibroblasts emerging from a cell-laden button into a fibrin gel. However, in their case, the migration was in a three-dimensional fibrin gel that most likely contained fibrin fibrils at different stages of formation. Therefore, it is not surprising that the streamer morphology was because of remodeling fibers within the gel. In our case, substrate deformation possibly modulates spatial deposition of newly synthesized ECM proteins that in turn imprints the oriented migratory patterns. Our results are consistent with the early observations of Weiss, whose work was reviewed recently (Grinnell and Petroll, 2010Grinnell Frederick Petroll WMatthew Cell motility and mechanics in three-dimensional collagen matrices.Annu Rev Cell Dev Biol. 2010; 26: 335-361Crossref PubMed Scopus (268) Google Scholar). Weiss, 1959Weiss P. Cellular dynamics.Rev Mod Phys. 1959; 31: 11-20Crossref Scopus (87) Google Scholar first proposed that cells generated tension tracks within a fibrin gel along which cells migrated in tissue fragments. In this model, the deformation fields, in combination with ECM proteins, established a pattern of “contact guidance” that resulted in coordinated en masse migration and the formation of ordered hierarchical structures in tissue. From the data, we can also obtain the dependence of the deformation profile on the substrate modulus. Deformation contours on hydrogels of different stiffness, emanating outward from the edge of the agarose droplets (colored dash curves in Figure 3b), can be mapped using the DISC analysis, and then the deformation gradients can be calculated from the distance between these curves. Not surprisingly, deformation gradients appeared dependent on the substrate modulus. The deformation contours were closer together on stiffer hydrogels, and thus the deformation gradient increased with the increase in hydrogel stiffness. In fact, a gradient was barely discerned on the softest gel. The solid lines (rays) originating at the droplet and drawn perpendicular to the contour lines delineate the direction of the deformation gradient (Figure 3b). A compelling interpretation of the migration pattern is that the cells can sense both the magnitude and the direction of the deformation gradient. Cell migration then follows the deformation gradient, which, for an isolated droplet, results in the radial pattern of vectors pointing in the direction of decreasing deformation, orthogonal to the deformation contour. In the case of the softest gel, the gradient is small and cells migrate least effectively out of the droplet. Even though the morphology of the cells on the softest gel is polarized and polarized cells are known to have the highest migration velocity, the lack of a well-defined gradient appears to prevent cells from finding a well-defined direction for migration. The displacements directly measured in Figure 3b were generated by all cells migrating outward from the droplet. Removing radial displacements allowed the measurement of local displacements generated by cells at the migration front (Figure 3c). Such measurements demonstrated that individual cells generate larger traction forces and displacements on the stiffer substrate—a result consistent with the previous single-cell studies (Ghosh et al., 2007Ghosh K. Pan Z. Guan E. et al.Cell adaptation to a physiologically relevant ECM mimic with different viscoelastic properties.Biomaterials. 2007; 28: 671-679Crossref PubMed Scopus (302) Google Scholar). In the previous work, the increased traction forces were responsible for reducing the single-cell velocity of cells migrating in isolation. In the case of en masse migration, it has been shown (Trepat et al., 2009Trepat X. Wasserman M.R. Angelini T.E. et al.Physical forces during collective cell migration.Nat Phys. 2009; 5: 426-430Crossref Scopus (794) Google Scholar; Angelini et al., 2010Angelini T.E. Hannezo E. Trepat X. et al.Cell migration driven by cooperative substrate deformation patterns.Phys Rev Letts. 2010; 104: 168104Crossref PubMed Scopus (203) Google Scholar) that collective deformation induced by overlapping force fields of multiple cells adds an additional factor in determining the cell migration velocity, hence differentiating cooperative migration from single-cell migration. Our results show that the larger forces exerted by the cells on the stiffer substrates are also responsible for creating larger cooperative gradient force fields, which in turn are responsible for faster en masse migration. To test the deformation gradient model, we placed two agarose droplets loaded with fibroblasts in close proximity to each other and observed the patterns established as the cells began to migrate outward from both droplets simultaneously (Figure 4a). The cells initially migrated along radial rays, which put them on a trajectory toward each other. As they approached each other near the central line, the deformation gradient rotated by 90°. The displacement map shows that the local displacements near the central line (between the two blue arrows) reach zero, which shift the deformation gradient about 90°. This provides a clear biomechanical explanation for why cells in the middle tended to turn and migrate along the central line. A similar agarose arrangement was also made on glass, where such a phenomenon was not observed. The degree of correlation between the two droplets can be quantified by measuring the average deflected angles of the lines drawn through the major axis of migrating cells from the lines along the radii of the droplet (Figure 4b). Deflection angles" @default.
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• W2046589586 title "Deformation Gradients Imprint the Direction and Speed of En Masse Fibroblast Migration for Fast Healing" @default.
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