Cell organization in soft media due to active mechanosensing

Abstract

Adhering cells actively probe the mechanical properties of their environment and use the resulting information to position and orient themselves. We show that a large body of experimental observations can be consistently explained from one unifying principle, namely that cells strengthen contacts and cytoskeleton in the direction of large effective stiffness. Using linear elasticity theory to model the extracellular environment, we calculate optimal cell organization for several situations of interest and find excellent agreement with experiments for fibroblasts, both on elastic substrates and in collagen gels: cells orient in the direction of external tensile strain; they orient parallel and normal to free and clamped surfaces, respectively; and they interact elastically to form strings. Our method can be applied for rational design of tissue equivalents. Moreover, our results indicate that the concept of contact guidance has to be reevaluated. We also suggest that cell-matrix contacts are up-regulated by large effective stiffness in the environment because, in this way, build-up of force is more efficient.T he mechanical activity of adherent cells usually is attributed to their physiological function. For example, fibroblasts are believed to maintain the structural integrity of connective tissue and to participate in wound healing by actively pulling on their environment. During recent years, it has become clear that there is another important role for mechanical activity of adherent cells: by pulling on their environment, cells can actively sense its mechanical properties and react to it in a specific way (1-3). Harris et al. (4) observed surprisingly large tension fields for fibroblasts on elastic substrates, which induce mechanical activity of other cells, even when located at considerable distance. When plated on elastic substrates of increased rigidity, many cell types show increased spreading and better developed stress fibers and focal adhesions (5). Fibroblasts on elastic substrates orient in the direction of tensile strain (6) and locomote in favor of regions of larger rigidity or tensile strain (7). The same response has been reported for vascular smooth muscle cells on rigidity gradients (8). Similar observations have been reported numerous times also for tissue cells in hydrogels. For fibroblasts in collagen gels, Bell et al. (9) not only found that traction considerably contracts the gel, but also reported orientational effects: cells align along the direction of pull between fixed points and parallel to free surfaces. When a collagen gel is stretched uniaxially, cells orient in the direction of principal strain (10). Moreover, cells align in a nose-to-tail configuration, thus forming strings running in parallel to the direction of external strain. If a collagen gel is cut perpendicular to the direction of tensile strain and if cells are present in sufficient numbers, they round up and reorient parallel to the free surface introduced (11).The response of adherent animal cells to mechanical input ...

Effect of Poisson Ratio on Cellular Structure Formation

“…(1) Here we consider the elastic interaction of a string of aligned dipoles spaced at equal distance a with a single additional force dipole at horizontal distance x and vertical offset y, both for (a) parallel and (b) perpendicular orientation. minimum for aligned force dipoles for all possible values of the elastic constants [4,5]. Recently, such alignment of cells in soft media has indeed been observed experimentally [11,12].…”

“…One example of this kind might be hydrodynamic interactions of active particles like swimming bacteria [3]. Here this is demonstrated for another example, namely mechanically active cells interacting through their elastic environment [4,5].…”

“…One example of this kind might be hydrodynamic interactions of active particles like swimming bacteria [3]. Here this is demonstrated for another example, namely mechanically active cells interacting through their elastic environment [4,5].Our starting point is the observation that generation and propagation of elastic fields for active particles proceed in a similar way as they do for passive particles like defects in a host crystal, e.g. hydrogen in metal [6,7].…”

“…For example, an anisotropic defect attracting the atoms of its host lattice turns away from tensile strain, in this way enhancing the displacement fields in the medium. In contrast, for mechanically active cells like fibroblasts, experimental observations suggest that they adopt positions and orientations in such a way as to effectively minimize the scalar quantity W = P ij u ij = −V [4,5]. For tensile strain, this implies that contractile cells actively align with the external field.…”

Biomimetic study of rolling transport through smooth muscle contraction

“…While it is clear that the transport of oosperm involves smooth muscle contraction [1,2], the detailed mechanism still remains elusive [1][2][3][4][5][6][7], due in part to the complexity of cellsubstrate interactions via receptor-ligand binding as well as various physical forces inside and outside of the cytoskeleton [8][9][10][11][12]. Cells are known to respond to mechanical forces exerted through surrounding fluid, adhering beads or substrates [9,[12][13][14], and they could detach, slip or roll on a substrate in response to these forces [15][16][17][18][19][20][21][22]. For example, cells on a cyclically stretched substrate tend to reorient themselves away from the stretching direction [23][24][25][26][27], and cells migrate along a substrate with rigidity gradient (durotaxis) [18].…”