Traction forces control cell-edge dynamics and mediate distance-sensitivity during cell polarization

Abstract

Traction forces are generated by cellular actin-myosin system and transmitted to the environment through adhesions. They are believed to drive cell motion, shape changes, and extracellular matrix remodeling [1][2][3]. However, most of the traction force analysis has been performed on stationary cells, investigating forces at the level of individual focal adhesions or linking them to static cell parameters such as area and edge curvature [4][5][6][7][8][9][10]. It is not well understood how traction forces are related to shape changes and motion, e.g. forces were reported to either increase or drop prior to cell retraction [11][12][13][14][15]. Here, we analyze the dynamics of traction forces during the protrusion-retraction cycle of polarizing fish epidermal keratocytes and find that forces fluctuate in concert with the cycle, increasing during the protrusion phase and reaching maximum at the beginning of retraction. We relate force dynamics to the recently discovered phenomenological rule [16] that governs cell edge behavior during keratocyte polarization: both traction forces and the probability of switch from protrusion to retraction increase with the distance from the cell center. Diminishing traction forces with cell contractility inhibitor leads to decreased edge fluctuations and abnormal polarization, while externally applied force can induce protrusion-retraction switch. These results suggest that forces mediate distance-sensitivity of the edge dynamics and ultimately organize cell-edge behavior leading to spontaneous polarization. Actin flow rate did not exhibit the same distance-dependence as traction stress, arguing against its role in organizing edge dynamics. Finally, using a simple model of actin-myosin network, we show that force-distance relationship may be an emergent feature of such networks.

Physical limits to sensing material properties

“…A cell could further reduce δμ 0 /μ 0 via sensory multiplexing. Indeed, cells have been known to modulate the forces they exert in order to vary the modes they apply, consistent with our predictions for behavior during sensory multiplexing 65 . A cell's spatial resolution is limited by the maximum number of focal adhesions that it can simultaneously apply to the network.…”

“…In particular, cells can obtain additional information about the stiffness of their environment by applying multiple probes using forces that vary in space and time. Interestingly, such regulation of probes has been found to influence cellular differentiation 73 , and cells in culture have recently been observed to vary the spatial symmetries of forces they exert 65 .…”

A novel method for sensor-based quantification of single/multicellular force dynamics and stiffening in 3D matrices

“…Moreover, the phase-contrast images show, for both cases, that when the cells are more elongated, i.e., polarized, the magnitude of their forces is much higher compared to the forces when they were not polarized. This finding is consistent with previous studies (33,54) that reported that traction forces increase with distance of focal adhesions from the cell center. Possible mechanism for this phenomenon involves protrusion-retraction and actin flow at the cell edge while migrating and polarizing (54).…”

Tyrosine Phosphorylation of the Myosin Regulatory Light Chain Controls Non-muscle Myosin II Assembly and Function in Migrating Cells

“…Recent studies have shown that filamentous NMII localizes to the trailing edge through a mechanism that involves actin retrograde flow [45]. In keratocytes, NMII filaments control traction stress in a manner dependent on the distance to the center of mass of the cell [46], consistent with the aberrant elongation of the cell body observed when NMII-A is deleted [15,17]. By maintaining RLC in a soluble, non-filamentous state, Y155 phosphorylation Article represents a mechanism to maintain a reservoir of exchangeable RLC that can be used by the cell to reassemble NMII filaments and generate traction in response to changes in their microenvironment.…”