Mechanical Response Analysis and Power Generation by Single‐Cell Stretching

During embryonic development and wound healing, the mechanical signals transmitted from cells to their neighbors induce tissue rearrangement and directional movements. It has been observed that forces exerted between cells in a developing tissue under stress are not always monotonically varying, but they can be pulsatile. Here we investigate the response of model tissues to controlled external stresses. Spherical cellular aggregates are subjected to one-dimensional stretching forces using micropipette aspiration. At large enough pressures, the aggregate flows smoothly inside the pipette. However, in a narrow range of moderate aspiration pressures, the aggregate responds by pulsed contractions or “shivering.” We explain the emergence of this shivering behavior by means of a simple analytical model where the uniaxially stretched cells are represented by a string of Kelvin–Voigt elements. Beyond a deformation threshold, cells contract and pull on neighboring cells after a time delay for cell response. Such an active behavior has previously been found to cause tissue pulsation during dorsal closure of Drosophila embryo.

Section: Discussionsupporting

confidence: 85%

Mechanosensitive shivering of model tissues under controlled aspiration

Guevorkian

Gonzalez‐Rodriguez

Carlier

et al. 2011

“…Because this passive strengthening and ab initio formation of domains under force occurs on time scales that are considerably faster than the active cytoskeletal response, we see it as a strong candidate for the elusive force-sensor (3)(4)(5)(6)(7)(8), which triggers the activation of signaling pathways leading to force-dependent regulation of adhesion in living cells. This passive sensing requires only an intact cell membrane with mobile adhesion proteins and should be noticeable even before proper focal adhesions or stress-fibers are formed, which indeed seems to be the case, not only in the motile cells capable of rapid adhesion and translation (36) but also in focal-adhesion forming cells (4).…”

Section: Statistical Elastic Theory and Discussionmentioning

confidence: 99%

“…Under force, the adhesion domains grow (3) (a phenomenon called mechanoresponse, which is also related to mechanosensing, the ability of cells to sense and respond to rigidity) presumably by applying internal forces that interrogate the substrate (4). Forceinduced strengthening is concomitant with the stiffening of the cytoskeleton (3,5,6), leading to the widespread belief that active regulation of the cytoskeleton is solely responsible for mechanoresponse (3,(5)(6)(7)(8)(9). However, this actively driven cytoskeletal remodeling due to external mechanical stimulus is expected to occur over time scales of minutes (4).…”

mentioning

confidence: 99%

Force-induced growth of adhesion domains is controlled by receptor mobility

Smith

Sengupta

Goennenwein

et al. 2008

136

173

In living cells, adhesion structures have the astonishing ability to grow and strengthen under force. Despite the rising evidence of the importance of this phenomenon, little is known about the underlying mechanism. Here, we show that force-induced adhesion-strengthening can occur purely because of the thermodynamic response to the elastic deformation of the membrane, even in the absence of the actively regulated cytoskeleton of the cell, which was hitherto deemed necessary. We impose pN-forces on two fluid membranes, locally pre-adhered by RGD-integrin binding. One of the binding partners is always mobile whereas the mobility of the other can be switched on or off. Immediate passive strengthening of adhesion structures occurs in both cases. When both binding partners are mobile, strengthening is aided by lateral movement of intact bonds as a transient response to force-induced membrane-deformation. By extending our microinterferometric technique to the suboptical regime, we show that the adhesion, as well as the resistance to force-induced de-adhesion, is greatly enhanced when both, rather than only one, of the binding partners are mobile. We formulate a theory that explains our observations by linking the macroscopic shape deformation with the microscopic formation of bonds, which further elucidates the importance of receptor mobility. We propose this fast passive response to be the first-recognition that triggers signaling events leading to mechanosensing in living cells.cell adhesion under force ͉ dynamic reflection interference contrast microscopy ͉ magnetic tweezers ͉ mobile integrin-RGD bonds ͉ model systems T he formation of adhesion domains is a ubiquitous event in the early stages of cell adhesion. The domains are agglomerates of bonds formed between receptors and counterreceptors (1). For cell-cell contact, before adhesion, both binding partners are mobile, whereas for cells adhering to the extracellular matrix, the counterreceptors are fixed. In the late, actively regulated stage of adhesion, the actin cytoskeleton couples to the adhesion domains (2). Under force, the adhesion domains grow (3) (a phenomenon called mechanoresponse, which is also related to mechanosensing, the ability of cells to sense and respond to rigidity) presumably by applying internal forces that interrogate the substrate (4). Forceinduced strengthening is concomitant with the stiffening of the cytoskeleton (3, 5, 6), leading to the widespread belief that active regulation of the cytoskeleton is solely responsible for mechanoresponse (3, 5-9). However, this actively driven cytoskeletal remodeling due to external mechanical stimulus is expected to occur over time scales of minutes (4). Although it has been mooted previously that, at shorter time scales, the response is dominated by the physical properties of the membrane (1, 10), the force-response of cells over subsecond time scales has rarely been explored. At the same time, several studies have shown that, even in the absence of force, the adhesion is enhanced if both the liga...

“…Since the early 1980s, several techniques have been developed to characterize the forces generated by living cells (3)(4)(5) and to investigate the effect of the mechanical properties of twodimensional (2D) substrates (6)(7)(8). It was shown that cells are able to sense and respond to the rigidity of their surroundings.…”

mentioning

confidence: 99%

Single-cell response to stiffness exhibits muscle-like behavior

Mitrossilis

Fouchard

Guiroy

et al. 2009

210

254

Living cells sense the rigidity of their environment and adapt their activity to it. In particular, cells cultured on elastic substrates align their shape and their traction forces along the direction of highest stiffness and preferably migrate towards stiffer regions. Although numerous studies investigated the role of adhesion complexes in rigidity sensing, less is known about the specific contribution of acto-myosin based contractility. Here we used a custom-made single-cell technique to measure the traction force as well as the speed of shortening of isolated myoblasts deflecting microplates of variable stiffness. The rate of force generation increased with increasing stiffness and followed a Hill force-velocity relationship. Hence, cell response to stiffness was similar to muscle adaptation to load, reflecting the force-dependent kinetics of myosin binding to actin. These results reveal an unexpected mechanism of rigidity sensing, whereby the contractile acto-myosin units themselves can act as sensors. This mechanism may translate anisotropy in substrate rigidity into anisotropy in cytoskeletal tension, and could thus coordinate local activity of adhesion complexes and guide cell migration along rigidity gradients.mechanosensing | adaptation to load | cell migration | cell spreading | cell mechanics A s part of their normal physiological functions, most cells in the organism need to respond to mechanical stimuli such as deformations, forces, and the geometry and stiffness of the extracellular matrix (1, 2). Aberrant mechanical responsiveness is often associated with severe diseases, including cardiovascular disorders, asthma, fibrotic diseases, or cancer metastasis.Since the early 1980s, several techniques have been developed to characterize the forces generated by living cells (3-5) and to investigate the effect of the mechanical properties of twodimensional (2D) substrates (6-8). It was shown that cells are able to sense and respond to the rigidity of their surroundings. For instance, cells cultured on elastic substrates with a rigidity gradient preferably locomote towards stiffer regions and align their shape, their cytoskeletal structures, and their traction forces along the direction of highest stiffness (9-11). Moreover, it has been demonstrated that matrix rigidity could direct stem cells' lineage specification (12).It is generally assumed that rigidity sensing is based on mechanochemical signal-transduction pathways. The search for the mechanosensing element has generated numerous plausible candidates (reviewed in ref.2). The most prominent of them is the focal adhesion complex (13,14). These molecular assemblies consist of numerous proteins that are associated with integrin adhesion receptors (15) and provide the pathway of force transmission from the cytoskeleton to the extracellular matrix (16). Adhesion of integrins to extracellular matrix proteins triggers the formation of focal adhesions, their connection to actin, and the contraction of the cytoskeleton by myosin II (17-19). On a soft substrat...