To pull or be pulled: parsing the multiple modes of mechanotransduction

Abstract

A cell embedded in a multicellular organism will experience a wide range of mechanical stimuli over the course of its life. Fluid flows and neighboring cells actively exert stresses on the cell, while the cell's environment presents a set of passive mechanical properties that constrain its physical behavior. Cells respond to these varied mechanical cues through biological responses that regulate activities such as differentiation, morphogenesis, and proliferation, as well as material responses involving compression, stretching, and relaxation. Here, we break down recent studies of mechanotransduction on the basis of the input mechanical stimuli acting upon the cell and the output response of the cell. This framework provides a useful starting point for identifying overlaps in molecular players and sensing modalities, and it highlights how different timescales involved in biological and material responses to mechanical inputs could serve as a means for filtering important mechanical signals from noise.

Figure 1

Schematic representation of active and passive mechanical inputs and active biological and passive material outputs, in the context of stiffness, force, and displacement. (a) Substrate stiffness (i) is a passive mechanical input. Applied stress or strain (ii) is an active mechanical input. Viscoelastic deformation and stress stiffening (iii) are passive material outputs. Changes in contractile behavior, cytoskeleton remodeling, and the activation of signaling pathways are active biological outputs. (b) Diagram highlighting major relationships (solid arrows) between input and output types. In the context of a cell, more complex relationships often occur (dashed arrows).

Figure 2

Examples of modes of mechanotransduction behavior, sorted by input and output types. (a) Mechanical property measurements in cells make use of assaying the passive material response to an active mechanical input [15, 16, 17•]. (b) Compression applied to cell aggregates inhibiting proliferation [27] is an example of an active mechanical input influencing an active biological output. (c) Differential adhesion governing cell sorting in aggregates is a passive, diffusion-driven behavior that occurs downstream of the passive material input of adhesive affinity [40]. (*There are no passive material responses that are directly due to stiffness.) (d) Changes in transcription factor localization is an active biological output that can occur in response to the passive mechanical input of substrate stiffness [53••].

Figure 3. Mechanical response behaviors span a wide range of biologically relevant timescales

Passive material responses to mechanical stimuli can span many timescales, as seen in material response behavior, protein sorting [42•], and differential adhesion [40]. Active biological responses to mechanical stimuli occur on disparate timescales, as seen in the activation of signaling [4, 64]; changes in contraction behavior [47, 49]; focal adhesion strengthening, phosphorylation, and growth [8, 35, 66]; transcriptional regulation [32••, 33•, 53••], and differentiation and proliferation [11, 27].