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Essential Info: What is Mechanobiology?

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Essential Info: What is Mechanobiology?

1.2 Common Themes in Mechanobiology

Overall mechanobiology describes the relationship between a cell and its environment; how a cell can detect, measure and respond to the rigidity of its substrate and how these processes apply to larger biological systems. As the field of mechanobiology developed, several common themes applicable to various cell types and biological systems were described.

Cells Modulate their Stiffness According to their Substrate

A key process in maintaining the balance of forces between a cell and its surroundings, is the ability of the cell to modulate its stiffness. This determines the elastic nature of the cytoskeleton and so in turn affects a diverse range of cellular processes [1]. Currently three models have been widely proposed for the regulation of cytoskeletal stiffness by force:

i) Tensegrity: This model states that pre-existing tension within the architecture of both the cytoskeleton and the extracellular matrix (ECM) determines cytoskeletal rigidity upon the application of load (stress), such that stress is proportional to rigidity. This model assumes the cytoskeleton acts as a network of tensed cables interspersed by soft cellular material [2, 3, 4]. These cables tense and pull in response to an applied force in order to regain cellular stability.

ii) Semiflexible chain: On the assumption that actomyosin filaments are distributed uniformly throughout the cell, this model states that the filaments are non-linearly elastic (similar to cytosol) and stiffen under stress. Hence, actomyosin filaments can be defined as semi-flexible structures, which are suggested to respond to force isotropically i.e. uniformly throughout their structure irrespective of the directionality of the force applied [5, 6, 7].

iii) Dipole polarization: On the assumption that actomyosin filaments are distributed uniformly throughout the cell, this model states that upon the application of force, the elastic filaments form dipoles. These dipoles propogate force through the cytoskeletal network through polarization and subsequent pulling on the filaments in direction-dependent manner. Hence, actomyosin filaments are suggested to respond to force anisotropically i.e. differentially throughout their structure dependent on the direction of the force applied [7, 8, 9].

Figure: Models for force-induced modulation of cytoskeletal stiffness. (A) Tensegrity model: Top left- A simplified version with compression struts and tensed cables exemplifying that stress levels regulate cytoskeletal rigidity. Top right- In the cellular context, microtubules (gold rod) apply compression on cell-matrix adhesions (represented by actin linking modules in pink and integrin dimers) while the actin filaments (red) experience the cellular tension and hence stiffen accordingly. (B) Semiflexible chain model is represented by the flexible actin cables (red) that locally rigidify at points of stress application i.e. myosin (blue bundle) contraction. (C) Dipole polarization model: Formation of contractile actomyosin dipoles is symbolically represented by the arrow pairs. According to this model, they freely orient in response to applied stress as experienced at a particular point. Adapted from [10,11].


Mechanotransduction of Forces in a Cellular Environment

The application of these models to biological scenarios has proven most successful in the case of the tensegrity hypothesis (as reviewed in [12]). The models described above lead us to consider the following three key concepts, which characterize the mechanotransduction of forces in a cellular environment.

1) Mechanical signal propagation is rapid
Compared to soluble, ligand-induced signal transduction (by diffusion or motor-based translocation), mechanical forces applied to a cell are transmitted more than a 1000 times faster, along cytoskeletal filaments. For example, the activation of Src kinase via mechanical stimulation has been shown to occur in under a second, whilst activation via chemical stimulation requires tens of seconds or longer [13].

Figure: Mechanical versus chemical signal propagation. Top- Mechanical stress, whether applied to cytoskeleton-linked receptor or generated due to contractility, reaches the nucleus in less than 5 microseconds. Arrow shows direct of tension applied and propagation is depicted as a mechanical wave across the cytoskeletal networks. Bottom-Biochemical signals that originate at the membrane take tens of seconds to travel through their linked network and cause a change in the nucleus (e.g. chromosome remodeling, activate/deactivate gene expression- depicted by color change of nucleus). Adapted from [14, 15].

2) Prestressed cell structures promote long distance force propagation

The tensegrity model characterizes the cell as a hard-wired entity, composed of prestressed cytoskeletal filaments and an elastic cytosol. This is in contrast to other models representing the cell as a homogeneous elastic solid. In the latter case where all stress bearing components, namely the cytoskeleton and cytosol, have the same stiffness, force signals will rapidly decay (according to St Venants principle).

In contrast, in a prestressed environment, as defined by the tensegrity model, mechanical signals can be channeled through the cytoskeleton that is able to stiffen relative to the surrounding cytoplasm [15, 16]. The decay therefore occurs at a much slower rate than when transmitted through softer components and so the force signal is able to travel further.

The tensegrity model also supports the fact that the higher the stiffness differentials between intracellular components, the longer the distance of force propagation. The elastic cytosol and prestressed cytoskeleton are therefore ideally suited to long distance force propagation. A similar process is suggested in context of the stiff nuclear and intranuclear structures relative to the softer cytosol [17, 18].

3) Mechanochemical conversion can be induced from a distance

Mechanotransducers under tension are mechanically anisotropic i.e. elicit a response dependent on the direction of stress loading. Externally applied stress is distributed to points a few microns away from that of the applied force, according to the distribution at the time of pre-existing tensile forces (prestress) [19, 20]. A mechanochemical response can therefore be observed at local as well as distant sites, depending on the directionality of the response, as governed by the orientation of filaments interacting with the point of force application (reviewed in [21]).

Common Themes: Energy Transfer Across the Cellular System

Cellular systems function at a nanometer level and use a highly dynamic set of components. Both of these factors act as primary constraints that prevent the generation of momentum within the cell. Energy is therefore introduced into the system by high energy ligands, such as ATP and GTP (adenosine and guanosine triphosphate, respectively). The effect of energy transfer, across a cellular system, on molecular processes follows the two principles below:

1) Energy is harnessed by capturing conformational states

The assembly and activity of functional modules (i.e. protein complexes) requires ligand hydrolysis. The resultant energy introduced into these modules can be stored in particular conformations of proteins in a complex and can be later used to drive reactions and/or transfer energy onto other molecules by change of conformations.

2) Molecular dynamics are regulated by force sensing

When in a complex, a protein has bonds that mediate protein-protein interactions as well as those that maintain its own conformation. Upon force application, the dissociation of bonds between proteins in the complex competes with the dissociation of bonds within the protein, with the latter instance being favored as this allows the complex as a whole to maintain tension. This has been demonstrated using actin, filamin and α-actinin [22].

A change in conformation can be explained as a transition between two energy minima that are separated by a high energy state that slows down the transition [23]. Applied force favors this transition by lowering the energy requirement and altering the energy minima i.e. stabilizing the new conformation [24] (see figure below). Thus conformational changes are therefore dependent on force sensing, in terms of both the magnitude and duration of the detected force [25, 26]. The conformational changes pass the signal onto neighboring molecules by exposing catalytic sites for initiating reactions and binding sites for signaling and/or cytoskeletal components.

Figure: Energy state graphs. Adapted from [24]

With increase in load, cytoskeletal and cell adhesion structures initially display catch bond behavior, where bond lifetime increases until a threshold is reached when subsequent load then results in slip bond behavior i.e. reduction of lifetime leading to bond dissociation [27].

References

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Sruthi Jagannathan,
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