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What is Mechanobiology?

Essential Info: What is Mechanobiology?

1.1 Role of Mechanobiology in Shaping Cells and Tissues

In any given system, there always exists a structural hierarchy- cells, tissues and organs; physically connected through a force-sensing network on the macroscale (organs, tissues) to the microscale (cells, protein complexes), to the nanoscale (individual proteins). These hierarchical structures constantly adapt to their micro-environment by mechanically stabilizing themselves through tensional forces transmitted along the continuum of the cytoskeleton filament systems. As a result, perpetual force-induced deformations of this architecture take place, which in certain circumstances lead to cell motility.

Such mechanotransduction is an integral part of cellular physiology and plays a critical role in organism homeostasis. Numerous models and design principles have emerged to describe how cells sense the geometry and physical forces of their environment, and how they convert these signals into biochemical pathways (reviewed in [1, 2]). For an introduction to the different types of force encountered by cells see 1.3 Types of forces cells may encounter.

In general, mechanobiology can be described based on the individual cellular components involved. However, it is important to note that in most biological systems these components do not act in isolation and form part of a complex network of pathways. Each seemingly discrete event or individual component exerts an influence on the others. This allows the system to continuously adjust to changes in its environment in order to maintain integrity by eliciting an appropriate response.

This cyclical process involves four main steps (as described in more detail below). First, the detection of the environment by the system (mechanosensing). Next, transduction of the detected signal (intracellular signaling) and integration of this signal at a genetic level (signal integration to the nucleus). Finally an appropriate response is elicited, which causes the system to once again test its environment, thereby producing a feedback loop.

1. Mechanosensing

In general, cells test their environment through a diverse group of mechanosensory proteins and cellular structures. Mechanosensors use force-induced modification(s) and conformation-dependent biochemical reactions to transmit and convey information about the cells environment. Adhesion receptors and other membrane proteins that link the cell to its external environment act as mechanoreceptors, while the proteins/complexes that link these receptors to the internal cytoskeleton are nanoscale mechanosensory organelles (reviewed in [3, 4]). Cells may utilize motility as a means for their mechanosensors to reach out and sense their immediate environment.

2. Intracellular signaling

The initial mechanical signal occurs locally [5] and is transduced to other mechanosensors along the linked network [6] (activating functional modules). This leads to transient cytoskeletal rearrangements and in turn, generation of an equivalent opposing force within the extracellular matrix (ECM) resulting in remodeling of ECM components according to intracellular force changes. These events may lead to local force-induced deformation or regain homeostasis (for low-magnitude signal). Thus, the ECM and interconnected network of cytoskeletal elements play a central role as force conduits in tissues.

3. Signal integration to the nucleus

Signal integration happens by accumulation of low-magnitude signals over time (i.e. cyclic activation and deactivation of functional modules from different functions) until a ‘switch’ is turned on. This is important to make accurate decisions in order to produce a cohesive, high-fidelity response. Such repeat events also aid in acquired learning or ‘memory’ that prevents a precipitous response to a transient stimulus.

Repeated intracellular deformations are transmitted to the nucleus eventually altering its architecture (reviewed in [7]). Thus chromatin conformations and transcription patterns are modulated to produce a response (e.g. motility type).

4. Response

The cellular response(s) to force occurs from seconds to minutes and the signals are integrated over space and time by mechanoresponsive pathways (reviewed in [8]). Mechanotransduction may result in a range of responses controlling cell shape, fate, motility, and, tissue growth and architecture.


Figure: Overview of mechanotransduction in a cell. Adapted from [9]. Mechanotransduction and response are often mediated by several overlapping signaling pathways. A variety of cellular components that are suggested to acts as mechanosensors and force transducers are depicted in a representative cell. Some of the features are specific to cell types. (A) Ion channels get activated in response to lipid fluidity and stretching of the plasma membrane to allow ion flow. Additionally changes in G-protein coupled receptors can induce intracellular signals. (B) A layer of glycoproteins found on the surface of endothelial cells, namely glycocalyx, have the ability to sense fluid shear. (C) Cell-cell adhesion complexes: Adherens junctions (red) and desmosomes (pale blue) serve as cytoskeletal communicative conduits while gap junctions connect the cytoplasm of adjacent cells. (D) Cell-matrix adhesion complexes probe the cellular environment, sense and signal the changes in the extracellular mileu. (E) Force-induced conformational changes in the ECM components can sensitize the receptors and initiate mechanotransduction signals. (F) Intracellular strain changes protein conformations and hence the binding capacity of cytoskeletal components, their crosslinkers and motor proteins to other molecules leading to alterations in signaling pathways. (G) The nucleus is proposed to sense the mechanical signals and accordingly modulate the transcription machinery by changing chromosome positions, chromatin arrangements and transport of molecules across the nuclear membrane. (H) It is to be noted that changes in inter-cellular space is cell-type specific. This can influence concentration of signaling molecules/ proteins that bind cell-surface receptors.

References

  1. Vogel V. Mechanotransduction involving multimodular proteins: converting force into biochemical signals. Annu Rev Biophys Biomol Struct 2006; 35:459-88. [PMID: 16689645]
  2. Vogel V. & Sheetz M. Local force and geometry sensing regulate cell functions. Nat. Rev. Mol. Cell Biol. 2006; 7(4):265-75. [PMID: 16607289]
  3. Ingber DE. Tensegrity: the architectural basis of cellular mechanotransduction. Annu. Rev. Physiol. 1997; 59:575-99. [PMID: 9074778]
  4. Geiger B., Bershadsky A., Pankov R. & Yamada KM. Transmembrane crosstalk between the extracellular matrix–cytoskeleton crosstalk. Nat. Rev. Mol. Cell Biol. 2001; 2(11):793-805. [PMID: 11715046]
  5. Choquet D., Felsenfeld DP. & Sheetz MP. Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell 1997; 88(1):39-48. [PMID: 9019403]
  6. Riveline D., Zamir E., Balaban NQ., Schwarz US., Ishizaki T., Narumiya S., Kam Z., Geiger B. & Bershadsky AD. Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. J. Cell Biol. 2001; 153(6):1175-86. [PMID: 11402062]
  7. Shivashankar GV. Mechanosignaling to the cell nucleus and gene regulation. Annu Rev Biophys 2011; 40:361-78. [PMID: 21391812]
  8. Geiger B., Spatz JP. & Bershadsky AD. Environmental sensing through focal adhesions. Nat. Rev. Mol. Cell Biol. 2009; 10(1):21-33. [PMID: 19197329]
  9. Jaalouk DE. & Lammerding J. Mechanotransduction gone awry. Nat. Rev. Mol. Cell Biol. 2009; 10(1):63-73. [PMID: 19197333]
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Sruthi Jagannathan,
Nov 5, 2012, 11:58 PM