The process of recognizing and responding to mechanical stimuli is critical for the growth and function of living cells. Examples are many sensory functions (including touch, hearing and gravity sensation), tissue growth/healing and bone remodeling. Also fundamental processes like cell growth, cell differentiation and cell death involve specialized mechanotransduction mechanisms. Despite its importance, cellular mechanotransduction --the conversion of external mechanical forces on living cells into a biochemical response that changes the gene program-- is not well understood.
Several excellent reviews have recently appeared [Refs. a-d] that suggest that cellular mechanotransduction can be provided by the structural organization and interconnectivity of the cytoskeleton. The cytoskeleton is a molecular network that extends from the cell nucleus to the cell membrane and is the internal supporting framework of the cell (see figure: courtesy of Invitrogen. Labels: blue-nucleus, green-tubulin, red-actin). The cytoskeleton consists of three types of polymer fibers, made from different proteins and having different diameters: actin microfilaments (typical diameter of 7 nm), intermediate filaments (8-12 nm) and microtubules (24 nm). Their role in the dynamic mechanical behavior of the cytoskeleton is different. Intermediate filaments form a stable network whose role is primarily structural: to reinforce cells and to organize cells into multicellular tissues. In many cases, microtubules are co-aligned with intermediate filaments, performing coordinated structural functions. Actin microfilaments form a highly dynamic network, whose structural form (bundled, isotropic) is mediated by cross-linking molecules (i.e. actin-binding proteins). An important manifestation of actin filaments appears when they combine with the motor-protein myosin, forming contractile stress fibers.
The stress-induced cellular deformation and associated structural alterations of the cytoskeleton appear to be linked to specific signal transduction pathways, but a thorough understanding is lacking. The objective of this Journal club is to discuss the current state-of-the-art in cell and cytoskeletal mechanics with a view on mechanotransduction. The following papers propose different cytoskeletal mechanisms of force transduction and are put forward for discussion.
In discussing the origin of mechanotransduction the following issues seem relevant.
The three components of the cytoskeleton will likely have different roles in mechanotransduction. Is one of the three components in isolation sufficient to enable MT or does it rely on a combination of two or three components, forming an intelligent force-transmitting composite? If so, is experimental evidence on the connectivity of the different cytoskeletal components available to support this? Similarly, different cells operate under different environmental/mechanical conditions and therefore receive different mechanical signals (e.g. fluid flow in epithelial cells, localized loads at focal adhesions/integrins in fibroblasts). Is there one generic transduction mechanism or does nature solve the problem cell-type-specific? Finally, how are mechanical signals that arrive at the nucleus transmitted inward such as to initiate or change gene activity?
References
c. Chang L, Goldman RD (2004) Intermediate filaments mediate cytoskeletal crosstalk, Nature Reviews Molecular Cell Biology 5, 601-613.
What makes a cell unique mechanically?
The issues raised by Dr. Onck are very important. Although significant advaces have been made in this area, the governing principles remain elusive. Ingber's tensegrity model received experimental support; however, specific quantitative prediction based on this model regarding these issues has not been made. Forgacs's percolation model is about phase transition when cytoskeletal polymer concentration reaches a critical level; however, it appears that stress distribution and connecting a local deformation to a global mechanical response have not been quantitatively predicted by the percolation model. The tensed actin bundle model by Dr. Suo and me is used to explain the peculiar long-distance force propagation in the cell; it remains to be seen if it also applies to other bundle systems (eg, vimentin bundles). Added to these models is soft glass rheology model (Fabry and Fredberg) that is used to explain the weak power law bahavior in response to loading frequency; it appears that lack of structural basis makes it difficult to predict anisotropy, heterogeneity, and force propagation inside the cell. It is also not clear how a single molecule adhesion/mechanics (E Evans, Science) and a local force activation of biochemical processes (Vogel and Sheetz) are integrated inside the cell.
Cell-ECM coupling
Further to the list of challenges noted above, I'd like to flag the issue of cell-extracellular matrix coupling as another topic of significant interest and insufficient understanding. The fundamental mechanical responses of cells (including cytoskeletal mechanics) and extracellular matrix (tissue-level) responses are most often considered in isolation. There have been many experimental studies of "mechanobiology" in which tissues or tissue-like constracts are stimulated mechanically and the cell response to mechanical stimulation (either productive or destructive) is measured, but it's unclear how these mechanical signals cross over from ECM networks to cytoskeletal networks--with orders of magnitude difference in mechanical stiffness between the two network types.
In reply to Cell-ECM coupling by MichelleLOyen
naive question
Patrick and others,
Do electrical effects also play a role in these transduction mechanisms? For example, in addition to chemical-mechanical coupling is there a electromechanical coupling also?
In reply to naive question by Pradeep Sharma
Electrical effects in mechanotransduction
Pradeep, I came across one or two theoretical papers modelling the mechanotransduction in bone as a piezo-electric process. However, I have not seen similar papers in the more biology-oriented journals (other than of course the signal transduction in nerve cells).
In reply to Electrical effects in mechanotransduction by Patrick Onck
tissue piezoelectricity
Several tissues themselves demonstrate piezoelectric effects (bone and articular cartilage). In the biological literature the discussion of this topic is associated with the term "streaming potentials" and there are about 200 hits in a medline search for this keyword, about half of which examine bone.
Info on bone piezoelectric effects is on R. Lakes' website .
In reply to Cell-ECM coupling by MichelleLOyen
Cell-ECM cross-talk
Michelle, that's another example where the competition in force transmission between two different networks come into play. This time it is not the composite-like nature of the three cytoskeletal components in the cell, but the force-partitioning of the ECM and the cell. Could you mention an example of typical ECM-cell stiffness ratios?
ECM mechanics and CSK mechanics
Dr. Oyen mentioned another important issue. There is growing evidence that ECM stiffness can greatly influence cellular mechanical and biological responses (see a review by Discher et al, Science, 05). Recent experimental work from D Discher group (Cell, 06) and P Janmey group (Biophys J, 07) clearly demonstrates that cell stiffness, tractions, gene expression patterns, and cell differentiation patterns are much dependent on ECM stiffness. The underlying mechanisms are not clear, however.
seizure controlling?
Can the study on mechanotransduction be applied to seizure controlling, which relates to the strange behaviors of brain cells in recognizing and responding?
Protein deformation: a possible mechanism for machnotransduction
Although cell cytoskeleton, ECM and cell/ECM interactions are all important components of machnotransduction, the molecular mechanism(s) for machnotransduction remains elusive. For example, it is still not well understood what happens at the molecular level that converts mechanical stress or strain to a biological/biochemical response. My own feeling is that, protein deformation, including protein domain deformation and unfolding, could be a dominant mechanism for machnotransduction. This has been stated in several reviews I wrote. It is well known that the unique three-dimensional structure (that is, the conformation) of a protein determines its function. However, proteins in a cell are deformable and can assume different (altered) conformations under physical forces. Just as proteins can transform from a native or biologically active state to a denatured or inactive state in response to small changes in temperature or pH of the surroundings, the application of mechanical forces can lead to protein domain deformation and unfolding. Specifically, protein-protein interactions rely on good conformational matches. However, the conformational match at the binding site can change when the protein domains are deformed or unfolded under mechanical forces. It is likely that protein deformation, or conformational change due to mechanical force, can affect protein–protein and protein–DNA recognition, binding and unbinding, causing changes in downstream biochemical processes that control cellular behavior. Protein deformation is therefore an important new concept in molecular biomechanics.
In reply to Protein deformation: a possible mechanism for machnotransduction by Gang Bao
Typical forces for protein deformation?
Thanks for your comments. I appreciate that the conformational changes of proteins are an important mechanism of signal transduction, linking mechanics to biochemistry. Do you see a role of this mechanism in the transmission of forces from the cell membrane to the nucleus through the cytoskeleton? Or does protein deformation primarily come into play at the ECM-cytoskeleton connection (integrins) or at the cytoskeleton-nucleus contact? In that light an important question is: what magnitude of forces should be transmitted form the cell membrane to the nucleus in order for the protein deformation mechanism (e.g. unfolding/conformational change) to be triggered?
These discussions are
These discussions are excellent and explain the excitement in the field. People from
a wide range of disciplines are investigating these issues (e.g. engineering,
biology, physics, computer science, chemistry, etc.) and there will continue to
be many advances on these fronts. With this field though, one thought always seems
to cross my mind:
Besides the exciting science of understanding cellular and molecular mechanics, can
lessons learned from cells and molecules in this field be applied to developing
novel technology?
This is an area where I see many advances already happening with a very large upside
for exciting potential applications as well (In this, we were honored to have
been invited to submit a manuscript discussing this idea through using
mechanically inclined small scale biological systems such as the cytoskeleton
and DNA to produce unique characteristics that can be used in future technology).
One area of focus would be to use the structural biological elements, which have
some intriguing properties such as their hierarchical and organization
abilities, and use them as basic building block molecular components to
generate novel technologies. Understanding the science behind the link between
mechanics and biochemistry is extremely fascinating to many people (including
myself) and finding ways to apply it to future potential technology can
generate an intriguing direction in this field that has interesting potential
as well.
Mechanotransduction during Morphogenesis
electro-machnotransduction?
Is a combination of electrical and mechanical transduction possible?
This U-TX slide demonstrates coiling [helicity] of actin and myosin which may allow for solenoid-like activity?
http://courses.cm.utexas.edu/jrobertus/ch339k/overheads-1/ch7_myo-actin.jpg
Mechanotransduction in Cancer Cells
There is a recent review article entitled "Biomechanics and biophysics of cancer cells" by Subra Suresh. Some interesting examples related to cancer cells are given there.
http://sureshgroup.mit.edu/papers/2007_Acta_Bio_Cancer_S.Suresh.pdf