Mechanotransduction

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Entry by Andrew Capulli, Fall 2011

Definition: Mechanotransduction

Mechanotransduction is the process of converting physical forces into intracellular biochemical responses. The rebirth/change in view toward tissue engineering has made "mechanotransduction" a major buzzword in the field. Essentially, this term generally refers to the mechanical factors that influence cell behavior and differentiation. Stretch, substrate stiffness, loading (compressive, tensile, shear): these are all mechanical loads that are 'sensed' or felt by a cell and are converted into biochemical response such as up or down regulated expression of proteins, cell movement, and/or cell spreading. Ion channels, integrins which are connected to the cytoskeleton, growth factor receptors, cytoskeletal filaments, and even the nucleus of a cell are thought to be 'mechanically activated' and respond directly to, say, stretch of a cell. While exact pathways of converting mechanical stimulus into biochemical response varies among cell types (and even within a cell type) it has become clear that cells have a strong sense of their mechanical environment and respond to changes in this environment.

Traditional biology and tissue engineering relied upon the influence of multiple growth factors and the chemical environment (ion concentration, pH, etc) of a cell to dictate the behavior and lineage of a cell. While these chemical factors are crucial to cell phenotype, just as important are the mechanical ques and environment a cell experiences. New-age tissue engineering focuses on both chemical and mechanical factors in the development of a cell. Stem cell based tissue therapies (the current state of research) attempt to differentiate pluripotent cells (such as embryonic stem cells or the less controversial mesenchymal stem cells found in bone marrow) by both adding known chemical factors such as cytokines and growth factors in addition to providing 'mechanically appropriate' environments for what types of tissue are being attempted. The stiffness of the extracellular matrix "ECM" (material such as collagen that the cell attaches to) can strongly influence the lineage and behavior of a cell. Mesenchymal stem cells for example have the ability to differentiate into fat tissue, bone tissue, or even muscle tissue based on a number of factors including ECM stiffness and stretch/loading (image below which can also be found larger at: http://www.abcam.com/index.html?pageconfig=resource&rid=11815). What exactly the 'mechanical factors' are that help to differentiate or dictate a cell's behavior is exactly what the state of the technology is... today's tissue engineering research hopes to address these variables.

HMSCdiff.jpg

Where can we start to investigate the mechanical ques that dictate cell phenotype (ie how can we define the mechanical variables that contribute to the mechanotransduction of a cell)? This is where the physiologists and engineers meet; there is no better place to start than what nature has created. Bone, for example, is a relatively hard material compared to other tissues in the body. Long bone (generally speaking) has orthotropic linear elasticity properties along the shaft of the bone. Tissue engineered bone materials should then be designed similarly, ie with similar (or as close as possible) material elastic stiffness/compliance constants to that of the native bone. Similarly, the tissue engineered material, when seeded with stem cells, should be loaded (in compression for bone) to provide an environment mechanically appropriate for the tissue being 'created'. As another example, many cardiac tissue engineered materials are subjected to cyclic loading (at around 10% strain) which mimics the the environment experienced in a healthy heart. The Wikipedia article is not the an overwhelmingly great source on mechanotransduction but it does give some further examples and can be found at: http://en.wikipedia.org/wiki/Mechanotransduction.

Here at Harvard in SEAS...

Here at Harvard there are a number of tissue engineering laboratories focused on addressing these questions; in particular Professor Dave Mooney's lab (Mooney Lab website: http://www.seas.harvard.edu/mooneylab/) and Professor Kit Parker's lab (Parker Lab website: http://diseasebiophysics.seas.harvard.edu/). One of Professor Parker's main research goals is to better characterize the causes of traumatic brain injury in soldiers due to explosions such as IEDs and the resultant shock waves. Today's technology equips our soldiers and protects them from harm like never before; however, while the modern soldier's helmet (for example) may save the soldier's life from an explosion, it cannot stop the shock wave which causes irreparable nerve and brain damage. How do these shock waves impact the nerve cells? Do they physically rip the cells off of their ECM? Is the wave sensed somehow by the cells and translated into some degenerative response? These are just some of the current questions being asked here at Harvard, just some of the mechanotransduction issues that have a real impact on thousands of patients.


References

[1] "The Role of Mechanical Forces in Guiding Tissue Differentiation, Chapter 5" Tissue Engineering in Regenerative Medicine, Sean Sheehy and Kit Parker (Harvard SEAS).

[2] "Matrix Elasticity Directs Stem Cell Lineage Specification" Adam J. Engler, Dennis E. Discher (UPenn) link: http://www.sciencedirect.com/science/article/pii/S0092867406009615

Keyword in References:

Evidence for an upper limit to mitotic spindle length

Multiscale approach to link red blood cell dynamics, shear viscosity, and ATP release

N. Wang, Z. Suo," Long-distance propagation of forces in a cell." Biochemical and Biophysical Research Communications 328, 1133-1138 (2005). Submitted for publication on 12 January 2005.Accepted for publication on 18 January 2005