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Inner World of the Cell

Effect of Mechanical Force

Mechano-transduction, Examples While the effect of mechanical force on embryonic development has been demonstrated conclusively by many experiments. The most common examples of mechano-transduction are the various kinds of massage, which facilitate the circulation of interstitial fluid by mechanical force. Meditation helps to promote movement of the fluid by relaxing the muscles as well as the mind. Qi-gang directs the fluid to move along the meridians. Then some forms of martial art use internal fluid pressure against external force (Figure 23). While these cases at macroscopic scale are easier to

Figure 23 Mechano-transduction, Examples [view large image]

discern, the advance in technology makes it possible now to observe the effect at cellular level. For example, structural change of actin in response to applied force has been observed by AFM in 2013 (see Science Daily, more examples in Figure 26, and possible effect on "acupuncture").

Mechanical Cues on Cell Functions It is known that cells response to various kinds of biological, chemical, and mechanical inputs (Figure 24). It has been found that mechanical induction of structural change in ECM has profound effect on cell fate. Mechanical stimuli such as elasticity, topography and force would alter cell migration, over all morphology, structure of the cytoskeleton, expression of specific genes, as well as the lineage of stem cell differentiation. For example, stiff gels promote spreading and scattering of adherent cells, while soft gels promote soft tissue differentiation and tissue-like cell-cell

Figure 24 External Cues on Cell Functions

associations. In addition, adherent cells migrate preferentially toward stiffer regions, and differentiation of mesenchymal stem cells is highly sensitive to substrate stiffness.

Mechanical Processes on Cells Mechanobiology is the field to decipher how cells receive and response to mechanical inputs. The mechanical inputs that cells interpret are a combination of force and geometry over length scales of nano- to micro-metres. In all cases, signals are eventually transduced to changes at molecular level. To give the required specificity of action, for example in turning a particular genetic program on or off, these molecular-scale signals must be regulated with very precise spatial and temporal accuracy. Ultimately, mechanical, chemical, and biological processes all play out in sustaining a living cell. Figure 25 shows the inter-play of mechanical and cellular effects. The term "remodeling" means structural

Figure 25 Mechanical Processes on Cells

change, while "transcription factor" controls the rate of transcription of genetic information from DNA to messenger RNA (also see "Focal Adhesion").

Mechanical of Measurements of Cellular Movement In order to quantity the mechanobiological processes, it requires innovative tools to measure tiny amount of force on the scale of 10-12 Newtons (~ 10-9 the weight of a paper clip) at m-size. By 2017, scientists have finally acquired tools that make it possible to measure movement of skin cells (in wound healing) and program cells to blink on and off as proteins stretch and relax.

Figure 26 Mechanical Measurements of Cellular Movement [view large image]

Researchers are beginning to understand how force is translated into function. Three of the measuring methods are shown in Figure 26, and summarized briefly below.
  1. Traction Force Microscopy (TFM) - Cells interact with environment through proteins embedded in the membranes, where the mechanical signals are transmitted inside to generate cellular processes. The TFM method was developed in the 1990's by embedding fluorescent beads within gelatinous material to mimic the ECM (see the one dimensional version in Figure 26,a). Movement of the cell drags the bead along, the displacement is interpreted as mechanical force according to the Hook's Law. This method has become a standard tool for studying cell migration. Extension to 3 dimensional presents more analytical and computational challenges; nevertheless, it is successful in probing the spread of breast cancer cells in a synthetic 3-D tissue.

  2. Poly-DiMethyl-Siloxane (PDMS) - This device built with micropillars (elastic material called PDMS, Figure 26,b) on electronic microchip. The length of the pillar is related to the stiffness - shorter, thicker pillars are more rigid and unyielding. The degree of of rigidity can trigger considerable reorganization of a cell's cytoskeleton and in turn can influence cellular proliferation, movement and maturation. For example, a relationship is found between surface rigidity and stem-cell differentiation by measuring the deflection of the micropillars.

  3. Forster Resonance Energy Transfer (FRET) - This sensor is based on the FRET phenomenon in which one fluorescent molecule (fluorophore) excites another one only at close proximity (Figure 26,c). Thus, fluorescent emission is an indicator of separating distance (indirectly force) when the fluorophores are inserted on proteins. For example, the push and pull of cells on each other in a tissue can be measured by integrating the FRET sensors into the E-cadherin protein which couples cells together.

These measuring devices are still in the stage of development. There are problems with computational demand (in TFM), the PDMS imposes an unnatural pattern of interaction between cells and their substrates, while FRET is rather invasive with the requirement of insertion of the fluorescent molecule on a protein. See "Mechanobiology : A Measure of Molecular Muscle" for a 2017 update on the subject of mechanical measurement at cellular scale.

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