Neutrophils are highly motile, phagocytic immune cells that are responsible for eliminating pathogenic bacteria from the body.  Usually neutrophils do their job well, but when they do not, serious medical conditions such as infection or chronic inflammation can be the result.  Neutrophils originate in the bone marrow, circulate in the blood, and migrate into any tissue that becomes infected with bacteria.  Neutrophils locate pathogens by sensing chemical signals released by bacteria, but no one is absolutely sure how this system works.  Two models have been proposed to explain how neutrophils sense chemical gradients.  The first model suggests that each neutrophil orients itself by comparing signals from receptors on one side of the cell to signals from receptors on the other side.  The second model suggests that neutrophils compare current chemical concentrations to past concentrations and modify their movements accordingly.  This second hypothesis is similar to what is known to occur in bacteria, but neutrophils do not exhibit the run-and-tumble behavior of bacteria.  Determining how neutrophils decide where to move promises to lead to new insights into clinical disease, and microfluidic devices are being developed to facilitate this research.           

Using microfluidic devices, one can generate almost any chemical gradient that one desires, and one can also switch rapidly from one chemical gradient to another.  With these tools, one can manipulate a neutrophil’s environment in order to observe how the cell’s behavior is affected.  Researchers led by Daniel Irimia, PhD, of Massachusetts General Hospital have determined that neutrophils temporarily stop moving if the slope of the chemical gradient around them decreases or if the direction of the gradient is reversed.  These scientists have also observed that the time it takes for a neutrophil to start moving again is randomly distributed around a certain mean.  A final observation that they have made is that motionless neutrophils repeatedly change their shape before beginning to move again.  Taken together, all these observations suggest a new model of neutrophil mobility.  Irimia proposes that neutrophils sense gradients using a number of independent protrusions.  Protrusions seem to begin randomly but continue to grow only if the concentration of a chemical signal increases as they grow.  If a protrusion becomes stable enough, a leading edge is formed, and the neutrophil takes off in the direction of the protrusion.  The microfluidic tools being developed by Irimia’s group could allow other aspects of neutrophil motility to be studied, and these devices could someday play an important role in the development of drugs to treat medical conditions involving dysfunctional neutrophils.   

If the heart is considered from the perspective of an engineer, it presents a major spatial scaling problem.  Crucial ion channels are only nanometers in diameter whereas the dimensions of the entire organ are measured in centimeters.  In the past, drugs designed to prevent arrhythmias have worked on the level of ion channels but have failed in vivo.  The heart’s overall effectiveness seems to be determined at least in part by the shape of its muscle cells, or myocytes.

Each myocyte is rectangular in shape, and in a healthy individual, the length-to-width ratio, or aspect ratio, of the average myocyte is around seven.  In patients with pressure-overload hypertrophy, however, the aspect ratio can be below three, and in patients with dilated cardiomyopathy, the aspect ratio can be around eleven.  Thus, it seems that there is a “sweet spot” for the aspect ratio and that the heart is less effective when its cells do not occupy this “sweet spot.”

The shape of a myocyte seems to determine how actin and myosin, the proteins responsible for muscle cell contractions, are deposited.  Researchers in the lab of Kit Parker, PhD, of Harvard have developed a way to control the shape of a myocyte, and they have used this technique to study how myofibrils of actin and myosin function in cells of different shapes.  They have found that predictable myofibrillar bundles of actin and myosin do not form in circular myocytes but do form in cells with corners.  The corners of a cell seem to become attachment sites for myofibrils.  

The researchers in Parker’s lab are using traction force microscopy to study how the contractile strength of a muscle varies with its dimensions.  The technique involves a soft substrate impregnated with beads.  A myocyte is placed on the surface of the substrate, and when it contracts, one can measure the displacement of the beads in order to determine the force exerted by the muscle cell.  Using this method, Parker’s team confirmed that myocytes with an aspect ratio of around seven pull harder than other myocytes.  It seems that geometric cues and local boundary conditions determine a cell’s shape and thus affect its contractile strength, an insight with important implications for scientists seeking to engineer cardiac tissue.   

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