Biological complexity: mechanical forces in cells (Introduction)

by David Turell , Wednesday, February 15, 2017, 18:32 (2838 days ago) @ David Turell

Many cell functions are affected by mechanical stress and forces in cells, and play roles from embryology to adult roles:

http://www.the-scientist.com/?articles.view/articleNo/48096/title/May-the-Force-Be-with...

"Almost all living cells and tissues exert and experience physical forces that influence biological function. Touch, hearing, proprioception, and certain other senses are well-known examples of specialized force sensors. But force detection and sensing are not limited to these special cases; rather, they are shared by all living cells in all tissues and organs.  The underlying mechanisms of force generation and detection are not well understood, however, leaving many open questions about force dynamics; the distance over which a force exerts its impact; and how cells convert mechanical signals into biochemical signals and changes in gene expression.

"In recent years, biologists have begun to uncover the molecular players that mediate force sensation and propagation at the cellular level, and they’re collecting clues as to how mechanical stimuli influence biological function.

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"Since the early 2000s, my group has demonstrated that forces do propagate across relatively vast cellular distances—on the order of tens of micrometers—in living cells, and that this long-distance signal is dependent on the inherent tension in the cytoskeleton.

"Most recently, we have found that specific signaling molecules—in particular, the tyrosine kinase Src and the GTPase Rac1—can be activated at distances of more than 60 μm away from the site of the local force application via integrins at the cell membrane. Importantly, this activation is fast, taking less than 300 ms from force application to the activation of Src and Rac1, making mechanotransduction much faster than the 10 to 20 seconds it takes a soluble growth factor–induced signal to travel over the same distance.

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"However, the cytoplasm of a living cell is neither homogeneous nor isotropic; it is heterogeneous and anisotropic, meaning that the material’s mechanical properties do depend on the direction of force. Importantly, there are stiff, prestressed actin bundles (also called stress fibers) in the cell. Applied forces concentrate at these actin bundles and propagate over longer distances in the cytoplasm.

"Since the early 2000s, my group has demonstrated that forces do propagate across relatively vast cellular distances—on the order of tens of micrometers—in living cells, and that this long-distance signal is dependent on the inherent tension in the cytoskeleton. Just as a violin string can only ring with the correct resonance and sound the right note if it has proper tension, when the prestressed actin bundles are disrupted, force propagation becomes short-range (acting over only a few μms). The higher the tension, the farther the force will be propagated.

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"Belmont’s team used bacterial artificial chromosomes to insert multiple green fluorescent proteins and the gene for dihydrofolate reductase (DHFR), an essential enzyme for the synthesis of thymine, into the same chromatin domain in Chinese hamster ovary (CHO) cells. My lab applied a local force to those modified cells via integrins. Sure enough, we measured an uptick in DHFR transcription in response to the applied force. Conversely, disrupting cytoskeletal tension, or the force transmission pathways from the cell surface to lamins and to the nuclear structural proteins that connect to the chromatin, abolished force-induced DHFR expression.

"This work provides the first evidence that externally applied forces can stretch chromatin and promote gene expression. As expected with physical force–mediated processes, the response was rapid; we were able to quantify DHFR transcription upregulation within 15 seconds after force application. Interestingly, force-triggered transcription is sensitive to the angle and direction of force relative to the actin bundles: the higher the stress angle, the greater the transcription. Because endogenous forces are constantly generated inside a living cell, these findings suggest that gene expression might be incessantly regulated by physical forces via this direct structural pathway and the indirect pathways of matrix rigidity–dependent nuclear translocation of certain factors, such as yes-associated protein (YAP) and TWIST1.

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"Later, Adam Engler of the University of California, San Diego, and Dennis Discher of the University of Pennsylvania reported that mesenchymal stem cell differentiation can be directed by extracellular matrix stiffness. And my lab has demonstrated that applying local force can spur the differentiation of a single embryonic stem cell. Physical forces also appear critical in the patterning and organization of germ layers during early mammalian embryonic development."

Comment: The layers of complexity increase. What is presented is a logical extension of research. Areas of cell growth will apply force, especially in embryology, implying those forces were planed or understood as organisms were designed.