In a new study, scientists from Israel, the United States and Germany discovered how the cells sense the degree of hardness of the "bed", and why only a certain degree of elasticity of the "springs" will allow them to take the shape of a muscle.
Stem cells, like Goldilocks in the tale of the three bears, need a bed of just the right size to turn into muscle. When the "bed" is too soft, they turn into nerve cells or brain cells, and when it is too hard, they turn into bone. In a new study, scientists from Israel, the United States and Germany discovered how the cells sense the degree of hardness of the "bed", and why only a certain degree of elasticity of the "springs" will allow them to take the shape of a muscle.
Several years ago Prof. Dennis Disher from the University of Pennsylvania made a surprising discovery: he was able to direct the fate of stem cells in the laboratory solely through changes in the stiffness of the substrate on which they are placed. Cells placed on a soft surface not only developed a different shape than cells placed on a hard surface, but also expressed different sets of genes. Prof. Shmuel Shafran, from the Department of Materials and Surfaces in the Faculty of Chemistry, was interested in these findings. He wanted to know exactly how the stem cells react to signs that are only physical - such as the degree of stiffness of the substrate. Together with Dr. Assaf Zemel, who was a post-doctoral researcher in his group and is currently at the Hebrew University, Prof. Shafran proposed a theory that explains how the growth medium controls the arrangement of the fibers that form the intracellular skeleton. Prof. Disher and his group members - including Andre Braun and Dr. Florian Rapfeldt - tested the theory in laboratory experiments. The intracellular skeleton is made of thin and strong strands of the protein actin, which are arranged in a structure of parallel networks or bundles. The flexible structure gives the cell partial solidity - roughly like toothpaste. But the actin fibers also function as springs: they bind to another protein, called myosin, which grabs two parallel actin fibers and pulls them. This pull creates a contraction force in the cell. Such springs are found in many types of cells, and cause internal tension in the cell structure.
Prof. Shafran and Dr. Zamel hypothesized that a living cell, which naturally tends to stretch and spread out on certain surfaces, tries to collect and pull itself back by activating the contractile skeletal fibers. The balance between these two tendencies is determined by the ratio between cell stiffness and surface stiffness. According to the model developed by the scientists, at a certain degree of flexibility the skeletal fibers arrange themselves in bundles more or less parallel to the longitudinal axis of the cell. The experiments carried out in Prof. Disher's laboratory, in which substrates were tested that imitated the degree of stiffness of various materials on which the differentiating stem cells are placed, supported the model. An article describing the theory and the results of the experiment recently appeared in the scientific journal Physics Nature.
On a surface that is too soft, the contractile fibers easily overcome the tensile forces of the cell. When the cell is relatively relaxed, it produces few fibers, and these do not pull in a certain direction. On the other hand, on a harder surface, the elliptical shape of the cell plays a more significant role and carries important consequences, because the longitudinal fibers, which are long, stretch more than the transverse fibers. As a result, the newly added fibers develop mainly along the longitudinal axis. "This is exactly the arrangement you need to create a muscle," says Prof. Shafran. As the surface stiffness increases further, the fibers become so stretched that the shape and orientation of the cell no longer play a role, and new fibers are formed in all directions. Prof. Shaffern, together with the post-doctoral researcher Dr. Benjamin Friedrich, and in collaboration with Prof. Disher's group, is now examining the way in which the stiffness of the surface affects the formation of the tension fibers in the muscles. Research in this field may find a method that will allow directing the development of cells and tissues for medical and biotechnological uses.
