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Cell-Cell Mechanical Communication through a Deformable Substrate

Cynthia Reinhart-King, Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, Micah Dembo, Boston University, Boston, MA, and Daniel A. Hammer, University of Pennsylvania, Department of Bioengineering, 120 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104.

It is now well-established that cells have the ability to sense and respond to substrate stiffness by migrating towards areas of greater elastic modulus and away from softer substrates. Moreover, our laboratory has demonstrated that endothelial cells are capable of exerting strong contractile forces. Because cells have been shown to sense mechanical disturbances in their substrate and cells are capable of disturbing the substrate through traction forces, we sought to determine whether endothelial cells can detect and respond to the substrate disturbances created by adjacent cells (ie mechanically communicate through the substrate). To measure the effect of cell-generated substrate tension on the migratory behavior of neighboring cells, we used time-lapse microscopy of both single cells and cells that are in close proximity to a neighboring cell on substrates of varying compliances. Mean-squared displacement calculations of these two cell populations revealed that the dispersion of single cells on compliant substrates is much greater than the dispersion of cells that are located within range of an adjacent cell. Moreover, the average separation distance between interacting cells correlates closely with the propagation of substrate disturbances created by cell tractions, indicating that cell-cell separation may be influenced by displacements created between the cells in the underlaying substrate. Additionally, we are the first group to use Traction Force Microscopy to study the changes in cell contractility during cell-cell contact. We show that cell-cell interactions elicit both global and local changes in the force distribution of cells.

Our study is the first to show a novel, mechanical means by which cells can communicate, namely that cells have the ability to sense and respond to another cell through cell-generated mechanical disturbances in compliant substrates. Cell-cell mechanical communication through deformable substrates will prove to be an important consideration in tissue morphogenesis and the design of biomaterials for induction of tissue formation