Models of Sub-cellular systems



Cellular mechanosensation involves the interaction of several sub-cellular systems: 1) cell-surface adhesions, that link the cell to its surroundings; 2) the cytoskeleton, the cell's internal support structure that forms direct links to the adhesions; and 3) molecular motors, that work together to apply forces between the cytoskeleton and the adhesions.  Cell models typically incorporate simplified versions of these systems; it is also important to study these systems in detail.  One advantage of detailed models is that they can be quantitatively compared to experimental measurements.





Reference: Walcott, S., Kim, D. -H., Wirtz, D., Sun, S. X., Nucleation and decay initiation are the stiffness-sensitive phases of focal adhesion maturation. 
Biophysical Journal, Volume 101, pages 2919-2928, 2011. PDF


In this project, in collaboration with the Wirtz lab who performed experimental measurements, we studied how cell-surface adhesions evolve with time.  To do so, we developed a molecular-mechanical model for cell-ECM adhesions.  Based on Monte-Carlo simulations of this model, we made five specific predictions of adhesion behavior.  The Wirtz lab performed experimental measurements to test the predictions.  Their measurements supported all five.  We then developed a theoretical framework to understand the model behaviors.



Figure 1: A molecular-mechanical model predicts aspects of cell-ECM adhesion growth and their ECM stiffness dependence.  A. The model predicts that adhesion area initially increases quadratically with time, then transitions to a quadratic decrease with time (left).  Measurements of cell-ECM adhesions display similar behavior (right).  B. The model predicts that adhesion number (top left) and area (bottom left) increase with ECM stiffness, described here by the Young's modulus, E.  Additionally, the model predicts a critical stiffness below which adhesions cannot be formed (dashed line).  Measurements are consistent with these predictions (right), including a critical stiffness below which cells do not adhere to the ECM and consequently die (dashed line).


This work demonstrates two important results: 1) ECM stiffness affects whether an adhesion is initially formed and how long it grows, but not the growth or decay processes; and 2) adhesion dynamics and mechanosensitivity are emergent properties of generic molecular systems with load- and strain-dependent chemical reactions.





Dong-Hwee Kim

Sean Sun

Denis Wirtz