Mechanics of cell-substrate interaction
Open Access
- Author:
- Zhao, Tiankai
- Graduate Program:
- Engineering Science and Mechanics
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 18, 2020
- Committee Members:
- Sulin Zhang, Dissertation Advisor/Co-Advisor
Sulin Zhang, Committee Chair/Co-Chair
Long-Qing Chen, Committee Member
Christian Peco, Committee Member
Spencer Szczesny, Outside Member
Judith Todd Copley, Program Head/Chair - Keywords:
- cell-substrate interaction
traction force
focal adhesion
myosin motor
thermodynamics
phase-field model
finite elements method - Abstract:
- Mechanics of cell-substrate interactions has recently emerged one of the most exciting topics to study, propelled by the discovery of unusual fundamental physical phenomena such as durotaxis and newly developed experimental techniques such as Traction-force-microscopy (TFM). The intensive interest on the mechanics of cell-substrate interactions arises also because of the decisive role that forces play in well-known biological processes such as proliferation, durotaxis, and metastasis. The discovery of the novel importance of cell-substrate interactions has inspired an endeavor that leads to the establishment of new physical theories. Such monumental pushes, however, still have some flaws based on the assumptions and simplifications and require a deeper physical understanding and more detailed modeling on the mechanism of cell-substrate interactions. This dissertation contributes to the mechanics of cell-substrate interactions and mainly focuses on the establishment of physical models based on formulating the free energy of cell-substrate interactions. As a living cell adheres to a substrate, it will contract, pull the substrate, and generate external tensions. The Rho and Ca pathways control the stress-dependent myosin motor recruitment and binding with the cytoskeleton. The stress fiber network applies tensile forces on the ligand-receptor complex, which facilitates the aggregation of the complex and forms the focal adhesions. The focal adhesions then transmit more tensions between the cell and the substrate, enabling more and more myosin motor activation and stress fiber assembly. This positive feedback loop is the mechanism of cell-substrate interaction. Enormous efforts have been undertaken in computationally modeling cell-substrate interactions. Formal models proposed on cell-substrate interactions are either too simplified which fail to capture the essential details or too complicated which are difficult to implement. To achieve both physical accuracy and computational efficiency, this dissertation aims to develop new models to predict the focal adhesion formation, the traction force generation, and the stress fiber assembly in cell-substrate interactions. In particular, the free energy is written as a functional of the cellular displacement, the integrin density and myosin motor density. The equilibrium is achieved by finding the minimum of the functional. For the time-dependent evolution of stress fiber assembly, a phase-field method is applied to trace the morphology of stress fibers at any given time. To deal with the irregular shapes of cells, the finite element method is used to solve the equations. A commercial package named COMSOL is used as the major computing tool in this dissertation. The new models enable the prediction of the traction forces, the formation of focal adhesions and stress fibers; and they replicate a range of interesting phenomena observed in experiment, typically inaccessible to previous models and experiments. For arbitrary-shaped single cells on homogeneous substrate, our model is able to predict the profile of the traction force and the focal adhesion, which are determined by the geometry of the cells. We find that the intracellular tension is highly dependent on the shape of the patterned cell on glass and governs the number of the nanoparticle uptake. For strip-like cells on alternatively coated gels, our model suggests that the interfacial tension play an important role in a variety of interesting phenomena such as dorsal stress fiber bending and dorsal stress fiber formation failure. For cohesive cell colonies, a variety of experimental observations, such as the size effect and the stiffness effect, are replicated by our model. We also conclude that the metastasis is governed by the intercellular tension from the model. These findings show not only the effectiveness of the new model, but also the possible guidance that the model can offer to the further study on cell-substrate interactions.