Multiscale Studies On Cell-matrix Interaction

Experiments have shown that mechanical properties of extracellular matrix(ECM),such as stiffness,topology,deformation,and so on,can regulate the morphology,motility,and gene expression of cells.The ability for cells to sense and respond to mechanical signals of ECM is called mechanosensitivity.Cell-matrix interaction is an important part of cellular mechanosensing,which is studied at the molecular scale,subcellular scale,and cellular scale,respectively,in this thesis.This thesis provides new ideas and methods for further understanding cell-matrix interaction from a mechanical perspective.The main contents of this thesis are listed in the following.(1)At the molecular scale:(a)Strength of a slip bondConventional theory predicts that molecular bond strength becomes trivial at very low loading rates.However,this prediction is inconsistent with some experiments.Based on the assumption of bond reassociation at low loading rate,this thesis proposes the theory of average bond strength.The analysis indicates that there exists an asymptotic value of average bond strength at low loading rates,which increases with the stiffness of the loading system.Therefore,the thesis suggested that average bond strength could be a new physical quantity characterizing the strength of single slip bond,and be measured in dynamic force spectroscopy experiments.(b)History-dependence of catch bondTwo types of catch bonds based on two-state model are established,and their dynamical behaviours are studied upon varied loads.The two types of catch bonds have similar force-lifetime profile upon a force-clamp loading.However,when a single catch bond of either type is subjected to other kinds of varied forces,it is found that they behave very differently in force-history dependence.(c)Association of a receptor with an oscillating ligandThe stability of a bond cluster upon oscillated loads under physiological conditions is strongly regulated by the kinetics of association and dissociation of a single bond.By solving the diffusion-reaction equation for the association of a receptor to an oscillating ligand,it is demonstrated that the process can be simplified to be diffusion-independent under most physiological conditions.The results indicate that the average time for bond association saturates at high oscillating frequencies and there exists an optimal bond elasticity for bond association.(2)At the subcellular scale:(a)Stability of slip bond cluster upon cyclic loadingA coupled finite element analysis and Monte Carlo method is developed and employed to investigate the stability of a cluster of slip bonds upon cyclic loads.Simulation results indicate that there exist two characteristic failure modes:gradual sliding with a relatively long lifetime and catastrophic failure with a relatively short lifetime.The lifetime of the bond cluster decreases with increasing stretch amplitude and also decreases with increasing cyclic frequency,which saturates at high cyclic frequencies.An unusual case is also discovered,where stability of the cluster might be substantially enhanced by a fluctuated force at a relatively low fluctuation frequency and high fluctuation amplitude.Parametric studies indicate that such stability enhancement is strongly affected by the stochastic features of a single bond,as well as the profile of the cyclic forces.(b)Stability of catch bond cluster upon cyclic loadingStability of bond cluster comprised by Type I or Type Ⅱ catch bond upon cyclic loads is studied.Simulation results indicate that cyclic loads tend to destabilize both types of catch bond cluster.The lifetime of both types of catch bond cluster decreases with increasing stretch amplitude and also decreases with increasing cyclic frequency,which saturates at high cyclic frequencies.(3)At the cellular scale:Cell orientation under biaxial cyclic stretchingOn a substrate under biaxial cyclic stretching,cells reorient themselves,whose final angle is related with the stretch ratio.To explain such phenomenon which appears to be inconsistent with existing theories,a group of researchers have established a new theory based on cell’s passively stored elastic energy.Based on elastosarcomere-adhesion model considering both tensile and shear forces of focal adhesion,this theis studies cell reorientation on biaxially stretched substrate.Final angle and rotational velocity under differnet conditions predicted in this model are consistent with the experiments,demonstrating that the theory proposed in the thesis can successfully explain the experimental observation of cell orientation on biaxially stretched substrate.