Graduate Thesis Or Dissertation
 

Mechanics of three-dimensional microenvironments of cells

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  • The structure and mechanics of tissues affect many important cellular functions such as migration, differentiation, and growth. Mechanical interactions between cells and the extracellular matrix (ECM), as well as ECM-mediated mechanical communication between cells, plays a part in coordinating collective cellular dy- namics during critical processes such as morphogenesis, tissue regeneration, and immune response. Mechanical coupling and collective cell migration is particularly important to the study of cancer progression. Collagen gels are widely used as an in vitro model for ECM because they mimic the extracellular matrix in physi- ological conditions. Type I collagen abounds in mammalian extracellular matrix (ECM) and is crucial to many biophysical processes. We report experimental tech- niques to study the structure and mechanical properties of collagen-based ECM at the microscopic scale. We also present computational models that provide insight into how ECM structure and mechanics depend on environmental factors and cell activity. While previous studies have mostly focused on bulk averaged properties, here we provide a comprehensive and quantitative spatial-temporal characterization of the microstructure of type I collagen-based ECM as the gelation temperature varies. The structural characteristics including the density and nematic correla- tion functions are obtained by analyzing confocal images of collagen gels prepared at a wide range of gelation temperatures. As temperature increases, the gel mi- crostructure varies from a bundled network with strong orientational correlation between the fibers to an isotropic homogeneous network with no significant orienta- tional correlation, as manifested by the decaying of length scales in the correlation functions. We develop a kinetic Monte-Carlo collagen growth model to better un- derstand how ECM microstructure depends on various environmental or kinetic factors. We show that the nucleation rate, growth rate, and an effective hydrody- namic alignment of collagen fibers fully determines the spatiotemporal fluctuations of the density and orientational order of collagen gel microstructure. Collagen gels are often characterized by their bulk rheology; however, variations in the collagen fiber microstructure and cell adhesion forces cause the mechanical properties to be inhomogeneous at the cellular scale. We study the mechanics of type I collagen on the scale of tens to hundreds of microns by using holo- graphic optical tweezers (HOT) to apply pN forces to microparticles embedded in the collagen fiber network. We find that in response to optical forces particle displacements are inhomogeneous, anisotropic and asymmetric. Gels prepared at 21◦C and 37◦C show qualitative difference in their micromechanical characteris- tics. We also demonstrate that contracting cells remodel the micromechanics of their surrounding extracellular matrix in a strain- and distance-dependent manner. To further understand the micromechanics of cellularized extracellular matrix, we have constructed a computational model which reproduces the main experiment findings. Interactions between cells and the ECM are a dynamic process, in which the cells actively deform and remodel their surroundings. We show that 3D collagen gels are significantly and irreversibly remodeled by cellular traction forces. In addition we find that plasticity of collagen gels can be described in mechanical terms, even when no cells are present. This is shown by irreversible deformation in collagen gels due to macroscopic strain. We present a computational model that describes collagen plasticity in terms of the sliding and merging of ECM fibers. We have confirmed the model predictions agree with experimental results. These results suggest that cell-induced remodeling of the ECM may enhance mechanical coupling between cells and have a dramatic effect on cell-cell communications in 3D fibrous matrices. This could have important implications for the study of tissue development and cancer progression.
  • Keywords: extracellular matrix, biomechanics, cells
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