The structure and mechanics of tissues is constantly perturbed by endogenous forces originated from cells, and at the same time regulate many important cellular functions such as migration, differentiation, and growth. Here we show that 3D collagen gels, major components of connective tissues and extracellular matrix (ECM), are significantly and irreversibly remodeled by cellular traction forces, as well as by macroscopic strains. To understand this ECM plasticity, we develop a computational model that takes into account the sliding and merging of ECM fibers. We have confirmed the model predictions with experiment. Our results suggest the profound impacts of cellular traction forces on their host ECM during development and cancer progression, and suggest indirect mechanical channels of cell-cell communications in 3D fibrous matrices.
*Biopolymer Networks play an important role in coordinating and regulating collective cellular dynamics via a number of signaling pathways. Here, we investigate the mechanical response of a model biopolymer network due to the active contraction of embedded cells. Specifically, a graph (bond-node) model derived from confocal microscopy data is used to represent the network microstructure, and cell contraction is modeled by applying correlated displacements at specific nodes, representing the focal adhesion sites. A force-based stochastic relaxation method is employed to obtain force-balanced network under cell contraction. We find that the majority of the forces are carried by a small number of heterogeneous force chains emitted from the contracting cells. The force chains consist of fiber segments that either possess a high degree of alignment before cell contraction or are aligned due to the reorientation induced by cell contraction. Large fluctuations of the forces along different force chains are observed. Importantly, the decay of the forces along the force chains is significantly slower than the decay of radially averaged forces in the system. These results suggest that the fibreous nature of biopolymer network structure can support long-range force transmission and thus, long-range mechanical signaling between cells.
Collagen gels are widely used in experiments on cell mechanics because they mimic the extracellular matrix in physiological conditions. 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 holographic optical tweezers 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 characteristics. We also demonstrate that contracting cells remodel the micromechanics of their surrounding extracellular matrix in a strainand distance-dependent manner. To further understand the micromechanics of cellularized extracellular matrix, we have constructed a computational model which reproduces the main experiment findings.micromechanics | collagen | fiber network T he mechanical properties of the extracellular matrix (ECM) play a central role in developmental biology (1), tissue homeostasis, and remodeling (2). Alteration of the ECM elasticity is a signature of many diseases such as pulmonary and atrial fibrosis, Ehlers-Danlos syndrome, and infantile cortical hyperostosis (3). The mechanical cues from the ECM also strongly correlate with the clinical prognosis of various types of cancers (4).In recent years, many studies have shown that to mimic the physiological conditions in vitro, mechanical cues from a truly 3D ECM are necessary (5). Type I collagen gel has gained popularity as arguably the most used in vitro model of a 3D ECM (2). As the most abundant protein in animal tissue and accounting for 25% of the human whole-body protein content (6), type I collagen is the major component of the ECM in skin, tendon, and organs. Despite its lack of biochemical complexity compared with live tissue, reconstituted type I collagen gel has been successfully used to provide mechanistic insights into processes such as morphogenesis (7), wound repair (8), and cell migration (9). In particular, the rheology and especially the rigidity of collagen gel have been shown to tune the growth and migratory phenotypes of cancer cells in vitro (10, 11).Structurally, collagen gels are formed by fibrous networks and typically have pore sizes of a few to tens of microns (12)(13)(14). The typical size of these structural discontinuities is comparable to the size of cells and is much larger than cell-ECM adhesion complexes (15,16). It is therefore expected that a cell senses the micromechanical properties of its surrounding matrix, rather than the macroscopic rheology of the ECM (16,17). Although many studies have focused on the (nonlinear) bulk rheology of empty and cellularized collagen ECM (18-22), the micromechanics of the porous biopolymer network is largely unexplored, presumably...
Type I collagen abounds in mammalian extracellular matrix (ECM) and is crucial to many biophysical processes. 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 correlation functions are obtained by analyzing confocal images of collagen gels prepared at a wide range of gelation temperatures (from 16 °C to 36 °C). As temperature increases, the gel microstructure varies from a "bundled" network with strong orientational correlation between the fibers to an isotropic homogeneous network with no significant orientational correlation, as manifested by the decaying of length scales in the correlation functions. We develop a kinetic Monte-Carlo collagen growth model to better understand how ECM microstructure depends on various environmental or kinetic factors. We show that the nucleation rate, growth rate, and an effective hydrodynamic alignment of collagen fibers fully determines the spatiotemporal fluctuations of the density and orientational order of collagen gel microstructure. Also the temperature dependence of the growth rate and nucleation rate follow the prediction of classical nucleation theory.
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