Remodeling of Fibrous Extracellular Matrices by Contractile Cells: Predictions from Discrete Fiber Network Simulations

Abstract

Contractile forces exerted on the surrounding extracellular matrix (ECM) lead to the alignment and stretching of constituent fibers within the vicinity of cells. As a consequence, the matrix reorganizes to form thick bundles of aligned fibers that enable force transmission over distances larger than the size of the cells. Contractile force-mediated remodeling of ECM fibers has bearing on a number of physiologic and pathophysiologic phenomena. In this work, we present a computational model to capture cell-mediated remodeling within fibrous matrices using finite element-based discrete fiber network simulations. The model is shown to accurately capture collagen alignment, heterogeneous deformations, and long-range force transmission observed experimentally. The zone of mechanical influence surrounding a single contractile cell and the interaction between two cells are predicted from the strain-induced alignment of fibers. Through parametric studies, the effect of cell contractility and cell shape anisotropy on matrix remodeling and force transmission are quantified and summarized in a phase diagram. For highly contractile and elongated cells, we find a sensing distance that is ten times the cell size, in agreement with experimental observations.

Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices

“…Following our earlier work on active biopolymer networks (14,15), 2D fiber networks representing electrospun matrices were created with randomly organized linear elastic fibers and breakable cross-links. The fiber properties used in our DFN simulations were based on recent experiments on electrospun methacrylated dextran (16) scaffolds.…”

“…However, in vivo, many cells reside within 3D fibrous scaffolds where the density and diameter of fibers can vary depending on the nature of the tissue (11)(12)(13). The local architecture of these fibrous networks may change significantly when cells exert forces on them, leading to phenomena such as nonlinear stiffening, reorientation, and physical remodeling of the ECM (14,15). Our recent study on cells in synthetic fibrous matrices with tunable mechanics and userdefined architecture showed that increasing fiber stiffness suppresses spreading, in contrast to hydrogels, where increased stiffness always promotes cell spreading (16).…”

The Interaction of BMP2‐Induced Defect Healing in Rat and Fixator Stiffness Modulates Matrix Alignment and Contraction

“…Additionally, contractility can facilitate and accelerate cellular alignment to traction forces and static strain. Interestingly, cell alignment does not necessarily follow preexisting matrix fiber orientation,47 but cells can use contractility to align ECM fibers 16. Using SHG imaging on nonmineralized sections, we were able to visualize a sandglass‐like fiber alignment in the defect gap along the bone axis upon flexible stabilization.…”

“…Adaption of cells to their biomechanical surrounding plays a critical role in wound healing and tissue regeneration 12, 13, 14, 15, 16. The initial healing phase is sensitive to mechanical conditions represented by the movement of the bone fragments.…”

3D culture models of tissues under tension

“…Although the mechanism is unclear, it is likely that cells at the periphery of the tissue engage α5β1 integrins to interact with the full-length fibronectin; this activates downstream RhoA-Rockmyosin-II signaling, thus increasing contractility as well as adhesion maturation and stability (da Rocha-Azevedo et al, 2013;Schiller et al, 2013). We speculate that localization of cells to the periphery could be due to multiple factors -haptotactic sensing of the higher peripheral levels of fibronectin, a preference for the strongly aligned ECM fibers at the periphery versus less-aligned ECM in the tissue core -perhaps due to tensional remodeling (Abhilash et al, 2014) -or even a durotactic preference for increased ECM stiffness at the periphery due to changes in ECM alignment, composition or crosslinking (Baker et al, 2015;Pelham and Wang, 1997;Plotnikov et al, 2012). Thus, the use of a microtissue system could provide insights into how gradients in provisional matrix assembly lead to changes in cell and matrix distribution.…”