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Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MissouriDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri
Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MissouriDepartment of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri
How do isolated cells reach out collectively to remodel the environment in which they reside? We have known for some time that in certain processes, such as wound-healing, cells appear to act together, contacting one another through bands of remodeled collagen stretching over distances that are very long compared to the size of a cell (Fig. 1, left panel). We also know that fibroblasts act locally, synthesizing and remodeling extracellular matrix (ECM) proteins in response to signals that are only partially understood (Fig. 1, right panel). Dissecting these signals and responses is vital for developing a mechanobiological understanding of key physiological and pathophysiological processes including tissue growth and development, wound healing, fibrosis, and metastasis.
The problem is multifaceted, and the community has been working for years to untangle it. Experimental and theoretical models have led to a consensus that cell-driven mechanical forces in remodeling affect the cells themselves. We know with certainty that mechanical signals from, and transferred through, the ECM cause cells to align (
). However, this process is recursive: forces transduced from the ECM, primarily through transmembrane ligand structures, trigger signaling pathways initiating the remodeling of the cells themselves, as actin stress fibers are recruited within the cytoskeletal network of the cells (
). Experiments on cell-seeded collagen lattices indicate that this recursive process affects both cells and ECM mechanically; the fibroblast cells appear to stiffen their ECM to a target value, while responding to this stiffening by becoming more compliant themselves (
How do cells act locally while having impact over length scales sufficient to produce bands of collagen like those in Fig. 1? The distances covered by these collagen bands are too large compared to the size of a cell to be explained by simple linear elasticity. The field has been stepping toward the answer to this question for decades, beginning with the work of Murray and Oster (
), among others, and their sophisticated modeling of syneresis. Similarly, advanced statistical tools are available for defining the mathematical elements needed to describe the architecture of a collagenous tissue and following its progression over time (
). Continuum constitutive models exist that relate approximate models of local collagen rearrangement to stress-strain responses of ECM. Once collagen density and orientation distributions are known, Lanir-Sacks homogenization can be performed over the orientation distribution and responses of tissues can be estimated using the well-established toolbox of continuum mechanics (
An important piece of this puzzle that had been missing, however, is a continuum constitutive model that can predict changes in density and collagen orientation over time and the associated changes to the strain-dependent mechanical responses of the ECM. In two recent articles in the Biophysical Journal, Abhilash et al. (
) presented the first tool for this, and applied it to provide important insight about how cells take advantage of the fibrous nature of the ECM to facilitate communication with distant neighbors. In a finite-element-based discrete fiber network model of contractile cell-mediated remodeling in fibrous matrices, Abhilash et al. (
) showed that very simple drawing in of a fibrous network by cells can explain a broad range of well-known experimental observations, including long-range force transmission in fibrous matrices. They further characterized many key factors such as the role of cell shape anisotropy in the extent of this communication and the degree of spatial heterogeneity that arises, showing clearly that the fibrous nature of the ECM allows communication that would not be possible in a simple Neo-Hookean ECM.
Discrete simulations of analogous phenomena have been performed by others (
), a continuum constitutive model that scales up these complicated discrete simulations to the level of tissues. This first-order, biophysically based continuum model of ECM mechanics captures the behaviors observed in the earlier discrete fiber network simulations, but further lends itself to the development of scaling laws for the distances of cellular communication in a fibrous ECM. The result is a clear picture of the conditions under which cells can act locally on their pericellular environment to communicate over distances many times their diameter to unionize with their neighbors.
This new advance in our understanding of cellular locomotion and remodeling offers great potential for additional refinements. The models of Abhilash et al. (
) account for communication across long distances, but are limited because, like all constitutive models, they are approximate at the local level. Another limitation of these first-order models of ECM compaction is their inability to account for cell digestion of collagen by enzymes such as matrix metalloproteinases or for the production of collagen by the cell (e.g., Fig. 1), and thus need to be further refined in the pericellular region. Excellent models exist for this (
). The recursive nature of cellular and ECM remodeling is also a frontier that remains open; although models are available that predict how internal and external forces affect cellular remodeling, the interplay between cellular and ECM remodeling remains unclear, but it is surely of great importance and should be addressed in future models of cell-ECM remodeling. In their present form, these models from Abhilash et al. (
) shed light on the fundamental processes that enable cells, acting locally and independently, to form and communicate over long-range mechanical networks, and provide us with a solid foundation for future study.
This article was funded in part by the National Institutes of Health through grant No. HL109505 and the Changjiang (Yangtze River) Scholars Program of the Chinese Ministry of Education.
Theoretical concepts and models of cellular mechanosensing.
Cells can sense and respond to mechanical signals over relatively long distances across fibrous extracellular matrices. Recently proposed models suggest that long-range force transmission can be attributed to the nonlinear elasticity or fibrous nature of collagen matrices, yet the mechanism whereby fibers align remains unknown. Moreover, cell shape and anisotropy of cellular contraction are not considered in existing models, although recent experiments have shown that they play crucial roles. Here, we explore all of the key factors that influence long-range force transmission in cell-populated collagen matrices: alignment of collagen fibers, responses to applied force, strain stiffening properties of the aligned fibers, aspect ratios of the cells, and the polarization of cellular contraction.
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.