SignificanceTissues are made up of cells and an extracellular matrix (ECM), a cross-linked network of stiff biopolymers. Cells actively alter the ECM structure and mechanics by applying contractile forces, which allow them to sense other distant cells and regulate many tissue functions. We study theoretically the decay of cell-induced displacements in fibrous networks, while quantifying the changes in the elastic properties of the cell's local environment. We demonstrate that cell contraction induce an anisotropic elastic state, i.e., unequal principal elastic moduli, in the ECM which dictates the slow decay of displacements. These observations suggest a new mechanical mechanism through which cells can mechanically communicate over long distances, and may provide biomaterials design parameters to guide morphogenesis in tissue engineering. AbstractThe unique nonlinear mechanics of the fibrous extracellular matrix (ECM) facilitates long-range cell-cell mechanical communications that would be impossible on linear elastic substrates. Past research has described the contribution of two separated effects on the range of force transmission, including ECM elastic non-linearity and fiber alignment. However, the relation between these different effects is unclear, and how they combine to dictate force transmission range is still elusive. Here, we combine discrete fiber simulations with continuum modeling to study the decay of displacements induced by a contractile cell in fibrous networks. We demonstrate that fiber non-linearity and fiber reorientation both contribute to the Page 2 of 32 strain-induced anisotropy of the elastic moduli of the cell's local environment. This elastic anisotropy is a "lumped" parameter that governs the slow decay of the displacements, and it depends on the magnitude of applied strain, either an external tension or an internal contraction as a model of the cell. Furthermore, we show that accounting for artificially-prescribed elastic anisotropy dictates the displacement decay induced by a contracting cell. Our findings unify previous single effects into a mechanical theory that explains force transmission in fibrous networks. This work provides important insights into biological processes that involve the coordinated action of distant cells mediated by the ECM, such that occur in morphogenesis, wound healing, angiogenesis, and cancer metastasis. It may also provide design parameters for biomaterials to control force transmission between cells, as a way to guide morphogenesis in tissue engineering.In addition, we find in Fig. 3C that the data points of 2 / 1 for all types of fibers can be approximately fitted by a master curve if plotted versus the normalized strain, / crit . Here crit is the critical strain, a characteristic parameter of the network, in which 2 / 1 becomes smaller than 0.9, and the strain-induced elastic anisotropy is significant. The normalized strain, / crit , similar to the normalized cell contraction, / crit in cell contraction networks, is another "emergent" dimensionless p...

The ability of cells to sense distant neighbors, through the ECM, is a fundamental mechanism in various biological processes. In fibrin, we demonstrate how cell forces deform the matrix and allow for distant cells to be mechanically coupled by the aligned and dense fibers of the matrix. Such long-range coupling influences cellular morphology.

Cells sense, manipulate and respond to their mechanical microenvironment in a plethora of physiological processes, yet the understanding of how cells transmit, receive and interpret environmental cues to communicate with distant cells is severely limited due to lack of tools to quantitatively infer the complex tangle of dynamic cell-cell interactions in complicated environments. We present a computational method to systematically infer and quantify long-range cell-cell force transmission through the extracellular matrix (cell-ECM-cell communication) by correlating ECM remodeling fluctuations in between communicating cells and demonstrating that these fluctuations contain sufficient information to define unique signatures that robustly distinguish between different pairs of communicating cells. We demonstrate our method with finite element simulations and live 3D imaging of fibroblasts and cancer cells embedded in fibrin gels. While previous studies relied on the formation of a visible fibrous ‘band’ extending between cells to inform on mechanical communication, our method detected mechanical propagation even in cases where visible bands never formed. We revealed that while contractility is required, band formation is not necessary, for cell-ECM-cell communication, and that mechanical signals propagate from one cell to another even upon massive reduction in their contractility. Our method sets the stage to measure the fundamental aspects of intercellular long-range mechanical communication in physiological contexts and may provide a new functional readout for high content 3D image-based screening. The ability to infer cell-ECM-cell communication using standard confocal microscopy holds the promise for wide use and democratizing the method.

Cells sense, manipulate and respond to the mechanical properties of their microenvironment in a plethora of physiological processes, yet whether and how cells interpret environmental cues to communicate with distant cells is mostly unknown. We present a computational method to systematically infer and quantify long-range mechanical cell-cell communication through the extracellular matrix (cell-ECM-cell communication). By correlating local ECM remodeling fluctuations, in finite element simulations and live 3D imaging of fibroblasts embedded in fibrin gels, our method matched pairs of communicating cells with high accuracy, and identified whether and to what extent one cell was influenced by its communication partner. Using this method, we revealed that cells actively respond to the mechanical signal that they sense from the other cell, amplifying the formation of a dense fibrin band between the communicating cells. Our method sets the stage to measure the fundamental aspects of intercellular long-range mechanical communication in physiological contextes and may provide a new functional readout for high content 3D image-based screening.

A value of 200 mg/dL or more in the OGTT is not an indicator of perinatal complications.