Abstract
Cell-driven plastic remodeling of the extracellular matrix (ECM) is a key regulator driving cell invasion and organoid morphogenesis in 3D. While, mostly, the linear properties are reported, the nonlinear and plastic property of the used matrix is required for these processes to occur. Here, we report on the nonlinear and plastic mechanical properties of networks derived from collagen I, Matrigel, and related hybrid gels and link their mechanical response to the underlying collagen structure. We reveal the predominantly linear behavior of Matrigel over a wide range of strains and contrast this to the highly nonlinear and plastic response of collagen upon mechanical load. We show that the mechanical nonlinear response of collagen can be gradually diminished by enriching the network stepwise with Matrigel. This tunability results from the suppression of collagen polymerization in the presence of Matrigel, resulting in a collagen network structure with significant smaller mesh size and consequent contribution to the mechanical response. Thus, the nonlinear plastic properties and structure of the ECM is not simply the addition of two independent network types but depends on the exact polymerization conditions. The understanding of this interplay is key toward an understanding of the dependencies of cellular interactions with their ECM and sheds light on the nonlinear cell-ECM interaction during organogenesis.
Highlights
Within hybrid gels consisting of 1.3 mg/ml collagen and 50% Matrigel, the mean mesh size further reduces to 10 lm2, with distinctly shorter fibers
We contrast the opposing linear and nonlinear mechanical properties of Matrigel and collagen and emphasize the gradually changing nonlinear behavior of hybrid gels consisting of both components with varying stoichiometry
The plastic response of pure and crosslinked collagen with its concomitant strain softening can be described by the Mullins effect
Summary
Besides controlling the biochemical milieu, mechanosensing of the ECM by the cells has become an additional key regulator driving 3D cell invasion. Here, mainly the stiffness of the ECM was thought to be a crucial factor in guiding the outgrowth. Mostly in this context, stiffness is understood as the linear modulus of a gel, neglecting possible nonlinear or even plastic responses. Yet, recent studies have highlighted that, the nonlinear and plastic properties of the ECM are shown to sculpt the developing morphologies via pronounced fiber alignment. Explicitly, it is the plastic nature of the ECM that steers cellular migration in three-dimensional matrices. these nonlinear properties are becoming a major focus in materials research and still need to be fully unraveled. Hereby, the characteristic nonlinear strain stiffening and plastic behavior of collagen networks are of major interest. collagen networks polymerized at different temperatures exhibit comparable storage and loss moduli, their yield strain upon cyclic deformations differs drastically. Further, with increasing cycle number, a delay in the onset of strain stiffening can be observed. Mainly the stiffness of the ECM was thought to be a crucial factor in guiding the outgrowth.16,17 In this context, stiffness is understood as the linear modulus of a gel, neglecting possible nonlinear or even plastic responses.. Recent studies have highlighted that, the nonlinear and plastic properties of the ECM are shown to sculpt the developing morphologies via pronounced fiber alignment.. Recent studies have highlighted that, the nonlinear and plastic properties of the ECM are shown to sculpt the developing morphologies via pronounced fiber alignment.20 It is the plastic nature of the ECM that steers cellular migration in three-dimensional matrices.. We highlight the nonlinear mechanical response of Matrigel and collagen I gels by comparing the cycle-dependent load and contrast the observed strain stiffening of collagen to the predominantly linear stress response of Matrigel. It becomes apparent that collagen–Matrigel hybrid gels cannot be described solely as the sum of its components but need to be analyzed individually regarding their linear, nonlinear, and plastic properties
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