Abstract
The mechanical properties of the extracellular matrix (ECM)–a complex, 3D, fibrillar scaffold of cells in physiological environments–modulate cell behavior and can drive tissue morphogenesis, regeneration, and disease progression. For simplicity, it is often convenient to assume these properties to be time-invariant. In living systems, however, cells dynamically remodel the ECM and create time-dependent local microenvironments. Here, we show how cell-generated contractile forces produce substantial irreversible changes to the density and architecture of physiologically relevant ECMs–collagen I and fibrin–in a matter of minutes. We measure the 3D deformation profiles of the ECM surrounding cancer and endothelial cells during stages when force generation is active or inactive. We further correlate these ECM measurements to both discrete fiber simulations that incorporate fiber crosslink unbinding kinetics and continuum-scale simulations that account for viscoplastic and damage features. Our findings further confirm that plasticity, as a mechanical law to capture remodeling in these networks, is fundamentally tied to material damage via force-driven unbinding of fiber crosslinks. These results characterize in a multiscale manner the dynamic nature of the mechanical environment of physiologically mimicking cell-in-gel systems.
Highlights
The Extracellular Matrix (ECM) is a scaffolding medium that helps transmit mechanical signals among cells in cancer [1,2], fibrosis [3,4], vascular networks [5,6], and more generally, morphogenesis [7,8]
Our findings show that for mechanically active cells that exert dynamic forces onto the extracellular matrix, the physical properties of the surrounding environment that they sense are dynamic, and these dynamic properties should be taken into consideration in studies involving cell-matrix interactions, such as 3D traction force microscopy experiments in physiologically relevant environments
We explore remodeling by quantifying ECM dynamics in two physiologically relevant cellECM combinations cultured in 3D in vitro conditions
Summary
The Extracellular Matrix (ECM) is a scaffolding medium that helps transmit mechanical signals among cells in cancer [1,2], fibrosis [3,4], vascular networks [5,6], and more generally, morphogenesis [7,8]. The fibrillar nature and local architecture of the ECM can lead to directed cell migration [15], and increased density and alignment in the tumor stroma are correlated with more aggressive disease and worse prognosis in preclinical and clinical samples [16,17]. ECM remodeling through cell contractility is potentially a fundamental factor in tissue folding and shaping during development [18]. It is not clear, how ECM spatiotemporal evolution in living systems is controlled by cells to promote physiological and pathological states
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