The role of extracellular matrix viscoelasticity in development and disease

Abstract

For several decades, research has studied the influence of the extracellular matrix (ECM) mechanical properties in cell response, primarily emphasising its elasticity as the main determinant of cell and tissue behaviour. However, the ECM is not purely elastic; it is viscoelastic. ECM viscoelasticity has now emerged as a major regulator of collective cell dynamics. This review highlights recent findings on the role of ECM viscoelasticity in development and pathology.

Keywords: Biological physics; Biophysics; Biotechnology; Cell biology; Diseases; Physics.

Fig. 1. Mechanical properties of materials and relevant mechanisms that regulate ECM viscoelasticity.

a Under a constant force, purely elastic materials deform instantly and maintain that deformation until the load is removed, at which point they immediately return to their original shape. Different from elastic materials, purely viscous materials undergo continuous deformation. Viscoelastic materials display an initial immediate response to force (elastic component) followed by an increase in the deformation over time (viscous component). Stress and strain colours are red and blue, respectively. b Under a constant force (black arrows), the deformation of a purely elastic matrix is time-independent: the matrix immediately deforms and returns to its initial shape when the force is applied and removed, respectively (top). Contrary to elastic matrices, viscoelastic matrices response changes with time: under a constant load, the deformation increases over time and they do not immediately return to their original shape once the load is removed (middle). Purely viscous matrices will continuously deform due to the force, and retain their deformed shape after the force is removed (bottom). c Creep test showing the deformation of a viscoelastic material in response to a constant force. The more viscoelastic the material is, the more it deforms over time under the load. d A stress relaxation test shows the evolution of the stress in the material in response to constant deformation. Purely elastic materials experience constant stress. In a deformed viscoelastic material, the stress decreases over time. The stress relaxation half-time (t_1/2) is defined as the time needed for the stress to reach half its initial value. The more viscoelastic material is, the faster the stress decreases and, therefore, the lower t_1/2 is. e Decreasing the molecular weight of the ECM components decreases the network connectivity and, therefore, increases ECM viscoelasticity, as it favours energy dissipation and fibre movements. f Purely elastic materials are typically crosslinked by covalent bonds (left), while viscoelastic materials usually contain weaker crosslinks such as ionic bonds (right) or physical entanglements that favour stress relaxation. g In viscoplastic materials, permanent deformations remain after the load is removed due to the breaking of bonds and the formation of new bonds. h During a creep test, viscoplastic materials do not return to their original shape and retain permanent deformations.

Fig. 2. The viscoelastic properties of the ECM regulate tissue response during development.

a Collagen fibres can be realigned by cells in the direction of the deformation, resulting in permanent, plastic deformations. b Breast organoids cultured in collagen gels undergo branching morphogenesis. Branch extension is mediated by plastic deformation of the matrix due to the cyclic pulling of cells on the matrix (t₁). This process leads to the alignment of collagen fibres in front of the branch, resulting in a strong enrichment of aligned collagen fibres along the branch as it extends (t₂). Black arrows represent the direction of the strain. c Intestinal organoids are unable to break symmetry in elastic matrices and grow as cysts. In contrast, intestinal organoids cultured in viscoelastic matrices form crypt-like structures containing stem cells (green) and Paneth cells (orange). d In purely elastic matrices, when a group of cells applies force to deform the matrix, the matrix resists with an equal force (top). In viscoelastic matrices, however, stresses gradually relax over time, facilitating cell groups to maintain the deformation and proceed with morphogenesis (bottom). e In an elastic matrix with photoinducible increase in viscoelasticity, a local increase in matrix viscoelasticity (yellow) increases intestinal organoid curvature and membrane tension, leading to YAP nuclear translocation and symmetry breaking.

Fig. 3. Distinct cellular responses to viscoelasticity in disease.

a Cancer cell spheroids cultured in purely elastic matrices grow but are unable to invade regardless of matrix stiffness. In viscoelastic matrices, cancer cells are able to break symmetry, undergo epithelial to mesenchymal transition and migrate into the matrix. Viscoelasticity and stiffness seem to have a synergistic effect, and these behaviours are enhanced in stiff, viscoelastic matrices. b The liver of non-alcoholic steatohepatitis (NASH) and type 2 diabetes mellitus (T2DM) patients has a similar stiffness but an increased viscoelasticity compared to healthy patients. This increase in viscoelasticity is due to the accumulation of advanced glycation end-products affecting the structure of the ECM, decreasing collagen fibre length and network homogeneity. This increase in viscoelasticity favours hepatocellular carcinoma progression. c Following vaccination, lymph node expansion is accompanied by an increase in viscoelasticity and a strong hyaluronic acid (HA) enrichment in the follicles. The immune response efficacy scales with lymph node expansion.