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Studies of cellular mechanotransduction commonly use elastic substrates, whereas biological substrates are viscoelastic, exhibiting stress relaxation. Here, the authors show through computational modelling and experiments that viscoelastic substrates can stimulate cell spreading to a greater extent than purely elastic substrates with the same initial stiffness.

An atomic force microscope with a side-view fluorescent imaging path facilitates the direct correlation of mechanical force measurements with observations of changes in cell shape and cytoskeleton rearrangements resulting from the applied forces or during active generation of forces by the cell. The combined instrument could help lead to insights in understanding cell mechanics, contractility and cell-cell adhesion.

Hydrogels with faster stress relaxation enhance the spreading, proliferation, and osteogenic differentiation of embedded mesenchymal stem cells.

The spreading and differentiation of stem cells depends on the stiffness of the extracellular matrix. Now, experiments on human epidermal and mesenchymal stem cells cultured on substrates with covalently attached collagen fibres show that the cells sense and respond to the anchoring of the collagen fibres to the substrate.

It is now shown that cells migrate robustly on soft, viscoelastic substrates with fast stress relaxation using a migration mode marked by a rounded cell morphology and filopodia protrusions extending at the leading edge.

For mesenchymal stem cells (MSCs), matrix remodeling is associated with enhanced osteogenic differentiation. Here authors find that MSCs in viscoelastic hydrogels exhibit volume expansion during cell spreading, and greater volume expansion is associated with enhanced osteogenesis.

Forces resulting from global cell volume expansion and local cell contractions distort the basement membrane of an in vitro three-dimensional model of breast cancer, to promote collective cell invasion that precedes metastasis.

Hydrogels with improved mechanical properties, made by combining polymer networks with ionic and covalent crosslinks, should expand the scope of applications, and may serve as model systems to explore mechanisms of deformation and energy dissipation.

Blood platelets aggregate to form clots that prevent haemorrhage. Knowledge of single-platelet mechanics is scarce, however. Atomic force microscopy experiments now show that platelets contract rapidly on contact with fibrinogen, and adhere strongly to multiple fibrin polymers, enhancing the elasticity of clots. These findings are relevant to disorders of platelet function, such as thrombosis.

In a 3D model of breast cancer, a stiff extracellular matrix promotes a tumorigenic phenotype through broad changes in chromatin accessibility and in the activity of histone deacetylases and the transcription factor Sp1.

Structural changes mediated by advanced glycation end-products enhance extracellular matrix viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

The transcriptional regulator YAP is regarded as the universal mechanotransducer, largely from 2D culture studies. Here the authors show that in breast cancer patient tissues and cells in 3D culture, mechanical signals are transduced independently of YAP, questioning YAP as a therapeutic target.

Little is known about how a cell’s surroundings within tissue influence the mechanics of its division. Experiments on constrained dividing cells reveal that they create protrusive forces in order to undergo the shape changes required for division.

In order to metastasize, cancer cells must migrate through basement membranes and dense stroma, and proteases are thought to be required due to the confining nature of these matrices. Here the authors use synthetic matrices to show that cells can migrate through confining matrices using force generation alone, rather than protease degradation, if the matrices exhibit mechanical plasticity.

The mechanical properties of biomaterials affect cell growth through mechanotransduction signals. Here, hydrogels with fast stress relaxation were developed and showed increased cartilage matrix formation by cartilage cells compared to slow relaxation hydrogels.

A dysfunctional TRPV4–GSK3β pathway in osteoarthritic chondrocytes renders the cells unable to respond to viscoelastic changes in the extracellular matrix.

The DNA methylation of the promoter region of the oncogenic Yes-associated protein is reversibly regulated by the stiffness of the extracellular matrix.

Matrix elasticity, which has been shown to regulate the fate of mesenchymal stem cells in vitro, can also be harnessed to therapeutically control bone formation.

Malignant phenotypes in the mammary epithelium have been correlated to increases in extracellular matrix stiffness. It is now shown that the effect of matrix stiffness in normal mammary epithelial cells can be offset by an increase in basement-membrane ligands and that both the stiffness and composition of the matrix are sensed by the β4 integrin. The results suggest that the relationship between matrix stiffness and composition is a more relevant predictor of breast-cancer progression.

The physical properties of biomaterials affect cell behaviour. Here, the authors investigate how stiffness and degradation of hydrogels affect signalling pathways that modulate the maintenance of stemness of neural progenitor cells.

This Perspective reviews the complementary developments in synthetic biology and biomaterials and discusses how convergence of these two fields creates a promising design strategy for the fabrication of tailored living materials for medicine and biotechnology.

Mechanical cues from the extracellular matrix (ECM) regulate cell fate and behaviour through cell–ECM mechanotransduction. Studies of cell–ECM mechanotransduction have largely focused on cells cultured in 2D, and only recently have we begun to unravel how these processes occur in 3D — a context native to many cells in vivo.

Hydrogels are used to mimic cells’ local environment, enabling the study of cellular responses to biochemical and mechanical cues. Here, Blache et al. discuss the challenges of creating hydrogels for mechanobiology studies and how they can be used to analyse cell behaviour in the context of mechanobiological processes and harnessed to create regenerative therapies.

This Review explores the role of viscoelasticity of tissues and extracellular matrices in cell–matrix interactions and mechanotransduction and the potential utility of viscoelastic biomaterials in regenerative medicine.