Cell biology

Substrate-rigidity-dependent microtubule acetylation is now shown to be triggered by mechanosensing at focal adhesions, and in turn controls the mechanosensitivity of Yes-associated protein (YAP) translocation, focal adhesion distribution, actomyosin contractility and cell migration.

The role of actin/tropomyosin filaments in the assembly of cell–substrate adhesions has been investigated and it is now shown by cryo-electron tomography that they are essential for adhesion assembly and also regulate mechanosensing, matrix remodelling and transformation of cells towards a cancer phenotype.

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.

It is now revealed, using cell cultures and in silico models, that weakening intercellular contacts is a fundamental process essential for switching from extensile to contractile tissue behaviour.

Molecular motors destroy a microtubule lattice as they walk on it, but it is now shown that a self-healing process incorporates new dimers in the damaged regions and prevents microtubule disassembly.

Extrusion-based bioprinting has been shown to rapidly and reproducibly generate kidney organoids from a cell-only paste, with the number and maturation of functional units within the kidney tissue capable of being further improved by bioprinting tissue sheets.

The mechanism of stress fibre assembly by the coalescence of actin filaments in the cell cortex has now been found to account for the transmission of mechanical forces throughout the entire cell along stress fibres.

This Review highlights approaches used to generate somatic cell-derived organoids for modelling epithelial tissue to understand disease progression and how they are employed in preclinical drug screening.

The polarity of primary hepatocytes has now been shown to be inducible at the single-cell level by passive artificial micro-niches, indicating that the early development of polarity occurs largely independently of the types and response of the neighbouring cells.

Receptor tyrosine kinase (RTK)–Ras oncogenes have now been shown to reprogram normal primary human and mouse cells into tumour precursors by empowering cellular mechanotransduction, in a process requiring permissive extracellular-matrix rigidity and intracellular YAP/TAZ/Rac mechanical signalling sustained by activated oncogenes.

As in haematopoietic cells and platelets, agonist binding to protease-activated receptors PAR1 and PAR2 in non-haematopoietic cells also triggers signalling pathways that lead to α₅β₁-integrin-mediated cell adhesion.

A mechanism of cell response to localized tension shows that syndecan-4 synergizes with EGFR to elicit a mechanosignalling cascade that leads to adaptive cell stiffening through PI3K/kindlin-2 mediated integrin activation.

Lamin mutations responsible for muscular dystrophy are shown to reduce nuclear envelope stability, resulting in mechanically induced nuclear envelope rupture, DNA damage and activation of DNA damage response pathways that lead to muscle cell death. Preventing nuclear envelope damage by reducing cytoskeletal forces on the nucleus improves muscle fibre health and function.

Anticancer drugs such as Taxol can affect microtubule dynamics and organization in cells. Direct visualization of the action of such drugs has shown that they can trigger local and cooperative changes in microtubule lattice and induce formation of stable microtubule regions that promote rescues.

The generation of aligned extracellular matrices by fibroblasts is shown to depend on cell reorientation following collision, leading to closer alignment of the cells’ long axes. This cell collision guidance depends on the transcription factor TFAP2C and localized regulation of actomyosin contractility.

A range of cancer cell types are shown to lack rigidity-sensing due to alteration in specific cytoskeletal sensor proteins and this sensing ability can be reversed from a transformed to a rigidity-dependent growth state by the sensor proteins, resulting in restoration of contractility and adhesion.

Integrin-mediated adhesions required for cell spreading and growth have now been shown, using super-resolution microscopy, to form on fibrous matrices through the dense assembly of integrins in nanoclusters that contain both ligand-bound and unliganded integrins.

A RAB5A-mediated, epidermal growth factor-dependent activation of endosomal ERK1/2 is identified as a key molecular route for a solid-to-liquid-like phase transition, sufficient to overcome kinetic and proliferation arrest in normal mammary epithelial assemblies and to promote collective invasion in breast carcinoma.

High-spatial-resolution mechanical imaging reveals that intracellular forces generate cellular nanoscale stiffness patterns.

The mechanism of cytokinetic failure in the migrating zebrafish epicardium leading to multinucleated cells is shown to be driven by the interaction of the cytokinetic ring and the extracellular matrix through adhesion reinforcement by high traction forces.

Crosstalk between microtubules and the actin cytoskeleton of cells is important in elucidating integrin-mediated adhesion and mechanotransduction. It is now shown that microtubule-mediated control of focal adhesions and podosomes occurs via KANK family proteins.

An intermediate affinity state of integrins on platelets has been identified to be induced by a biomechanical activation pathway and is shown to promote platelet aggregation.

Biomaterials have been utilized widely to study cellular mechanotransduction. This Review discusses how cells respond to mechanical cues elicited by a range of biomaterial characteristics via YAP/TAZ mechanosensitive transcriptional factor activity.

Physical confinement of macrophages is shown to down-regulate pro-inflammatory gene transcription, lowering pro-inflammatory macrophage activation and phagocytic potential.

The mechanism by which cell geometry regulates cell signalling is reported to be modulated by lipid rafts within the plasma membrane, which are now shown to be responsible for geometry-dependent mesenchymal stem cell differentiation.

Integrins play an important role in the adhesion of cells to their matrix. Here, the authors investigate how fibroblasts respond to mechanical loads, at the onset of cell adhesion to fibronectin, in distinct phases that are modulated by integrins.

Tissue mimics are of great interest in understanding diseases. Here, organoids were developed that resemble polycystic kidney disease cysts and it was demonstrated how material environment and adhesion can affect cystogenesis and disease progression.

Epidermal growth factor receptor and its isoform HER2 are recruited to nascent cellular adhesion sites and play an important role in the rigidity sensing of cells on stiff substrates, this activity being dependent on Src-mediated phosphorylation.

Increased cellular expression of RAB5A, an important regulator of endocytic processes, brings epithelial cells from a jammed state to coordinated motion, and can facilitate wound closure, gastrulation and migration in constrained environments.

A porous microwell platform that generates large-scale arrays of microparticles with varying shape, size and modulus with high specificity shows applicability in anti-counterfeiting and cell-screening applications.

Local surface forces of physiological magnitudes can directly stretch chromatin and induce transcription upregulation in a living cell.

N-cadherin can alter how the stiffening extracellular microenvironment is interpreted by mesenchymal stem cells, leading to subsequent changes in downstream cell proliferation and differentiation.

Many nanomaterials can induce cell autophagy, which can be either a concern in most in vivo situations or a benefit when exploited in cancer therapeutics. A family of short synthetic peptides that have a varied affinity to lanthanide oxide and lanthanide-based upconversion nanocrystals are now used to tune the degree of interaction between cells and nanocrystals, and thus the nanocrystals’ autophagy-inducing activity.

The mechanical stresses within and between cells inside an advancing cellular monolayer are mapped experimentally. Cellular migration is found to be oriented in the direction of maximum principal stress indicating that cells collectively migrate to maintain minimal local intercellular shear stress.

Actin filaments are a principal component of the cell cytoskeleton. Using micropatterning methods, physical influences on the growth of highly ordered actin structures are investigated. The spatial organization of actin nucleation sites is discovered to play an important role in establishing the architecture of actin networks.