Adhesion Dynamics Research Articles

Disturbance Observer-Based Tracking Control of High-Speed Trains Under Adhesion Dynamics

As the anti-skid control and speed tracking control of high-speed trains (HSTs) are interrelated and mutually constrained, it is very challenging to achieve simultaneous tracking of speed and slip ratio. In this paper, it is proposed for the first time that when the traction braking force has been limited to a reasonable range by the adhesion anti-skid condition, the high-precision tracking of the position and velocity curves of HSTs can be achieved, and the tracking error of the slip ratio is acceptable. Firstly, a novel modelling of the adhesion dynamics of HSTs under realistic gusts of wind disturbance is developed, and a model based on strict feedback is obtained by linearising the feedback for high-order non-linear systems. Then, this paper first presents the design scheme of fast terminal sliding mode controller based on disturbance observer for HSTs, which can ensure the anti-disturbance performance and accurate tracking of HSTs. Finally, an example is used to verify the validity of the results. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Note to Practitioners</i> —The actual traction/braking force of HSTs is provided by adhesion, and the existing literature on slip ratio tracking essentially sacrifices the tracking performance of the traction/braking system to meet the anti-skid requirements, while considering velocity and position tracking alone may leave the train in an undesired condition such as “idling” or “skidding”. This paper seeks to achieve high accuracy tracking of velocity and position profiles of HSTs under restricting the slip ratio to a reasonable range, which is expected to be an effective method for train tracking controller design. To avoid discomfort to passengers, nonlinearities dynamics are considered and an anti-disturbance controller is designed to compensate the impact of natural wind disturbances. To enhance the practicality, feedback linearization is introduced to reduce the complexity of the controller implementation. The designed fast terminal sliding mode controller also avoids jitter and singularity problems and obtains finite time stability. The stability analysis and numerical simulation have confirmed the effectiveness of the proposed scheme, which still needs to be verified by experiments in the future.

Abstract 1276: Kindlin-2: a novel target of Parkin regulating cancer metastasis

Abstract Although targeted therapies in prostate cancer have clinically shown successful outcomes, resistance to these therapies and acquisition of lineage plasticity pose challenges for fully treating prostate cancer. Among several microscopic perspectives to solve these obstacles, much evidence has emerged indicating that mitochondria dynamics are closely associated with tumor metastasis and tumor progression in various types of cancer. The E3 ubiquitin ligase Parkin is associated with PINK1-mediated mitophagy, allowing cells to control mitochondria damages and generate the needed energy to survive in harsh physiological conditions. Interestingly, we found that Parkin potentially ubiquitinates proteins independently of PINK1-associated mitophagy. By SALIC analysis, we found that K681 and K582 of Kindlin-2 is one of the potential ubiquitination sites by Parkin in prostate cancer cells. Kindlin-2 is a cytoskeletal membrane protein and is a component of the focal adhesion complex. Computational modeling suggested that N-terminal region of Kindlin-2 binds to Parkin, with K581 and K582 of Kindlin-2 exposed outside for ubiquitination. Our studies showed that Kindlin-2 is ubiquitinated and degraded by wild-type Parkin but not by the catalytic site, C431S, mutant Parkin. Furthermore, K581A and K582A mutant Kindlin-2 did not exhibit poly-ubiquitination under conditions of Parkin overexpression. Surprisingly, in our immunofluorescence study, Kindlin-2 was recruited to the mitochondria and co-localized with Parkin. From a mitochondrial functional perspective, wild-type Kindlin-2 reduced mitochondria dynamics, whereas mutant Kindlin-2 didn’t in the presence of Parkin. This suggests that the cytoskeletal protein Kindlin-2 might play a role in mitochondrial dynamics that mediates tumor metastasis. Wild-type Kindlin-2 reduced both focal adhesion generation and decay, unlike mutant Kindlin-2 under Parkin-induced condition. Additionally, this pattern was observed in the single cell lamellipodia dynamics through live cell imaging. 2D and 3D cell invasive assays supported the evidence that Parkin decreases tumor metastatic potential by ubiquitinating Kindlin-2 and regulating mitochondria and focal adhesion dynamics. Our findings indicate that Parkin reduces tumor metastatic potential by ubiquitinating Kindlin-2 and demonstrate the possibility as a therapeutic agent for advanced and immune suppressive tumors. Furthermore, Parkin could be a promising agent for Parkin suppressed tumor patients in line with personalized cancer therapy development. Citation Format: Minjeong Yeon, Irene Bertolini, Dario C. Altieri. Kindlin-2: a novel target of Parkin regulating cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1276.

Focal adhesions contain three specialized actin nanoscale layers

Focal adhesions (FAs) connect inner workings of cell to the extracellular matrix to control cell adhesion, migration and mechanosensing. Previous studies demonstrated that FAs contain three vertical layers, which connect extracellular matrix to the cytoskeleton. By using super-resolution iPALM microscopy, we identify two additional nanoscale layers within FAs, specified by actin filaments bound to tropomyosin isoforms Tpm1.6 and Tpm3.2. The Tpm1.6-actin filaments, beneath the previously identified α-actinin cross-linked actin filaments, appear critical for adhesion maturation and controlled cell motility, whereas the adjacent Tpm3.2-actin filament layer beneath seems to facilitate adhesion disassembly. Mechanistically, Tpm3.2 stabilizes ACF-7/MACF1 and KANK-family proteins at adhesions, and hence targets microtubule plus-ends to FAs to catalyse their disassembly. Tpm3.2 depletion leads to disorganized microtubule network, abnormally stable FAs, and defects in tail retraction during migration. Thus, FAs are composed of distinct actin filament layers, and each may have specific roles in coupling adhesions to the cytoskeleton, or in controlling adhesion dynamics.

The ER tether VAPA is required for proper cell motility and anchors ER-PM contact sites to focal adhesions.

Cell motility processes highly depend on the membrane distribution of Phosphoinositides, giving rise to cytoskeleton reshaping and membrane trafficking events. Membrane contact sites serve as platforms for direct lipid exchange and calcium fluxes between two organelles. Here, we show that VAPA, an ER transmembrane contact site tether, plays a crucial role during cell motility. CaCo2 adenocarcinoma epithelial cells depleted for VAPA exhibit several collective and individual motility defects, disorganized actin cytoskeleton and altered protrusive activity. During migration, VAPA is required for the maintenance of PI(4)P and PI(4,5)P2 levels at the plasma membrane, but not for PI(4)P homeostasis in the Golgi and endosomal compartments. Importantly, we show that VAPA regulates the dynamics of focal adhesions (FA) through its MSP domain, is essential to stabilize and anchor ventral ER-PM contact sites to FA, and mediates microtubule-dependent FA disassembly. To conclude, our results reveal unknown functions for VAPA-mediated membrane contact sites during cell motility and provide a dynamic picture of ER-PM contact sites connection with FA mediated by VAPA.

Cell adhesion and actin dynamics factors promote axonal extension and synapse formation in transplanted Drosophila photoreceptor cells.

Vision is formed by the transmission of light stimuli to the brain through axons extending from photoreceptor cells. Damage to these axons leads to loss of vision. Despite research on neural circuit regeneration through transplantation, achieving precise axon projection remains challenging. To achieve optic nerve regeneration by transplantation, we employed the Drosophila visual system. We previously established a transplantation method for Drosophila utilizing photoreceptor precursor cells extracted from the eye disc. However, little axonal elongation of transplanted cells into the brain, the lamina, was observed. We verified axonal elongation to the lamina by modifying the selection process for transplanted cells. Moreover, we focused on N-cadherin (Ncad), a cell adhesion factor, and Twinstar (Tsr), which has been shown to promote actin reorganization and induce axon elongation in damaged nerves. Overexpression of Ncad and tsr promoted axon elongation to the lamina, along with presynaptic structure formation in the elongating axons. Furthermore, overexpression of Neurexin-1 (Nrx-1), encoding a protein identified as a synaptic organizer, was found to not only promote presynapse formation but also enhance axon elongation. By introducing Ncad, tsr, and Nrx-1, we not only successfully achieved axonal projection of transplanted cells to the brain beyond the retina, but also confirmed the projection of transplanted cells into a deeper ganglion, the medulla. The present study offers valuable insights to realize regeneration through transplantation in a more complex nervous system.

Curing Kinetics of Epoxy Adhesive by Non-Isothermal DSC

Non-isothermal DSC has been used to investigate the curing kinetics of epoxy adhesives (DGEBA-cycloaliphatic amine). The epoxy samples were scanned on DSC with five heating rates (5°C/min, 7.5°C/min, 10°C/min, 12.5°C/min, and 15°C/min). The curing kinetics were obtained through ASTM standards E2890 and E698 (the Ozawa and Kissinger methods). The kinetic parameters obtained include Ea (activation energy), A (pre-exponential factor), and n (reaction order). The activation energy calculated from the Kissinger and Ozawa method was slightly different but insignificant. The reaction rate (dα/dt) and degree of curing/conversion (α) relationship towards temperature (T), and time (t) was also investigated. The curing process's reaction rate (dα/dt) has maximum value; it can no longer increase after a specific conversion rate (α).

Osiris17 is essential for stable integrin localization and function during insect wing epithelia remodeling

The dynamic adhesion between cells and their extracellular matrix is essential for the development and function of organs. During insect wing development, two epithelial sheets contact each other at their basal sites through the interaction of βPS integrins with the extracellular matrix. We report that Osiris17 contributes to the maintenance of βPS integrins localization and function in developing wing of Drosophila and locust. In flies with reduced Osiris17 expression the epithelia sheets fail to maintain the integrity of basal cytoplasmic junctional bridges and basal adhesion. In contrast to the continuous basal integrin localization in control wings, this localization is disrupted during late stages of wing development in Osiris17 depleted flies. In addition, the subcellular localization revealed that Osiris17 co-localizes with the endosomal markers Rab5 and Rab11. This observation suggests an involvement of Osiris17 in endosomal recycling of integrins. Indeed, Osiris17 depletion reduced the numbers of Rab5 and Rab11 positive endosomes. Moreover, overexpression of Osiris17 increased co-localization of Rab5 and βPS integrins and partially rescued the detachment phenotype in flies with reduced βPS integrins. Taken together, our data suggest that Osiris17 is an endosome related protein that contributes to epithelial remodeling and morphogenesis by assisting basal integrins localization in insects.

Dynamic adhesion and contractile assay with two-state micro-pattern

Dynamic adhesion and contractile assay with two-state micro-pattern

Drebrin is Required for Myosin-facilitated Actin Cytoskeletal Remodeling during Pulmonary Alveolar Development.

Alveolar septation increases gas-exchange surface area and requires coordinated cytoskeletal rearrangement in lung fibroblasts (LFs) to balance the demands of contraction and cell migration. We hypothesized that DBN (drebrin), a modulator of the actin cytoskeleton in neuronal dendrites, regulates the remodeling of the LF cytoskeleton. Using mice bearing a transgelin-Cre-targeted deletion of Dbn in pulmonary fibroblasts and pericytes, we examined alterations in alveolar septal outgrowth, LF spreading and migration, and actomyosin function. The alveolar surface area and number of alveoli were reduced, whereas alveolar ducts were enlarged, in mice bearing the dbn deletion (DBNΔ) compared with their littermates bearing only one dbn-Flox allele (control). Cultured DBNΔ LFs were deficient in their responses to substrate rigidity and migrated more slowly. Drebrin was abundant in the actin cortex and lamella, and the actin fiber orientation was less uniform in lamella of DBNΔ LFs, which limited the development of traction forces and altered focal adhesion dynamics. Actin fiber orientation is regulated by contractile NM2 (nonmuscle myosin-2) motors, which help arrange actin stress fibers into thick ventral actin stress fibers. Using fluorescence anisotropy, we observed regional intracellular differences in myosin regulatory light chain phosphorylation in control LFs that were altered by dbn deletion. Using perturbations to induce and then release stalling of NM2 on actin in LFs from both genotypes, we made predictions explaining how DBN interacts with actin and NM2. These studies provide new insight for diseases such as emphysema and pulmonary fibrosis, in which fibroblasts inappropriately respond to mechanical cues in their environment.

Blocking GPR15 Counteracts Integrin-dependent T Cell Gut Homing in Vivo.

The G protein coupled receptor GPR15 is expressed on and functionally important for T cells homing to the large intestine. However, the precise mechanisms by which GPR15 controls gut homing have been unclear. Thus, we aimed to elucidate these mechanisms as well as to explore the potential of targeting GPR15 for interfering with T cell recruitment to the colon in inflammatory bowel disease [IBD]. We used dynamic adhesion and transmigration assays, as well as a humanised in vivo model of intestinal cell trafficking, to study GPR15-dependent effects on gut homing. Moreover, we analysed GPR15 and integrin expression in patients with and without IBD, cross-sectionally and longitudinally. GPR15 controlled T cell adhesion to MAdCAM-1 and VCAM-1 upstream of α4β7 and α4β1 integrin, respectively. Consistently, high co-expression of these integrins with GPR15 was found on T cells from patients with IBD, and GPR15 also promoted T cell recruitment to the colon in humanised mice. Anti-GPR15 antibodies effectively blocked T cell gut homing in vitro and in vivo. In vitro data, as well as observations in a cohort of patients treated with vedolizumab, suggest that this might be more effective than inhibiting α4β7. GPR15 seems to have a broad, but organ-selective, impact on T cell trafficking and is therefore a promising target for future therapy of IBD. Further studies are needed.

Comparison between cure kinetics by means of dynamic rheology and DSC of formaldehyde-based wood adhesives

ABSTRACT Comparative analysis of the chemical and rheological curing kinetics of formaldehyde-based wood adhesives is crucial for assessing their respective performance. Differential scanning calorimetry (DSC) and rheometry are the conventional techniques used for monitoring the curing processes leading to crosslinking polymerization of the adhesives. However, the direct comparison of these techniques is inappropriate due to the intrinsic differences in their underlying procedures. To address this challenge, the two adhesive samples were sequentially cured, firstly with rheometry and followed by DSC. The observed higher curing degree in the subsequent DSC procedure underpins the incomplete curing of the samples during initial rheometry. Furthermore, the comparative assessment of the activation energies, molar ratios, and active groups of the two adhesives highlights the importance of the pre-exponential factor in addition to the activation energies, as it attributes to the probability of active groups coinciding at the appropriate spatial arrangement.

Cyclophilin A is a ligand for RAGE in thrombo-inflammation.

Cyclophilin A (CyPA) induces leucocyte recruitment and platelet activation upon release into the extracellular space. Extracellular CyPA therefore plays a critical role in immuno-inflammatory responses in tissue injury and thrombosis upon platelet activation. To date, CD147 (EMMPRIN) has been described as the primary receptor mediating extracellular effects of CyPA in platelets and leucocytes. The receptor for advanced glycation end products (RAGE) shares inflammatory and prothrombotic properties and has also been found to have similar ligands as CD147. In this study, we investigated the role of RAGE as a previously unknown interaction partner for CyPA. Confocal imaging, proximity ligation, co-immunoprecipitation, and atomic force microscopy were performed and demonstrated an interaction of CyPA with RAGE on the cell surface. Static and dynamic cell adhesion and chemotaxis assays towards extracellular CyPA using human leucocytes and leucocytes from RAGE-deficient Ager-/- mice were conducted. Inhibition of RAGE abrogated CyPA-induced effects on leucocyte adhesion and chemotaxis in vitro. Accordingly, Ager-/- mice showed reduced leucocyte recruitment and endothelial adhesion towards CyPA in vivo. In wild-type mice, we observed a downregulation of RAGE on leucocytes when endogenous extracellular CyPA was reduced. We furthermore evaluated the role of RAGE for platelet activation and thrombus formation upon CyPA stimulation. CyPA-induced activation of platelets was found to be dependent on RAGE, as inhibition of RAGE, as well as platelets from Ager-/- mice showed a diminished activation and thrombus formation upon CyPA stimulation. CyPA-induced signalling through RAGE was found to involve central signalling pathways including the adaptor protein MyD88, intracellular Ca2+ signalling, and NF-κB activation. We propose RAGE as a hitherto unknown receptor for CyPA mediating leucocyte as well as platelet activation. The CyPA-RAGE interaction thus represents a novel mechanism in thrombo-inflammation.

Programmable adhesion and morphing of protein hydrogels for underwater robots

Soft robots capable of efficiently implementing tasks in fluid-immersed environments hold great promise for diverse applications. However, it remains challenging to achieve robotization that relies on dynamic underwater adhesion and morphing capability. Here we propose the construction of such robots with designer protein materials. Firstly, a resilin-like protein is complexed with polyoxometalate anions to form hydrogels that can rapidly switch between soft adhesive and stiff non-adhesive states in aqueous environments in response to small temperature variation. To realize remote control over dynamic adhesion and morphing, Fe3O4 nanoparticles are then integrated into the hydrogels to form soft robots with photothermal and magnetic responsiveness. These robots are demonstrated to undertake complex tasks including repairing artificial blood vessel, capturing and delivering multiple cargoes in water under cooperative control of infrared light and magnetic field. These findings pave an avenue for the creation of protein-based underwater robots with on-demand functionalities.

Combining QCM-D with live-cell imaging reveals the impact of serum proteins on the dynamics of fibroblast adhesion on tannic acid-functionalised surfaces.

Nanocoatings based on plant polyphenols have been recently suggested as a potent strategy for modification of implant surfaces for enhancing host cell attachment and reducing bacterial colonisation. In this study we aimed to investigate how serum proteins impact the early adhesion dynamics of human gingival fibroblasts onto titanium surfaces coated with tannic acid (TA). Silicate-TA nanocoatings were formed on titanium and pre-conditioned in medium supplemented with 0, 0.1, 1 or 10% FBS for 1 hour. Dynamics of fibroblasts adhesion was studied using quartz crystal microbalance with dissipation (QCM-D). Time-lapse imaging was employed to assess cell area and motility, while immunofluorescence microscopy was used to examine cell morphology and focal adhesion formation. Our results showed that in serum-free medium, fibroblasts demonstrated enhanced and faster adhesion to TA coatings compared to uncoated titanium. Increasing the serum concentration reduced cell adhesion to nanocoatings, resulting in nearly complete inhibition at 10% FBS. This inhibition was not observed for uncoated titanium at 10% FBS, although cell adhesion was delayed and progressed slower compared to serum-free conditions. In addition, 1% FBS dramatically reduced cell adhesion on uncoated titanium. We revealed a positive relationship between changes in dissipation and changes in cell spreading area, and a negative relationship between dissipation and cell motility. In conclusion, our study demonstrated that serum decreases fibroblasts interaction with surfaces coated with TA in a concentration dependent manner. This suggests that controlling serum concentration can be used to regulate or potentially prevent fibroblasts adhesion onto TA-coated titanium surfaces.

Electric field-mediated adhesive dynamics of cells inside bio-functionalised microchannels offers important cues for active control of cell-substrate adhesion.

Adhesive dynamics of cells plays a critical role in determining different biophysical processes orchestrating health and disease in living systems. While the rolling of cells on functionalised substrates having similarity with biophysical pathways appears to be extensively discussed in the literature, the effect of an external stimulus in the form of an electric field on the same remains underemphasized. Here, we bring out the interplay of fluid shear and electric field on the rolling dynamics of adhesive cells in biofunctionalised micro-confinements. Our experimental results portray that an electric field, even restricted to low strengths within the physiologically relevant regimes, can significantly influence the cell adhesion dynamics. We quantify the electric field-mediated adhesive dynamics of the cells in terms of two key parameters, namely, the voltage-altered rolling velocity and the frequency of adhesion. The effect of the directionality of the electric field with respect to the flow direction is also analysed by studying cellular migration with electrical effects acting both along and against the flow. Our experiment, on one hand, demonstrates the importance of collagen functionalisation in the adhesive dynamics of cells through micro channels, while on the other hand, it reveals how the presence of an axial electric field can lead to significant alteration in the kinetic rate of bond breakage, thereby modifying the degree of cell-substrate adhesion and quantifying in terms of the adhesion frequency of the cells. Proceeding further forward, we offer a simple theoretical explanation towards deriving the kinetics of cellular bonding in the presence of an electric field, which corroborates favourably with our experimental outcome. These findings are likely to offer fundamental insights into the possibilities of local control of cellular adhesion via electric field mediated interactions, bearing critical implications in a wide variety of medical conditions ranging from wound healing to cancer metastasis.

High-strength thermochromic and mechanochromic liquid-crystal elastomers with responsive shape memory and dynamic adhesion

Versatile CLCEs with a loosely crosslinking density were developed, which exhibit exceptional high mechanical performances and responsive functionalities including thermochromic, mechanochromic, shape memory, and dynamic adhesion behaviors.

Modeling of Electrostatic and Contact Interaction between Low-Velocity Lunar Dust and Spacecraft

The accumulation of highly adhesive dust on spacecraft presents a serious issue to hinder long-term extravehicular activity and the establishment of a permanent station on lunar surface. In contrast to the immediate physical damage caused by hypervelocity (&gt;1.0 km/s) impacts, this adhesion observed at low-velocity (0.01 to 100 m/s) collisions can more unobtrusively and mortally degenerate the performance of equipment. This paper proposes a theoretical model aimed at comprehensively analyzing the dynamics of adhesion and escape phenomena occurring during low-velocity impacts between charged dust particles and spacecrafts enveloped by a plasma sheath. The electrostatic force is modeled using the image multipole method, and contact force is calculated based on the adhesive–elastic–plastic theory. The results reveal that the implementation of a dielectric coating possessing both low permittivity and low interface energy can substantially reduce energy dissipation during collisions. However, the ultimate adhesion on the surface or escape from the sheath for low-velocity charged dust is dominated by the long-range electrostatic interaction rather than short-range contact interaction. Positively charged particles of smaller sizes demonstrate a greater propensity for surface adhesion in comparison to negatively charged particles of larger sizes. Counterintuitively, without additional dust removal techniques, modifying the properties of the dielectric coating does not effectively reduce the accumulation of dust, which can be merely accomplished by decreasing the spacecraft’s potential. The model presented in this study serves as a crucial step toward understanding the mechanism of lunar dust pollution.

Real-Time Monitoring of Cell Adhesion onto a Soft Substrate by a Graphene Impedance Biosensor.

Soft substrates are interesting for many applications, ranging from mimicking the cellular microenvironment to implants. Conductive electrodes on such substrates allow the realization of flexible, elastic, and transparent sensors. Single-layer graphene as a candidate for such electrodes brings the advantage that the active area of the sensor is transparent and conformal to the underlying substrate. Here, we overcome several challenges facing the routine realization of graphene cell sensors on a canonical soft substrate, namely, poly(dimethylsiloxane) (PDMS). We have systematically studied the effect of surface energy before, during, and after the transfer of graphene. Thus, we have identified a suitable support polymer, optimal substrate (pre)treatment, and an appropriate solvent for the removal of the support. Using this procedure, we can reproducibly obtain stable and intact graphene sensors on a millimeter scale on PDMS, which can withstand continuous measurements in cell culture media for several days. From local nanomechanical measurements, we infer that the softness of the substrate is slightly affected after the graphene transfer. However, we can modulate the stiffness using PDMS with differing compositions. Finally, we show that graphene sensors on PDMS can be successfully used as soft electrodes for real-time monitoring of the cell adhesion kinetics. The routine availability of single-layer graphene electrodes on a soft substrate with tunable stiffness will open a new avenue for studies, where the PDMS-liquid interface is made conducting with minimal alteration of the intrinsic material properties such as softness, flexibility, elasticity, and transparency.

Identification of the Axis β-Catenin-BTK in the Dynamic Adhesion of Chronic Lymphocytic Leukemia Cells to Their Microenvironment.

In the microenvironment, cell interactions are established between different cell types to regulate their migration, survival and activation. β-Catenin is a multifunctional protein that stabilizes cell-cell interactions and regulates cell survival through its transcriptional activity. We used chronic lymphocytic leukemia (CLL) cells as a cellular model to study the role of β-catenin in regulating the adhesion of tumor cells to their microenvironment, which is necessary for tumor cell survival and accumulation. When co-cultured with a stromal cell line (HS-5), a fraction of the CLL cells adhere to stromal cells in a dynamic fashion regulated by the different levels of β-catenin expression. In non-adherent cells, β-catenin is stabilized in the cytosol and translocates into the nucleus, increasing the expression of cyclin D1. In adherent cells, the level of cytosolic β-catenin is low but membrane β-catenin helps to stabilize the adhesion of CLL to stromal cells. Indeed, the overexpression of β-catenin enhances the interaction of CLL with HS-5 cells, suggesting that this protein behaves as a regulator of cell adhesion to the stromal component and of the transcriptional regulation of cell survival. Inhibitors that block the stabilization of β-catenin alter this equilibrium and effectively disrupt the support that CLL cells receive from the cross-talk with the stroma.

Adherens junctions as molecular regulators of emergent tissue mechanics.

Tissue and organ development during embryogenesis relies on the collective and coordinated action of many cells. Recent studies have revealed that tissue material properties, including transitions between fluid and solid tissue states, are controlled in space and time to shape embryonic structures and regulate cell behaviours. Although the collective cellular flows that sculpt tissues are guided by tissue-level physical changes, these ultimately emerge from cellular-level and subcellular-level molecular mechanisms. Adherens junctions are key subcellular structures, built from clusters of classical cadherin receptors. They mediate physical interactions between cells and connect biochemical signalling to the physical characteristics of cell contacts, hence playing a fundamental role in tissue morphogenesis. In this Review, we take advantage of the results of recent, quantitative measurements of tissue mechanics to relate the molecular and cellular characteristics of adherens junctions, including adhesion strength, tension and dynamics, to the emergent physical state of embryonic tissues. We focus on systems in which cell-cell interactions are the primary contributor to morphogenesis, without significant contribution from cell-matrix interactions. We suggest that emergent tissue mechanics is an important direction for future research, bridging cell biology, developmental biology and mechanobiology to provide a holistic understanding of morphogenesis in health and disease.