Capillary constrictions prime cancer cell tumorigenicity through PIEZO1.

Metastasis is responsible for most cancer-related deaths. However, only a fraction of circulating cancer cells succeed in forming secondary tumours, indicating that adaptive mechanisms during circulation play a part in dissemination. Here, we report that constriction during microcapillary transit triggers reprogramming of melanoma cells to a tumorigenic cancer stem cell-like state.

Constitutive lipid scramblase activity underpins mechanosensitive TMEM63 channelopathies.

In this issue of Neuron, Zheng et al. show that disease-causing mutations identified in human TMEM63B alter its lipid scrambling but not ion channel function. These mutations disrupt a putative hydrophobic latch that may regulate scramblase activity in response to membrane thinning.

Evaluating the roles of ion channels in cellular force sensing.

Mechanosensitive ion channels are found across all classes of life, suggesting that cellular force sensing is an ancient sense. In mammals, mechanosensitive ion channels are expressed in many cells and tissues, and disrupting their function can impact an array of physiological processes. The identification and characterisation of mammalian mechanosensitive ion channels has been driven by in vitro patch-clamp electrophysiology studies.

The mechanosensitive channel ELKIN1 regulates cellular adaptations to simulated microgravity.

In conditions of microgravity the human body undergoes extensive alterations in physiological function. However, it has proven challenging to determine how these changes are mediated at the molecular and cellular level. Here, we investigated whether ELKIN1, a mechanically activated ion channel, regulates changes in cellular and molecular structures in conditions of simulated microgravity.

Re-evaluating TRP channel mechanosensitivity.

Transient receptor potential (TRP) channels are implicated in a wide array of mechanotransduction processes. However, a question remains whether TRP channels directly sense mechanical force, thus acting as primary mechanotransducers. We use several recent examples to demonstrate the difficulty in definitively ascribing mechanosensitivity to TRP channel subfamilies.

Touch sensation requires the mechanically gated ion channel ELKIN1.

Touch perception is enabled by mechanically activated ion channels, the opening of which excites cutaneous sensory endings to initiate sensation. In this study, we identify ELKIN1 as an ion channel likely gated by mechanical force, necessary for normal touch sensitivity in mice. Touch insensitivity in mice was caused by a loss of mechanically activated currents (MA currents) in around half of all sensory neurons activated by light touch (low-threshold mechanoreceptors).

Bacterial Virulence and Prevention for Human Spaceflight.

With the advancement in reusable rocket propulsion technology, space tourist trips into outer space are now becoming a possibility at a cost-effective rate. As such, astronauts will face a host of health-related challenges, particularly on long-duration space missions where maintaining a balanced healthy microbiome is going to be vital for human survival in space exploration as well as mission success. The human microbiome involves a whole list of micro-organisms that reside in and on the human host, and plays an integral role in keeping the human host healthy.

The dynamic nature of netrin-1 and the structural basis for glycosaminoglycan fragment-induced filament formation.

Netrin-1 is a bifunctional chemotropic guidance cue that plays key roles in diverse cellular processes including axon pathfinding, cell migration, adhesion, differentiation, and survival. Here, we present a molecular understanding of netrin-1 mediated interactions with glycosaminoglycan chains of diverse heparan sulfate proteoglycans (HSPGs) and short heparin oligosaccharides. Whereas interactions with HSPGs act as platform to co-localise netrin-1 close to the cell surface, heparin oligosaccharides have a significant impact on the highly dynamic behaviour of netrin-1.

Analysing Mechanically Evoked Currents at Cell-Substrate Junctions.

The precise study of mechanically activated ion channels requires a combination of electrophysiology to directly measure channel-mediated ionic flux and a means to apply meaningful mechanical stimuli to activate the channel. In metazoans, individual cells in vivo experience mechanical inputs at the cell-substrate interface where cells form connections to the local microenvironment. To study such processes in vitro, a technique is required where mechanical stimuli can be applied to cells via connections with an underlying substrate.

T cell cytoskeletal forces shape synapse topography for targeted lysis via membrane curvature bias of perforin.

Cytotoxic T lymphocytes (CTLs) lyse target cells by delivering lytic granules that contain the pore former perforin to the cytotoxic immunological synapse. Here, we establish that opposing cytoskeletal forces drive lytic granule polarization and simultaneously shape T cell synapse topography to enhance target perforation. At the cell rear, actomyosin contractility drives the anterograde movement of lytic granules toward the nucleus.

Testing 3D printed biological platform for advancing simulated microgravity and space mechanobiology research.

The advancement of microgravity simulators is helping many researchers better understanding the impact of the mechanically unloaded space environment on cellular function and disfunction. However, performing microgravity experiments on Earth, using simulators such as the Random Positioning Machine, introduces some unique practical challenges, including air bubble formation and leakage of growth medium from tissue culture flask and plates, all of which limit research progress. Here, we developed an easy-to-use hybrid biological platform designed with the precision of 3D printing technologies combined with PDMS microfluidic fabrication processes to facilitate reliable and reproducible microgravity cellular experiments.

Microgravity × Radiation: A Space Mechanobiology Approach Toward Cardiovascular Function and Disease.

In recent years, there has been an increasing interest in space exploration, supported by the accelerated technological advancements in the field. This has led to a new potential environment that humans could be exposed to in the very near future, and therefore an increasing request to evaluate the impact this may have on our body, including health risks associated with this endeavor. A critical component in regulating the human pathophysiology is represented by the cardiovascular system, which may be heavily affected in these extreme environments of microgravity and radiation.

The Diverse Physiological Functions of Mechanically Activated Ion Channels in Mammals.

Many aspects of mammalian physiology are mechanically regulated. One set of molecules that can mediate mechanotransduction are the mechanically activated ion channels. These ionotropic force sensors are directly activated by mechanical inputs, resulting in ionic flux across the plasma membrane.

From stretch to deflection: the importance of context in the activation of mammalian, mechanically activated ion channels.

The ability of cells to convert mechanical perturbations into biochemical information is an essential aspect of mammalian physiology. The molecules that mediate such mechanotransduction include mechanically activated ion channels, which directly convert mechanical inputs into electrochemical signals. The unifying feature of these channels is that their open probability increases with the application of a mechanical input.

Heterotypic tumor models through freeform printing into photostabilized granular microgels.

The tissue microenvironment contains a complex assortment of multiple cell types, matrices, and vessel structures, which is difficult to reconstruct in vitro. Here, we demonstrate model tumor microenvironments formed through direct writing of vasculature channels and tumor cell aggregates, within a cell-laden microgel matrix. Photocrosslinkable microgels provide control over local and global mechanics, while enabling the integration of virtually any cell type.

Modulating the Mechanical Activation of TRPV4 at the Cell-Substrate Interface.

Ion channels activated by mechanical inputs are important force sensing molecules in a wide array of mammalian cells and tissues. The transient receptor potential channel, TRPV4, is a polymodal, nonselective cation channel that can be activated by mechanical inputs but only if stimuli are applied directly at the interface between cells and their substrate, making this molecule a context-dependent force sensor. However, it remains unclear how TRPV4 is activated by mechanical inputs at the cell-substrate interface, which cell intrinsic and cell extrinsic parameters might modulate the mechanical activation of the channel and how mechanical activation differs from TRPV4 gating in response to other stimuli.

TMEM87a/Elkin1, a component of a novel mechanoelectrical transduction pathway, modulates melanoma adhesion and migration.

Mechanoelectrical transduction is a cellular signalling pathway where physical stimuli are converted into electro-chemical signals by mechanically activated ion channels. We describe here the presence of mechanically activated currents in melanoma cells that are dependent on TMEM87a, which we have renamed Elkin1. Heterologous expression of this protein in PIEZO1-deficient cells, that exhibit no baseline mechanosensitivity, is sufficient to reconstitute mechanically activated currents.

Modeling the Impact of Microgravity at the Cellular Level: Implications for Human Disease.

A lack of gravity experienced during space flight has been shown to have profound effects on human physiology including muscle atrophy, reductions in bone density and immune function, and endocrine disorders. At present, these physiological changes present major obstacles to long-term space missions. What is not clear is which pathophysiological disruptions reflect changes at the cellular level versus changes that occur due to the impact of weightlessness on the entire body.

TACAN Is an Ion Channel Involved in Sensing Mechanical Pain.

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elusive. Here we report identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain.

Mechanomics Approaches to Understand Cell Behavior in Context of Tissue Neogenesis, During Prenatal Development and Postnatal Healing.

represents the natural progression of knowledge at the intersection of mechanics and biology with the aim to codify the role of mechanical environment on biological adaptation. Compared to the mapping of the human genome, the challenge of mapping the mechanome remains unsolved. Solving this grand challenge will require both top down and bottom up R&D approaches using experimental and computational tools to visualize and measure adaptation as it occurs.

Mapping the Mechanome-A Protocol for Simultaneous Live Imaging and Quantitative Analysis of Cell Mechanoadaptation and Ingression.

Mechanomics, the mechanics equivalent of genomics, is a burgeoning field studying mechanical modulation of stem cell behavior and lineage commitment. Analogous to mechanical testing of a living material as it adapts and evolves, mapping of the mechanome necessitates the development of new protocols to assess changes in structure and function in live stem cells as they adapt and differentiate. Previous techniques have relied on imaging of cellular structures in fixed cells and/or live cell imaging of single cells with separate studies of changes in mechanical and biological properties.

PIEZO1-Mediated Currents Are Modulated by Substrate Mechanics.

PIEZO1 is a mammalian mechanically activated channel that has recently been shown to provide instructive cues during neuronal specification, texture sensing, and cell migration where mechanical inputs arise at the interface between the cells and their substrate. Here, we have investigated whether the mechanical properties of the substrate alone can modulate PIEZO1 activity, in response to exogenously applied stimuli, using elastomeric pillar arrays as force transducers. This methodology enables application of mechanical stimuli at cell-substrate contact points by deflecting individual pili.

Collagen Organization Within the Cartilage of Trpv4 Mice Studied with Two-Photon Microscopy and Polarized Second Harmonic Generation.

The polymodal channel TRPV4 has been shown to regulate development and maintenance of cartilage. Here we investigate whether TRPV4 activity regulates the early deposition and structure of collagen matrix in the femoral head cartilage by comparing the 3D morphology and the sub-micrometer organization of the collagen matrix between wild type and Trpv4 mice pups four to five days old. Two-photon microscopy can be used to conduct label-free imaging of cartilage, as collagen generates a second harmonic signal (second harmonic generation [SHG]) under pulsed infrared excitation.

Analysis of Mechanically Activated Ion Channels at the Cell-Substrate Interface: Combining Pillar Arrays and Whole-Cell Patch-Clamp.

Ionic currents can be evoked by mechanical inputs applied directly at the cell-substrate interface. These ionic currents are mediated by mechanically activated ion channels, where the open probability increases with increasing mechanical input. In order to study mechanically activated ion channels directly at the interface between cells and their environment, we have developed a technique to simultaneously monitor ion channel activity whilst stimuli are applied via displacement of cell-substrate contacts.

A 3D Magnetic Hyaluronic Acid Hydrogel for Magnetomechanical Neuromodulation of Primary Dorsal Root Ganglion Neurons.

Neuromodulation tools are useful to decipher and modulate neural circuitries implicated in functions and diseases. Existing electrical and chemical tools cannot offer specific neural modulation while optogenetics has limitations for deep tissue interfaces, which might be overcome by miniaturized optoelectronic devices in the future. Here, a 3D magnetic hyaluronic hydrogel is described that offers noninvasive neuromodulation via magnetomechanical stimulation of primary dorsal root ganglion (DRG) neurons.