Mechanobiology

We are inviting submissions of articles on the role of mechanobiology in health and disease with the aim of publishing high quality research devoted to advance our understanding of mechanics shaping biological function. We are also happy to present a Collection of papers already published in our journal in this exciting field.

In this Review, Laura Martinez-Vidal et al. summarize current knowledge of factors affecting extracellular matrix (ECM) remodeling in the context of pathological mechanical changes to tissue properties. They focus on the importance of research on tissue stiffness to the development of diagnostic tools and therapies to treat urological disease.

Dessalles et al review the responses of vascular endothelial cells to mechanical forces exerted by both blood flow and physical contact with the basement membrane. Special attention is paid to how endothelial cells respond to multiple mechanical cues that are exerted simultaneously.

Ellefsen et al. monitor Piezo-dependent Calcium signals in live cells by TIRF and super-resolution microscopy and find that Ca²⁺ flickers localize to areas of high traction force. They show that Myosin II activity and MLCK are needed for the generation of Piezo Ca²⁺ signals and that Piezo1 channels are mobile in the plasma membrane.

Using microfluidic systems, Michalaki et al show that lymphatic endothelial cells exposed to wall shear stress orient in the direction perpendicular to flow and show increased nuclear FOXC2 levels in a manner dependent on E-selectin, a transmembrane adhesion protein. These data provide insights into how lymphatic vessels respond to local flow-mediated mechanical cues.

Huw Colin-York et al. use advanced microscopy techniques to show that the cortical actin network within a model mast cell line undergoes a series of reorganizational events at the basal interface during activation. They find that actin patterns co-localize with zones of Arp2/3 nucleation and myosin-II activity accompanies network reassembly.

Padhi et al. employ nanofibers with controlled structure and alignment as an extra-cellular matrix model, on which they study the exertion of forces from adherent fibroblasts. Identifying force exerting 3D perpendicular lateral protrusions, authors describe a mechanism which leads to the contraction of parallel, neighbouring fibers, and the forces needed to move and align the neighbouring fibers. These findings have relevance in understanding cancer-associated desmoplastic expansion.

Qin et al. show the involvement of Kindlin-2 in osteocyte mechanotransduction. They show Kindlin-2 mediates skeletal responses to mechanical stimulation through Smad 2/3 mediated inhibition of Sclerostin.

Arora, Hazra & Rakshit investigate the significance of complex conformations in force sensing. They found that protein complexes possess a distinct response to mechanical force compared to individual force sensors.

Hagiwara et al. investigate how spatio-temporally remodeled ECM alters the resistance force exerted on cells using microfabrication techniques, optical tweezers and mathematical models. The authors demonstrate that active remodeling of the microenvironment modulates force exerted on cells by the ECM, contributing to directionality and pattern formation.

Fujii et al. investigate the stiffness of cells in ascidian embryos from the fertilised egg to the stage before gastrulation. They find two types of cell stiffening, occurring during cell division and in the interphase, the latter of which is associated with the Rho kinase pathway. They conclude that the mechanical properties of early embryonic cells are regulated specifically at the single cell level.

Ripamonti et al. provide mechanistic insight into the contribution of individual Paxillin LIM domains in targeting and maintaining the structural integrity of focal adhesions (FAs). They show that mechanical coupling of paxillin in the FA to the plasma membrane or integrin is important for FA stability and integrin-talin linkage.

Zonderland et al discover that fibroblasts and mesenchymal stromal cells (MSCs) differ in their response to bFGF when grown on microfibrillar substrates. They find that MSCs cultured on this substrate leads to reduced FGFR levels, as does inhibition of actomyosin contractility or MRT/SRF, suggesting mechanosensitive control of FGFR.

Mechanosensitive Piezo1 channels transduce mechanical stimuli into electrochemical signals. Jiang et al. show that due to the bending rigidity of the membrane, the overlap of neighboring Piezo1 footprints produces a flattening of the Piezo1 footprints and a cation-selective conducting pore. This study suggests that the clustering of Piezo1 channels may tune its sensitivity to applied force.

Ronald Biggs et al. report biophysical measurements of intact chromosomes isolated from mouse spermatocytes. They compare chromosomes in meiosis prophase I to mitotic chromosomes and find that meiotic chromosomes are much stiffer, and this stiffness does not depend on the central element of the synaptonemal complex (SYCP1).

Tajiri et al. describe how the cuticle coating the Drosophila larval body expands less efficiently along the body circumference than along the anteroposterior axis to drive body elongation. This “corset” property depends on cuticular proteins Cpr11A and Tubby, which may work together to change larval body shape.

Stanicek et al identify a shear stress-induced long non-coding RNA they name LASSIE, which stabilises junctions between endothelial cells through interactions with junctional and cytoskeletal proteins. This study provides insights into how a transcript that does not encode a protein controls endothelial response to forces associated with blood flow and endothelial barrier function.

Gao et al demonstrate that the angiogenesis regulator leucine-rich-alpha-2-glycoprotein 1 (LRG-1) links biomechanics to pathological angiogenesis in skin fibrosis progression. They find that LRG-1 is induced by the transcription factor ELK-1, which is activated through FAK and ERK signalling in response to mechanical force.

Compressive stress is associated with tumour progression. Using an in vitro assay, Kim et al now find that compression induces glycolysis-related genes in cancer-associated fibroblasts. They also show that expression of PFKFB3 correlates with EMT- and angiogenesis-related genes in breast cancer tissue.

Junmin Lee et al. study the role of geometric features at the perimeter regions of melanoma aggregates in programming stem cell-like state through histone marks. They use a tumor microengineering approach in vitro and report a spatial enrichment of histone modifications with stemness markers. Their work uncovers a mechanotransduction signaling that regulates epigenetic modifiers to regulate tumorigenicity.

Yubero et al. report a close connection between energy metabolism and cell stiffness in breast cancer cells, finding that healthy cell stiffness is based on ATP-driven actin polymerization, whereas in metastatic cells it is based on ATP-driven myosin II activity. They show that noninvasive cancerous cells exhibit an anomalous behavior, as their stiffness is little affected by the lack of nutrients and energy.

Pocaterra et al. demonstrate that Fascin1 F-actin bundling protein sustains YAP activation in the tumour environment in response to extracellular matrix mechanical cues. This study highlights Fascin1 as a potential clinical target in intrahepatic cholangiocarcinoma development.

Ishikawa, Takeo et al. present a 3D liver sinusoidal network analysis method and identify important parameters after partial hepatectomy. They find that in coordination with cytokine networks, mechanical homeostatic signalling, including shear stress and tension, plays critical roles in the initiation and termination of liver organ regeneration.

Kimura et al. reports a refined human skin equivalent (HSE) model that reproduces traction-force balance in the lateral direction. This tension improves HSE characteristics and promotes skin homeostasis. This model has great potential for applications in drug screening and understanding the molecular mechanisms of drug effects, skin ageing and diseases.

Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML.

Huang et al demonstrate that glioblastoma cells upregulate axon guidance molecule Plexin-B2 to gain invasiveness and that Plexin-B2 promotes glioblastoma cell infiltration along axon fiber tracts in intracranial transplant models by modulating cellular biomechanics.

Samadhan Patil et al. report a new method for improving the sensitivity and reproducibility of mechanobiological measurements in malignant cancer cells. Their findings provide insight into the interaction of cells with each other and the microenvironment and may impact our understanding of metastasis.

Fujita, Ochmachi et al combine a DNA origami approach with darkfield microscopy and AFM to study conformational changes in muscle myosin. They generate DNA origami-based thick filaments that enable the direct visualisation of mechanistic details of myosins during force generation under geometric conditions that resemble those in muscle.

Shuai Shao, Xiaoling Liao et al. present a new FRET biosensor for measuring the spatio-temporal activation of RhoGDIα upon binding Rho GTPases. They find that dissociation of the RhoGDIα-Rho GTPase complex is increased by shear stress and varies with subcellular location.

Callaghan et al. present a combinatory approach to culturing harvested adult mouse cardiomyocytes (aCMs). Under traditional culture protocols, aCMs rapidly lose their phenotype and undergo cell death. With their protocol, the authors show aCMs remain viable and retain their phenotype for 7 days, enough time to do genetic manipulation and small molecule screening.

Xindong Chen et al. simulate the sheet-like branched actin networks used by cells during cell migration using a novel 3D assembling model. They show how intracellular proteins regulate the network’s elastic properties and then affect cell migration, providing greater insight into the fundamental physical mechanisms of the previously published experimental observations.

Mathelié-Guinlet et al. investigate the molecular binding mechanisms of sexual agglutinins in budding yeast Saccharomyces cerevisiae. They report that mechanical tension enhances the strength of agglutinin interactions, supporting a new model in which physical stress induces conformational changes in the binding sites of agglutinins.

Beradi et al. establish a micropipette aspiration platform which enables sensitive real-time viscoelastic measurements of soft biomaterials. They use it to characterize the rheological behavior of cells and soft materials at very small deformations, yielding consistent and reproducible values.

Chan et al. apply Brillouin microscopy to study changes in tissue material properties during mammalian follicle development. Focusing on the Brillouin loss tangent which is independent of the refractive index and mass density, they find that mammalian folliculogenesis is characterised by region-specific changes in tissue micro-viscosity driven by cell differentiation and extracellular matrix remodelling.