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Nature Reviews. Molecular Cell Biology Jul 2023Mechanical properties of extracellular matrices (ECMs) regulate essential cell behaviours, including differentiation, migration and proliferation, through... (Review)
Review
Mechanical properties of extracellular matrices (ECMs) regulate essential cell behaviours, including differentiation, migration and proliferation, through mechanotransduction. Studies of cell-ECM mechanotransduction have largely focused on cells cultured in 2D, on top of elastic substrates with a range of stiffnesses. However, cells often interact with ECMs in vivo in a 3D context, and cell-ECM interactions and mechanisms of mechanotransduction in 3D can differ from those in 2D. The ECM exhibits various structural features as well as complex mechanical properties. In 3D, mechanical confinement by the surrounding ECM restricts changes in cell volume and cell shape but allows cells to generate force on the matrix by extending protrusions and regulating cell volume as well as through actomyosin-based contractility. Furthermore, cell-matrix interactions are dynamic owing to matrix remodelling. Accordingly, ECM stiffness, viscoelasticity and degradability often play a critical role in regulating cell behaviours in 3D. Mechanisms of 3D mechanotransduction include traditional integrin-mediated pathways that sense mechanical properties and more recently described mechanosensitive ion channel-mediated pathways that sense 3D confinement, with both converging on the nucleus for downstream control of transcription and phenotype. Mechanotransduction is involved in tissues from development to cancer and is being increasingly harnessed towards mechanotherapy. Here we discuss recent progress in our understanding of cell-ECM mechanotransduction in 3D.
Topics: Mechanotransduction, Cellular; Extracellular Matrix; Actin Cytoskeleton; Cell Differentiation; Integrins
PubMed: 36849594
DOI: 10.1038/s41580-023-00583-1 -
Cell Jul 2023Membrane tension is thought to be a long-range integrator of cell physiology. Membrane tension has been proposed to enable cell polarity during migration through...
Membrane tension is thought to be a long-range integrator of cell physiology. Membrane tension has been proposed to enable cell polarity during migration through front-back coordination and long-range protrusion competition. These roles necessitate effective tension transmission across the cell. However, conflicting observations have left the field divided as to whether cell membranes support or resist tension propagation. This discrepancy likely originates from the use of exogenous forces that may not accurately mimic endogenous forces. We overcome this complication by leveraging optogenetics to directly control localized actin-based protrusions or actomyosin contractions while simultaneously monitoring the propagation of membrane tension using dual-trap optical tweezers. Surprisingly, actin-driven protrusions and actomyosin contractions both elicit rapid global membrane tension propagation, whereas forces applied to cell membranes alone do not. We present a simple unifying mechanical model in which mechanical forces that engage the actin cortex drive rapid, robust membrane tension propagation through long-range membrane flows.
Topics: Actins; Actomyosin; Actin Cytoskeleton; Cell Membrane; Cell Movement
PubMed: 37311454
DOI: 10.1016/j.cell.2023.05.014 -
Science Advances Aug 2023In osteoarthritis (OA), a disease characterized by progressive articular cartilage degradation and calcification, the articular chondrocyte phenotype changes and this...
In osteoarthritis (OA), a disease characterized by progressive articular cartilage degradation and calcification, the articular chondrocyte phenotype changes and this correlates with actin cytoskeleton alterations suggesting that it regulates gene expression essential for proper phenotype. This study reports that OA is associated with the loss of adseverin, an actin capping and severing protein. Adseverin deletion (Adseverin) in mice compromised articular chondrocyte function, by reducing F-actin and aggrecan expression and increasing apoptosis, Indian hedgehog, Runx2, MMP13, and collagen type X expression, and cell proliferation. This led to stiffer cartilage and decreased hyaline and increased calcified cartilage thickness. Together, these changes predisposed the articular cartilage to enhanced OA severity in Adseverin mice who underwent surgical induction of OA. Adseverin chondrocyte RNA sequencing and in vitro studies together suggests that adseverin modulates cell viability and prevents mineralization. Thus, adseverin maintains articular chondrocyte phenotype and cartilage tissue homeostasis by preventing progression to hypertrophic differentiation in vivo. Adseverin may be chondroprotective and a potential therapeutic target.
Topics: Mice; Animals; Microfilament Proteins; Chondrocytes; Hedgehog Proteins; Osteoarthritis; Cell Differentiation; Cartilage, Articular; Actins
PubMed: 37540756
DOI: 10.1126/sciadv.adf1130 -
The Journal of Cell Biology Dec 2023Cellular actin networks exhibit a wide range of sizes, shapes, and architectures tailored to their biological roles. Once assembled, these filamentous networks are... (Review)
Review
Cellular actin networks exhibit a wide range of sizes, shapes, and architectures tailored to their biological roles. Once assembled, these filamentous networks are either maintained in a state of polarized turnover or induced to undergo net disassembly. Further, the rates at which the networks are turned over and/or dismantled can vary greatly, from seconds to minutes to hours or even days. Here, we review the molecular machinery and mechanisms employed in cells to drive the disassembly and turnover of actin networks. In particular, we highlight recent discoveries showing that specific combinations of conserved actin disassembly-promoting proteins (cofilin, GMF, twinfilin, Srv2/CAP, coronin, AIP1, capping protein, and profilin) work in concert to debranch, sever, cap, and depolymerize actin filaments, and to recharge actin monomers for new rounds of assembly.
Topics: Actin Cytoskeleton; Actin Depolymerizing Factors; Actins; Profilins; Mammals; Animals
PubMed: 37948068
DOI: 10.1083/jcb.202309021 -
The Journal of Cell Biology Oct 2023The architecture of the actin cytoskeleton that concentrates at presynapses remains poorly known, hindering our understanding of its roles in synaptic physiology. In...
The architecture of the actin cytoskeleton that concentrates at presynapses remains poorly known, hindering our understanding of its roles in synaptic physiology. In this work, we measure and visualize presynaptic actin by diffraction-limited and super-resolution microscopy, thanks to a validated model of bead-induced presynapses in cultured neurons. We identify a major population of actin-enriched presynapses that concentrates more presynaptic components and shows higher synaptic vesicle cycling than their non-enriched counterparts. Pharmacological perturbations point to an optimal actin amount and the presence of distinct actin structures within presynapses. We directly visualize these nanostructures using Single Molecule Localization Microscopy (SMLM), defining three distinct types: an actin mesh at the active zone, actin rails between the active zone and deeper reserve pools, and actin corrals around the whole presynaptic compartment. Finally, CRISPR-tagging of endogenous actin allows us to validate our results in natural synapses between cultured neurons, confirming the role of actin enrichment and the presence of three types of presynaptic actin nanostructures.
Topics: Actins; Nanostructures; Neurons; Synapses; Synaptic Vesicles; Cytoskeleton; Cells, Cultured
PubMed: 37578754
DOI: 10.1083/jcb.202208110 -
International Journal of Biological... 2024Disulfidptosis occurs as a result of the accumulation of intracellular cystine followed by disulfide stress in actin cytoskeleton proteins due to a reduction of NADPH...
Disulfidptosis occurs as a result of the accumulation of intracellular cystine followed by disulfide stress in actin cytoskeleton proteins due to a reduction of NADPH produced through the pentose phosphate pathway in cells with high expression of SLC7A11. It is a cell death caused by the redox imbalance resulting from the disruption of amino acid metabolism and glucose metabolism. The discovery of disulfidptosis has sparked immense enthusiasm, but there are numerous unresolved issues that need to be addressed. Solutions to these riddles will provide insights into the detailed mechanisms and the pathophysiological relevance of disulfidptosis and utilizing disulfidptosis as an actionable therapeutic target.
Topics: Cell Death; Disulfides; Microfilament Proteins; NADP
PubMed: 38322120
DOI: 10.7150/ijbs.90606 -
Science Advances Nov 2023The mechanical cues of the external microenvironment have been recognized as essential clues driving cell behavior. Although intracellular signals modulating cell fate...
The mechanical cues of the external microenvironment have been recognized as essential clues driving cell behavior. Although intracellular signals modulating cell fate during sensory epithelium development is well understood, the driving force of sensory epithelium formation remains elusive. Here, we manufactured a hybrid hydrogel with tunable mechanical properties for the cochlear organoids culture and revealed that the extracellular matrix (ECM) drives sensory epithelium formation through shifting stiffness in a stage-dependent pattern. As the driving force, moderate ECM stiffness activated the expansion of cochlear progenitor cell (CPC)-derived epithelial organoids by modulating the integrin α3 (ITGA3)/F-actin cytoskeleton/YAP signaling. Higher stiffness induced the transition of CPCs into sensory hair cells (HCs) through increasing the intracellular Ca signaling mediated by PIEZO2 and then activating KLF2 to accomplish the cell specification . Our results identify the molecular mechanism of sensory epithelium formation guided by ECM mechanical force and contribute to developing therapeutic approaches for HC regeneration.
Topics: Signal Transduction; Extracellular Matrix; Epithelium; Actin Cytoskeleton; Cell Differentiation
PubMed: 37922362
DOI: 10.1126/sciadv.adf2664 -
Science Advances Sep 2023The mechanistic target of rapamycin complex 1 (mTORC1) is part of the amino acid sensing machinery that becomes activated on the endolysosomal surface in response to...
The mechanistic target of rapamycin complex 1 (mTORC1) is part of the amino acid sensing machinery that becomes activated on the endolysosomal surface in response to nutrient cues. Branched actin generated by WASH and Arp2/3 complexes defines endolysosomal microdomains. Here, we find mTORC1 components in close proximity to endolysosomal actin microdomains. We investigated for interactors of the mTORC1 lysosomal tether, RAGC, by proteomics and identified multiple actin filament capping proteins and their modulators. Perturbation of RAGC function affected the size of endolysosomal actin, consistent with a regulation of actin filament capping by RAGC. Reciprocally, the pharmacological inhibition of actin polymerization or alteration of endolysosomal actin obtained upon silencing of WASH or Arp2/3 complexes impaired mTORC1 activity. Mechanistically, we show that actin is required for proper association of RAGC and mTOR with endolysosomes. This study reveals an unprecedented interplay between actin and mTORC1 signaling on the endolysosomal system.
Topics: Mechanistic Target of Rapamycin Complex 1; Actins; Signal Transduction; Actin Cytoskeleton; Lysosomes
PubMed: 37703363
DOI: 10.1126/sciadv.add9084 -
Biophysical Journal Aug 2023Tissue cells in epithelial or endothelial monolayers are connected through cell-cell junctions, which are stabilized by transmembrane E-cadherin bonds and intracellular...
Tissue cells in epithelial or endothelial monolayers are connected through cell-cell junctions, which are stabilized by transmembrane E-cadherin bonds and intracellular actin filaments. These bonds and junctions play a crucial role in maintaining the barrier function of epithelia and endothelia and are believed to transmit forces between cells. Additionally, E-cadherin bonds can impact the shape of cell-cell junctions. In this study, we develop a continuum mechanical model of the cell-cell junction by explicitly incorporating the cell membrane, distributions of E-cadherin bonds, cytoplasmic fluid pressure, and F-actin dynamics. The static force-balanced version of the model is able to analyze the influences of cell cortical tension, actin dynamics, and cytoplasmic pressure on the junction shape and E-cadherin bonds. Furthermore, an extended model that incorporates fluid flow, across the cell boundary as well as around the cell, is also examined. This model can couple cell-shape changes with cell cortical tension and fluid flow, and predicts the additional effect of fluid motion on cell-cell junction mechanics. Taken together, our models serve as an intermediate link between molecular-scale models of cell-junction molecules and cell-scale models of tissue and epithelia.
Topics: Intercellular Junctions; Cadherins; Actins; Cell Membrane; Actin Cytoskeleton
PubMed: 37475215
DOI: 10.1016/j.bpj.2023.07.011 -
The International Journal of... Jan 2024Talin protein (Talin 1/2) is a mechanosensitive cytoskeleton protein. The unique structure of the Talin plays a vital role in transmitting mechanical forces. Talin... (Review)
Review
Talin protein (Talin 1/2) is a mechanosensitive cytoskeleton protein. The unique structure of the Talin plays a vital role in transmitting mechanical forces. Talin proteins connect the extracellular matrix to the cytoskeleton by linking to integrins and actin, thereby mediating the conversion of mechanical signals into biochemical signals and influencing disease progression as potential diagnostic indicators, therapeutic targets, and prognostic indicators of various diseases. Most studies in recent years have confirmed that mechanical forces also have a crucial role in the development of disease, and Talin has been found to play a role in several diseases. Still, more studies need to be done on how Talin is involved in mechanical signaling in disease. This review focuses on the mechanical signaling of Talin in disease, aiming to summarize the mechanisms by which Talin plays a role in disease and to provide references for further studies.
Topics: Mechanotransduction, Cellular; Talin; Integrins; Cytoskeleton; Actins; Cell Adhesion
PubMed: 37914021
DOI: 10.1016/j.biocel.2023.106490