The coordinated interplay of cytoskeletal networks critically determines tissue biomechanics and structural integrity. Here, we show that plectin, a major intermediate filament-based cytolinker protein, orchestrates cortical cytoskeletal networks in epithelial sheets to support intercellular junctions. By combining CRISPR/Cas9-based gene editing and pharmacological inhibition, we demonstrate that in an F-actin–dependent context, plectin is essential for the formation of the circumferential keratin rim, organization of radial keratin spokes, and desmosomal patterning. In the absence of plectin-mediated cytoskeletal cross-linking, the aberrant keratin–desmosome (DSM)–network feeds back to the actin cytoskeleton, which results in elevated actomyosin contractility. Also, by complementing a predictive mechanical model with Förster resonance energy transfer–based tension sensors, we provide evidence that in the absence of cytoskeletal cross-linking, major intercellular junctions (adherens junctions and DSMs) are under intrinsically generated tensile stress. Defective cytoarchitecture and tensional disequilibrium result in reduced intercellular cohesion, associated with general destabilization of plectin-deficient sheets upon mechanical stress.
Pollen tube growth in the style is guided by an active mechanoresponsive system that is sensitive to the stiffness and resistance of the growth path.
Hollow titanium dioxide (TiO2) nanotubes offer substantially higher drug loading capacity and slower drug release kinetics compared to solid drug nanocarriers of comparable size. In this report, we load TiO2 nanotubes with iron oxide nanoparticles to facilitate site-specific magnetic guidance and drug delivery. We generate magnetic TiO2 nanotubes (TiO2NTs) by incorporating a ferrofluid containing Ø ≈ 10 nm iron oxide nanoparticles in planar sheets of weakly connected TiO2 nanotubes. After thermal annealing, the magnetic tubular arrays are loaded with therapeutic drugs and then sonicated to separate the nanotubes. We demonstrate that magnetic TiO2NTs are non-toxic for HeLa cells at therapeutic concentrations (≤200 µg/mL). Adhesion and endocytosis of magnetic nanotubes to a layer of HeLa cells are increased in the presence of a magnetic gradient field. As a proof-of-concept, we load the nanotubes with the topoisomerase inhibitor camptothecin and achieve a 90% killing efficiency. We also load the nanotubes with oligonucleotides for cell transfection and achieve 100% cellular uptake efficiency. Our results demonstrate the potential of magnetic TiO2NTs for a wide range of biomedical applications, including site-specific delivery of therapeutic drugs.
Aims Desminopathies comprise hereditary myopathies and cardiomyopathies caused by mutations in the intermediate filament protein desmin that lead to severe and often lethal degeneration of striated muscle tissue. Animal and single cell studies hinted that this degeneration process is associated with massive ultrastructural defects correlating with increased susceptibility of the muscle to acute mechanical stress. The underlying mechanism of mechanical susceptibility, and how muscle degeneration develops over time, however, has remained elusive. Methods Here, we investigated the effect of a desmin mutation on the formation, differentiation, and contractile function of in vitro‐engineered three‐dimensional micro‐tissues grown from muscle stem cells (satellite cells) isolated from heterozygous R349P desmin knock‐in mice. Results Micro‐tissues grown from desmin‐mutated cells exhibited spontaneous unsynchronised contractions, higher contractile forces in response to electrical stimulation, and faster force recovery compared with tissues grown from wild‐type cells. Within 1 week of culture, the majority of R349P desmin‐mutated tissues disintegrated, whereas wild‐type tissues remained intact over at least three weeks. Moreover, under tetanic stimulation lasting less than 5 s, desmin‐mutated tissues partially or completely ruptured, whereas wild‐type tissues did not display signs of damage. Conclusions Our results demonstrate that the progressive degeneration of desmin‐mutated micro‐tissues is closely linked to extracellular matrix fibre breakage associated with increased contractile forces and unevenly distributed tensile stress. This suggests that the age‐related degeneration of skeletal and cardiac muscle in patients suffering from desminopathies may be similarly exacerbated by mechanical damage from high‐intensity muscle contractions. We conclude that micro‐tissues may provide a valuable tool for studying the organization of myocytes and the pathogenic mechanisms of myopathies.
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