Abstract:The intracellular mechanical link tethering the nucleus to the cytoskeleton has been suggested to be the linker of the nucleoskeleton and cytoskeleton (LINC) complex. Previous studies have reported that knockdown of nesprin-1, a component of the LINC complex that directly binds to actin filaments, suppresses cellular morphological response to mechanical stimuli. The relation between nesprin-1 knockdown and cellular morphological changes, however, remains unclear. In this study, we examined the mechanical role … Show more
“…This suggested that silencing nesprin-1 could release the nucleus from the tension of F-actin filament, thus allowing for deformation before stretching. Also, fibroblastic cells manipulated with nesprin-1 siRNA showed decreased cell elongation under cyclic stretch [38]. Fig.…”
Section: Sensing Mechanical Environments Through the Linc Complexmentioning
Mesenchymal stem cells (MSCs) show tremendous promise as a cell source for tissue engineering and regenerative medicine, and are understood to be mechanosensitive to external mechanical environments. In recent years, increasing evidence points to nuclear envelope proteins as a key player in sensing and relaying mechanical signals in MSCs to modulate cellular form, function, and differentiation. Of particular interest is the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that includes nesprin and SUN. In this review, the way in which cells can sense external mechanical environments through an intact nuclear envelope and LINC complex proteins will be briefly described. Then, we will highlight the current body of literature on the role of the LINC complex in regulating MSC function and fate decision, without and with external mechanical loading conditions. Our review and suggested future perspective may provide a new insight into the understanding of MSC mechanobiology and related functional tissue engineering applications.
“…This suggested that silencing nesprin-1 could release the nucleus from the tension of F-actin filament, thus allowing for deformation before stretching. Also, fibroblastic cells manipulated with nesprin-1 siRNA showed decreased cell elongation under cyclic stretch [38]. Fig.…”
Section: Sensing Mechanical Environments Through the Linc Complexmentioning
Mesenchymal stem cells (MSCs) show tremendous promise as a cell source for tissue engineering and regenerative medicine, and are understood to be mechanosensitive to external mechanical environments. In recent years, increasing evidence points to nuclear envelope proteins as a key player in sensing and relaying mechanical signals in MSCs to modulate cellular form, function, and differentiation. Of particular interest is the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that includes nesprin and SUN. In this review, the way in which cells can sense external mechanical environments through an intact nuclear envelope and LINC complex proteins will be briefly described. Then, we will highlight the current body of literature on the role of the LINC complex in regulating MSC function and fate decision, without and with external mechanical loading conditions. Our review and suggested future perspective may provide a new insight into the understanding of MSC mechanobiology and related functional tissue engineering applications.
“…Nesprin-1 and Nesprin-2 are widely expressed, perform overlapping functions and contain large cytoplasmic spectrin-repeat domains with N-termini that bind to actin (Banerjee et al, 2014, Sakamoto et al, 2017, Zhou et al, 2018a. Nesprin-3 shares a similar KASH domain but its cytoplasmic region binds to plectin, mediating interactions with intermediate filaments (Wilhelmsen et al, 2005).…”
The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex mechanically couples cytoskeletal and nuclear components across the nuclear envelope to fulfil a myriad of cellular functions, including nuclear shape and positioning, hearing, and meiotic chromosome movements. The canonical model is that 3:3 interactions between SUN and KASH proteins underlie the nucleocytoskeletal linkages provided by the LINC complex. Here, we provide crystallographic and biophysical evidence that SUN-KASH is a constitutive 6:6 complex in which two constituent 3:3 complexes interact head-to-head. A common SUN-KASH topology is achieved through structurally diverse 6:6 interaction mechanisms by distinct KASH proteins, including zinc-coordination by Nesprin-4. The SUN-KASH 6:6 interface provides a molecular mechanism for the establishment of integrative and distributive connections between 3:3 structures within a branched LINC complex network. In this model, SUN-KASH 6:6 complexes act as nodes for force distribution and integration between adjacent SUN and KASH molecules, enabling the coordinated transduction of large forces across the nuclear envelope.
“…The linker of the nucleoskeleton and cytoskeleton (LINC) complex is considered an important structure for endothelial cell adhesion and adaptation to shear stress and cyclic stretch (Denis et al, 2021). Nesprin-1, a component of the LINC complex that directly binds to actin filaments, suppresses cellular morphological responses to mechanical stimuli, and nesprin-1 knockdown induces more rounded cellular shapes than non-treated cells under both static and cyclic stretching conditions (Sakamoto et al, 2017). This indicates a reduction in the morphological response of endothelial cells to mechanical stimuli.…”
Actin filaments play significant roles in many essential cellular processes including muscle contraction, cell motility, vesicle and organelle movement, cell signaling, and mechano-sensing mechanism of cells. However, one of the important cellular processes, the mechano-sensing mechanism of cells, is still debatable. To elucidate these mechanisms of cellular processes, it is important to observe the remodeling of the F-actin structure in cells. Although there are many reports about the remodeling of the F-actin structure during cellular processes, it needs to consider that the intracellular and extracellular proteins are fluctuating with thermal energy. We assumed that these small fluctuations affect the mechano-transduction in cells. We focused on an F-actin small fluctuation and tried to observe that in a living cell. Here, we propose the analyzing method of F-actin fluctuation in a living cell using the quasi super-resolution technique. To visualize F-actin filaments in living cells, Lifeact-GFP plasmid vector was transfected to NIH3T3 cells. Ten images of F-actin in living cells were taken every second under static culture conditions. First, we analyzed the small fluctuation of F-actin in living cells with Gaussian smoothed images. In this analysis, the amplitude of F-actin fluctuation was approximately 0.2 to 0.3 m, which is almost the same as the optical resolution. Therefore, we have reconstructed the F-actin image in cell from a cross-sectional fluorescent profile with the quasi super-resolution technique. We analyzed the fluorescent profile at several points along one F-actin filament, and the X and Y coordinates were picked up from the peak fluorescent in each fluorescent profile. From these X and Y coordinates in images, F-actin filament was approximated as a quadratic curve. We reconstructed the F-actin filament each time. The obtained spatial resolution was 0.08 m which was 2.5 times higher than the optical resolution. In quasi super-resolution images, the fluctuation amplitude of F-actin was 0.42 to 0.53 m in the peripheral region and 0.27 m in the center region. The frequency of F-actin fluctuation in both center and peripheral regions was approximately 3 Hz. The F-actin fluctuation was irregular, and several fluctuation patterns were observed. These phenomena might be caused due to the influence of restriction of the cytoskeletal network.
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