Nuclear mechanics and mechanotransduction

Introduction: Many studies have shown that mechanical forces inherent in the living body, such as fluid shear stress due to blood flow, play critical roles in regulating cellular physiology and pathogenesis (Davies 1995; Li et al. 2005; Haga et al. 2007). These extracellular forces are sensed at the cellular level, and inside the cells the forces are somehow transduced into changes in gene expression responsible for the cellular responses (Ingber 1997). The mechanism of this force-sensing process or mechanotransduction still remains unclear. Signaling pathways following mechanical force loadings have been identified by means of biochemistry (Li et al. 2005; Haga et al. 2007). In addition to the involvement of these signaling molecules, direct intracellular force transmission from the cell membrane or extracellular matrix to the nucleus via, probably, cytoskeletal filaments may be another possible pathway through which cells respond to extracelullar forces (Wang et al. 1993; Davies 1995; Ingber 1997; Maniotis et al. 1997; Janmey 1998): Loaded forces may cause a deformation of the nucleus that is the principal site of DNA and RNA synthesis, alter the spatial positioning or dynamics of the chromatin that is a complex of DNA and proteins (such as histone) making up chromosomes, and then affect gene expression because such changes in chromatin organization could expose new sites for transcriptional regulation (Dahl et al. 2004; Lammerding et al. 2004). There is actually considerable evidence that the cell nucleus is deformed or remodeled in response to extracellular forces when the cell adapts to the local mechanical environment by the reorganization of cytoskeletons. Flaherty et al. (1972) demonstrated by in vivo experiments that endothelial nuclei elongate and orient in the direction of blood flow, as do the whole cells (Figure 9.1). Lee et al. (2005) found, based on in vitro observations, that movement of the nucleus in the cytoplasm is enhanced by fluid flow and regulated by mediators of cytoskeleton reorganization. Deguchi et al. (2005a) suggested that not only the endothelial cell cytoskeleton but also its nucleus remodels structure under shear stress applied to the cell. This study suggested that the shear stress applied to the cell might induce structural rearrangement in the nucleus structure, which leads to a permanent alteration in its overall shape and stiffness. Thus, the nucleus deformation and remodeling appear during the force-loading and resultant cellular responses.