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Molecular Mechanisms for Statin Pleiotropy and Possible Clinical Relevance in Cardiovascular Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Brian Yu, Nikola Sladojevic, James K. Liao
Rho-associated protein kinases (ROCKs) are serine/threonine kinases directly activated by RhoA, a GTPase in the Rho family, and have received a great deal of attention due to their ability to regulate a wide variety of cellular and pathogenic processes (Fig. 10.5). RhoA translocation and activation is known to be dependent on geranylgeranylation (Laufs and Liao, 1998). ROCKs regulate the actin cytoskeleton through inhibition of the myosin binding subunit (MBS) of myosin light chain (MLC) phosphatase, thereby elevating MLC phosphorylation and promoting myosin contractility (Kimura et al., 1996). The resulting myosin contractility can drive formation of stress fibers, focal adhesions, smooth muscle contraction, and cell migration, and alter gene expression (Shimokawa and Rashid, 2007). Thus, RhoA/ROCK may regulate various cellular pathways that lead to changes in the vascular wall, cardiomyocytes, and other cells, either directly or indirectly contributing to cardiovascular disease (Fig. 10.5).
Cell Biology for Bioprocessing
Published in Wei-Shou Hu, Cell Culture Bioprocess Engineering, 2020
Many cell types, such as fibroblasts, extend their body and spread flat on a surface, both in tissues and in culture. The edge of an adherent cell has an irregular shape, much like an egg laid on a pan. In the protruding regions, actin fibers localize in the lamellipodia and filopodia. In the protruding filopodia, actin filaments form intensely labeled parallel bundles of fibers. While in the lamellipodia, they form cross-linked non-parallel networks. The two types of network can reorganize, the filopodium region protruding out from a lamellipodium during cell movement. In stationary cells, the actin fibers form long stress fibers that may span a large fraction of the entire cell length. The stress fibers connect to the focal adhesion (the location where the cytoplasmic membrane is in contact with the substrate surface) and establish a tension force between the cell and the extracellular matrix. Stress fibers also connect to adjacent cells through adhesion junctions.
Cell Adhesion in Animal Cell Culture: Physiological and Fluid-Mechanical Implications
Published in Martin A. Hjortso, Joseph W. Roos, Cell Adhesion, 2018
Manfred R. Koller, Eleftherios T. Papoutsakis
Even though they occupy only a small fraction of the interface, focal adhesions (also known as focal contacts or adhesion plaques) are the strongest sites of cell-substratum and cell-cell adhesion. Focal adhesions are formed between many cells and the appropriate substrata, and with other cells as well. Although focal adhesions begin to form in some transformed cells (see Sec. 5.4), they do not mature and acquire attached stress fibers as do normal focal adhesions, which correlates with the observed growth of these cells in suspension (20). Stress fibers contain parallel bundles of actin microfilaments and are responsible for generating the stress or tension that determines the flattened shape of many cells (21). These stress fibers are anchored to the plasma membrane at focal adhesion sites. In addition, focal adhesions probably also form the nucleation sites needed to regulate the assembly of the stress fibers (22), which occurs as the cell attaches and flattens on the substratum. In fibroblast cultures, these sites made up 22% of the total cell-substratum contacts in early culture, with the number falling to 6% in late culture. Focal adhesions were seen in 28% of the cell-cell contacts in late culture (19).
A computational model to predict cell traction-mediated prestretch in the mitral valve
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2019
M. A. J. van Kelle, M. K. Rausch, E. Kuhl, S. Loerakker
In the present study we aim to understand how cell-mediated traction forces may lead to the development of anisotropic tissue prestretch in the mitral valve. Towards this end, a model is required which predicts the development of traction forces by cellular actin stress fibers. Different models have been developed which use physically-motivated remodeling laws to predict cellular actin stress fiber remodeling. These models rely on stress and strain homeostasis (Deshpande et al. 2006, 2007; Vernerey and Farsad 2011; Obbink-Huizer et al. 2014) or on a thermodynamic equilibrium (Foucard and Vernerey 2012; Vigliotti et al. 2016) to predict stress fiber assembly and dissociation in response to topological and mechanical cues. Loerakker et al. (2014) coupled the cell-mediated remodeling laws of Obbink-Huizer et al. (2014) to an algorithm for collagen remodeling, and showed that cellular contractility is a very important affector of remodeling in tissue engineered heart valves in the pulmonary position (Loerakker et al. 2016).
Substrate regulation of vascular endothelial cell morphology and alignment
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2019
A. I. Barakat, C. F. Natale, C. Leclech, J. Lafaurie-Janvore, A. Babataheri
FAs organize actin stress fibers in cells; therefore, we wondered if FA clustering along pattern edges led to a particular stress fiber organization. To address this issue, we used confocal microscopy to visualize the spatial distribution of actin filaments in ECs cultured on all the different surfaces. In ECs cultured on unpatterned substrates, stress fibers were randomly oriented with dense peripheral actin microfilament bundles, typical of ECs cultured under static (no flow) conditions (Prasain and Stevens 2009). On the µP substrates, bundles of actin fibers at the EC basal plane were present in between adjacent fibronectin stripes, bridging FAs located at the borders of neighboring adhesive areas. In ECs cultured on µG surfaces, confocal z-stack imaging revealed two distinct stress fiber arrangements: stress fibers on the ridges had no clear spatial organization, whereas stress fibers in the grooves formed packed bundles oriented in the pattern direction. These bundles were associated with long and well aligned FAs detected inside the groove, suggesting that the groove surface provided directional guidance for the spatial organization of stress fibers. When ECs were cultured on µG-FnR surfaces in which the groove was no longer accessible for adhesion, the actin network exhibited similarities to that in cells on µP substrates, most notably suspended thick stress fiber bundles that connected FAs located at the boundaries of neighboring adhesive ridges and thus presumably formed suspended bridges between adjacent ridges.
Photoactivatable surfaces resolve the impact of gravity vector on collective cell migratory characteristics
Published in Science and Technology of Advanced Materials, 2023
Shinya Sakakibara, Shimaa A. Abdellatef, Shota Yamamoto, Masao Kamimura, Jun Nakanishi
Myosin is the main protein responsible for cellular force production and is activated through the phosphorylation of its light chain, which indicates higher myosin activity [28]. The localization of actomyosin structures determine their contraction outcomes [29]; for instance, the higher accumulation of actomyosin in apical surface relative basal region involves in the 3D architecture rearrangement and invaginations of intestinal epithelium [30]. Therefore, we checked the distribution of the phosphorylated myosin light chain in the upper junctional region surfaces within the clusters. As expected, a higher localization of pMLC was found in the upper intercellular junctions within the clusters cultured in inverted positions compared to upright ones (Figure 3(e,f)). This active myosin causes the sliding of actin filaments connecting the intercellular junctions, which might result in smoothening of the cellular apical surfaces. These observed alterations in the spatial distribution and activity of actomyosin cytoskeletal systems are correlated to inversion against gravity, presumably due to the adaptation mechanism for cellular clusters against the gravity vector. Previously, Zang et al. [5] reported that single cells in the inverted configuration responded to the gravity vector through alteration in actin stress fiber expression and redistribution. Actin filaments act as tension-resistant filaments that is necessary to adapt nuclear translocation in coordination with other cytoskeletal systems [5]. This cytoskeletal network remodeling is necessary for the single cells to adapt against the gravity vector. On the other hand, our experiments monitored cells in a group in which the actin cytoskeleton not only connects the cells to substrates in the form of stress fibers but also maintains the mechanical balance through the distribution of force within cells through the cortical actin and stress fibers associated with cell cohesion proteins [31,32]. Therefore, in our case, the clusters as a whole are expected to respond to such changes. These responses include the strengthening of actin localization in the peripheral bundles and higher intercellular tension that causes flattening of the cluster apical surfaces.