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Title: Nanomechanical adaptation of early apoptotic cell shrinkage to materials interface
Authors: Cai, Pingqiang
Keywords: DRNTU::Engineering::Materials
Issue Date: 2015
Source: Cai, P. (2015). Nanomechanical adaptation of early apoptotic cell shrinkage to materials interface. Doctoral thesis, Nanyang Technological University, Singapore.
Abstract: Deregulated apoptosis has been associated with many physiology disorder and diseases, such as heart fatigue, developmental disorders and cancer formation. While much study has been conducted to elucidate the biochemical pathways leading up to apoptosis, little attention has been given to apoptotic shrinkage, one of the earliest changes observed during apoptosis. Recently, the emergence of mechanobiology has revealed mechanotransduction pathways that involve the coupling of extracellular mechanical cues with intracellular biochemical events, shedding new light onto physiology and pathology. However, the understanding of such mechanotransduction pathways during the process of apoptosis is still in its infancy. Clues hint at the importance of mechanotransduction pathways in apoptosis; increased contractility and subsequent apoptotic shrinkage are believed to serve as the prerequisite of apoptosis, and cellular softening is also found in tumor cells present during evading apoptosis. This implies that apoptosis is associated with tensional pre-stress and cytoskeletal rigidity, and we hypothesize that the equilibrium between the two might dictate cellular sensitivity to apoptotic shrinkage and thus apoptosis. Extensive evidence has revealed that complex and dynamic interactions exist at cell-matrix interface. Engineering matrix materials, either physically or biochemically, could thereby be employed to modulate intracellular tension and cytoskeleton rigidity and hence to investigate the cellular adaptation of apoptotic shrinkage and apoptosis. By virtue of our customized Spatiotemporal Traction Stress Microscopy, we have unveiled the phenomenon of the Biphasic Early Apoptotic Shrinkage (BEAS), in terms of morphological and chemomechanical dynamics. This phenomenon consists of Phase I,kinases inhibition accompanied by dramatic diminution of cellular tension but little morphology change, and Phase II, microtubule buckling with remarkable cell shrinkage but a slight bounce of traction stress. A mechanotransduction pathway was first proposed, in which cell microtubule flexural rigidity and tensional pre-stress were identified to be the key factors. Based on this, we conducted a systematic evaluation by interfacing cells with substrates specifically engineered (e.g. through substrate elasticity and geometric constraints) to modulate the two factors. It was revealed that an increase in microtubule rigidity led to a decreased rate of apoptotic shrinkage, and was the predominant factor influencing apoptosis. On the other hand, it was shown that elevated cell tensional pre- stress, instead of retarding apoptotic shrinkage, actually expedited the process. This was achieved by confining cells within identical “enveloping” but varied adhesion clues; the former excluded variation in such parameters as spreading and adhesion area, cell polarity and microtubule architecture, while the latter allowed modulation of tensional pre-stress. Finally, we demonstrated the deleterious effect of elevated cell tensional pre-stress towards apoptotic shrinkage in epithelia. Elevated cellular tension induced by overcrowding contributed to apoptosis, which was significantly dependent on the mechanical integrity of the epithelia. With the mechanical integrity disrupted by gravitational forces, cells would escape from inverted epithelia and form multilayer epithelia, as an alternative way to maintain number homeostasis of the epithelia. In conclusion, we demonstrated the versatile nanomechanical adaptation of apoptotic shrinkage to engineered cell-materials interface, providing new perspectives of mechanotransduction of apoptosis and inspiring novel strategies to manipulate apoptosis on demand.
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