The Cell–Surface Interaction - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 20

stability. Finally, signal propagation through prestressed components is likely to
produce a dampened signal as prestress will hamper the deflection incurred by
each component [ 91 ].
Some insight into the theories behind mechanotransduction of the cytoskeleton
provides a basis for understanding how changes in focal adhesion distribution and
cell shape induced by a material can alter cellular function. Studies have shown
that nuclei react to changes in cell morphology caused by the topography of the
ECM and applied stress signals. Specifically, it has been shown that in response to
tension the intermediate filaments of the cytoskeleton reorient, causing a distortion
in the nucleus which results in nucleoli shifting along the appropriate axis [ 93 ].
Dahl et al. [ 94 ] showed that the nuclear lamina network is an elastic structure;
however, it appears to have a compression limit. This feature suggests that the
lamina functions as a molecular 'shock absorber'. Their experiments, using
dextran to swell the nucleus and micropipettes to compress it, concluded that the
DNA within the nucleus is afforded a degree of protection by the nuclear envelope,
but that this retains a degree of flexibility for adequate mechanotransduction.
Recently, Dalby et al. [ 89 ] have put forth a modified version of self-induced
mechanotransduction. Specifically, they suggest that by altering nuclear mor-
phology and consequently chromosomal positioning with changes in topography,
this will directly influence the probability of gene transcription. Investigations into
nuclear and laminin morphology changes as a reaction to various nanotopogra-
phies revealed differences in genome regulation and gene expression in support of
this theory. Fibroblasts cultured on nanocolumns (centre-to-centre spacing
184 nm) and nanopits (spacing 300 nm) react to both materials with reduced
spreading, which affects cytoskeletal organization, resulting in relaxation of the
nucleus size. Moreover, the interphase chromosome positioning by centromere
analysis of chromosomes 3, 11 and 16 showed a reduction in the centromere pair
distance, with a significant difference for chromosome 3 for cells cultured on
surfaces with nanocolumns and nanopits and for chromosome 11 for cells cultured
on surfaces with nanopits. Additionally, the reduction in cell spreading increases
the number of gene downregulations [ 95 ]. On the basis of these results it appears
that mechanotransduction as a reaction to topography is more likely to combine
features of both the percolation model and the tensegrity model, with the likeli-
hood of the involvement of additional factors.
3.4.2 Indirect Mechanotransduction
Signal propagation is also achieved through indirect mechanotransduction.
Activation of the extracellular-signal-regulated kinase (ERK)/mitogen-activated
protein kinase (MAPK) pathway is the main method by which indirect mecha-
notransduction is achieved. This pathway has fundamental roles in relaying
extracellular information to the nucleus [ 96 ], cellular differentiation and cell cycle
regulation. Further to this, the ERK/MAPK pathway has demonstrated a key
function in the response of osteoblast cells to a variety of signals, including