Biomedical Engineering Reference
In-Depth Information
Linking the Cytoskeleton to the Nucleus and Direct
Mechanotransduction
Maniotis
et al.
[93] reported that in reaction to tension, the intermediate filament cytoskel-
etone-oriented, the nucleus distorts, and the nucleoli rearranged along the applied axis.
Thus, it was concluded that the nucleus is mechanically integrated within the physical entity
of the cell via intermediate filaments and that active or passive cell extension can lead to
passive nuclear deformation [72, 94]. Micromanipulation experiments have illustrated that
transmission of force can occur from the peripheral cytoplasm into the nucleus [95], demon-
strated the mechanical interconnection of chromosomes and nucleoli [96], and shown the
importance of the nuclear lamina in force transmission [97, 98].
Topography has provided a useful tool in investigation of force transduction into the
nucleus and has been used to indicate that redistribution of chromosomal territories
(the space occupied by a given chromosome within the nucleus, reviewed in [99], or intrater-
ritory loci, the location of particular genes) could affect the cellular transcriptional profile.
Such movements could bring genes closer to choromosome factories (areas rich in RNA
polymerase II) [100, 101], or away from/towards the periphery of the nucleus - an area that
can promote downregulated transcription.
Wang
et al.
[72] suggested a number of models by which tensile forces from FAs could
modulate gene expression. It was proposed that the assembly or activity of transcription
factor complexes could be affected directly or indirectly by tension-mediated alterations in
the nucleoskeleton and that the telomeric ends of the chromosomes are attached to the lamina
via matrix attachment regions (MARs). Also, the authors suggested that gene expression or
mRNA transport could also be affected by tension-mediated changes in nuclear pores.
Even at the nanoscale, topography provides a useful means to investigate mechano-
transductive effects on the nucleus. Nanocolumn substrates were shown to induce reposi-
tioning of chromosome 3 (Ch 3) [102, 103] relative to planar controls. The Ch 3 centromeres
were more closely apposed in cells cultured on the nanocolumns, probably as a consequence
of the decreased cell spreading and nuclear area. On hexagonally arrayed nanopits, the
intercentromeric distance was reduced for both chromosomes 3 and 11, and the cells
were markedly less spread than controls [103]. As the authors noted, the changes were
consistent with the tensegrity model (see papers by Ingber
et al.
[72, 104, 105]). Tension
on the cytoskeleton and nucleus should be reduced, which is likely to have lessened the
force exerted on chromosomes.
Furthermore, micro- and nanotopography have been used to illustrate movement of large
chromosomes in fibroblasts [106] and MSCs [88], with the nuclear lamina indicated as
central in the conveyance of mechanical signals to permit these movements. This is partic-
ularly interesting with MSCs, which, as has been described, differentiate in response to
intracellular tension. The genome is surveyed with respect to gene positioning in relation to
the telomeres (attached to lamins and hence mechanically sensitive) and the centromeres
(not attached and thus not mechanically sensitive). It is seen that many osteogenic genes
reside on larger chromosomes (which all these studies show to be more mechanically
sensitive) at the telomeric regions (e.g., osteocalcin at 1q25-31, osteopontin at 4q22, osteo-
nectin at 5q31 and alkaline phosphatase at 2q37). This indicates that the “osteogenic”
genome of MSCs may be in a position to respond rapidly to changes in tension, as the
telomeric ends may “unravel”, or at least become less dense and more euchromatic, faster
in response to tension. This change in DNA density may be permissive to transcription
factor and polymerase access, thus aiding phenotype selection.
