Biomedical Engineering Reference
In-Depth Information
F-actin
α-actinin
Vinculin
Talin
FAK
Cell membrane
β
ə
Integrins
ECM
Biomaterial surface
Figure 12.1
A simplified overview of the focal adhesion. Focal adhesions are macromolecular
structures that serve as mechanical linkages of the cell cytoskeleton (F-actin) to the extra cellular
matrix (ECM), and as biochemical signaling hubs involved with the transmission of external
mechanical forces through numerous signaling proteins that interact at sites of integrin binding and
clustering. Reproduced from [141] with permission from Elsevier.
of activation starts with pairing of β and α integrins. By the connection of integrins to the
ECM proteins, several signaling pathways inside the cell will be activated, and more than
100 proteins share this complex for transmission of signal to the nucleus [71-73].
The protein composition of FAs will change according to the size of the adhesion. In the
smallest FAs, known as focal complexes, at 1 μm or less in length, talin, vinculin, paxillin,
and integrins can be found and they are the point of initial contact between the ECM and
cell-surface receptors. In mature focal adhesions (up to 5 μm in length), paxillin, vinculin,
focal adhesion kinase (FAK), zyxin, and integrins are present. At the largest size, fibrillar, or
supermature FA (>5 μm in length) greater amounts of these connective proteins and also
tensin are found. All three types of adhesion are force sensitive. Forces from inside or outside
of the cells are triggers for integrin activation and FA formation. Traditionally, studies focus
on biochemical signals arising from changes in cytoskeletal assembly, especially actin cyto-
skeleton, as a result in changes in adhesion. Both FA- and FAK-directed activation of the
G-proteins aid “cell sensing” of the surface. For example, direction of lamellipodium (from
Rac activation) helps cell/surface exploration. Various factors determine cell movements,
such as: chemical attractant and mechanical forces such as gravity, liquid flow, physical
shape, ECM stiffness, and protein gradient. These are more attractive to integrin bonding,
and formation of advancing lamellipodium will guide cells to these sites. Other activations
arise from cell division-control protein 42 homolog (CDC42) activation, causing filopodial
formation. These fine membrane protrusions are integrin-containing and “sweep” in front
of the cells to locate binding sites for FA growth. The G-protein Rho is also involved in
motility and sensing through its role in myosin activation and resultant actin contraction.
RhoA inhibition shows significant decreases in cell motility [74].
In MSCs, it has been demonstrated that on nanotopography there is a shift from stem
cell to differentiated osteoblast. This occurs through changes in adhesion and intracel-
lular tension. Osteoblasts are large cells requiring larger adhesions to support the tensile
cytoskeletal scaffolding [75]. Such effects have also been demonstrated in MSCs cultured
on hydrogels [76] or forced to confine to morphologies using microcontact printing of
fibronectin [77, 78].
