CHARACTERIZATION OF THE ADHESIVE INTERACTIONS BETWEEN CELLS AND BIOMATERIALS - Micro and Nanotechnologies in Engineering Stem Cells and Tissues - page 161

ECM ligands but also have the ability to interact with cell surface ligands. Integrins
serve as a connection between the extracellular environment, where they bind to a
ligand or adjacent cell surface, and the intracellular environment, where they bind to
the cytoskeleton. Individual integrins may bind to multiple ligands, and multiple
integrins can share the same ligand. 3 Integrin activation results in alterations of cell
behavior (e.g., adhesion, proliferation, shape, survival or apoptosis, motility, gene
expression, differentiation). 1 Because of the importance of integrin activation on cell
function, biomaterials can be designed to mimic integrin interactions and achieve
specific cell functions.
The function of integrins as transmembrane links between their extracellular
connections and the cytoskeletal elements within the cell often plays an important
role in mechanosensing. With the exception of

4, which links to the intermediate
filaments of the cytoskeleton, most integrins form intracellular connections with the
actin cytoskeleton. 2 This anchoring function of integrins plays an important role in
several cell functions, including blocking apoptosis and triggering the progression of
the cell cycle.
Current research has supported the function of integrins in mechanotransduction,
indicating that integrin activation and initiation of downstream signaling pathways
can result in multiple cellular responses, including ECM remodeling, differentiation,
and survival signaling. In cardiomyocytes, hemodynamic overload results in stimu-
lation of cell growth and survival signaling. 4 Because of the stretch resulting from
hemodynamic overload, integrin binding domains on the ECM become exposed,
triggering integrin activation and the initiation of downstream signaling. Similarly,
intracellular integrin activation can occur through the deformation of the underlying
cytoskeleton because of stress. 5 Structural alterations of the actin-filamin cyto-
skeleton expose binding sites for the

a 6 b

b

tails of integrins, causing activation and
stimulation of downstream signaling pathways.
Integrin activation as controlled through substrate stiffness has recently been
shown to play a role in both osteogenic differentiation and tumor progression. The
differentiation of mesenchymal stem cells into osteoblasts varied with the stiffness of
the matrix, resulting in greater differentiation on stiffer substrates. 6 Additionally, a
similar correlation was found for 2 integrin expression, indicating that this integrin

subunit may play a role in transmitting mechanical signals into downstream signals
for differentiation. This hypothesis was confirmed through a knockdown of

a

2by
siRNA that resulted in a downregulation of osteogenic differentiation. 6 The integrin
a

a

1, which is important in the formation and remodeling of the fibronectin network
of the ECM, has been shown to play a role in matrix stiffening and tumor
progression. Increased matrix stiffening as a result of integrin activation was shown
to accelerate tumor metastasis. 7 Understanding the mechanisms of tumor progres-
sion is critical for developing methods of prevention or treatment.
The role of integrins in mechanotransduction should be exploited in order to
initiate or inhibit downstream signaling in response to integrin activation from
mechanical stress. Biomaterial design, specifically material properties and three-
dimensional structure, should address ways to promote integrin activation in
situations when activation can lead to positive effects such as cell survival or

5 b