Biomedical Engineering Reference
In-Depth Information
2. Adhere dynamically to their environment via adhesive molecules, i.e.,
integrins.
3. Generate the force necessary for propulsion by contraction of cytoskele-
tal elements.
4. Retract their rear ends [7, 229].
For migration within three-dimensional (3D) porous environments, in addition
to the basic principles above, the cell needs to find its way throughout steric
obstacles [110, 332, 410]. This can be achieved by
1. Passing through constricted openings of the ECM by significant cell
deformation and cytoskeletal force generation.
2. Activating a cell-derived proteolytic machinery able to degrade matrix
components and to open space for cell movement [141, 142, 219, 336,
411].
This basic motile behavior is further modulated by a number of mechanisms
that include determinants from both the surrounding ECM and the cell itself
(refer to [229, 410] and references therein) that we aim to systematically an-
alyze with our multi-scale modeling approach. Also in this case, each cell is
modeled as a discrete compartmentalized object, differentiated into nucleus
and cytosol. On the other hand, unlike what we have seen in most of the
previous chapters, the environments are constituted of two components, an
inhomogeneous fibrous collagen-like network, and a homogeneous interstitial
medium.
The model is highly flexible, being capable of characterizing the migra-
tory behavior of cells in several conditions, both on 2D substrata and in 3D
ECMs. In the simulations, characteristics like cell shape and directionality
are not imposed a priori, but are a result of the interaction with the matrix
fibrous component. As an outcome, we focus on experimentally addressable
characteristics of cell locomotion, i.e., cell overall displacement, velocity and
persistence time, and cell shape, predicting how these quantities are influenced
by manipulations of properties of either the matrix (i.e., adhesive ligands, fiber
distribution, pore size, elastic modulus), or the cell (i.e., adhesive strength,
deformability, and proteolysis).
Consistent with experimental observations, our findings provide evidence
for a biphasic cell migratory behavior for planar substrate in response to vari-
ations of the number of matrix ligands or adhesion strength, with maximal
movements at intermediate values. In 3D matrix environments, the geometri-
cal distribution of the collagenous network, such as matrix alignment or pore
size, or the matrix elasticity will be demonstrated to affect cell behavior in a
similar way. Further, the cell compartmentalization allows one to discern the
effect of the mechanical rigidity of the nucleus that, being higher than the
 
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