Cell Migration in Extracellular Matrices - Cellular Potts Models: Multiscale Extensions and Biological Applications - page 178

9.6 Varying Cell-Fiber Adhesiveness
Cell-matrix adhesion is mainly mediated by integrins on the cell surface that
form a link to connect ECM to the cytoskeleton and allow for the activation of
signaling pathways. Adhesion can be modulated by a number of parameters,
such as

1. The number of substratum ligands.

2. The expression and activation levels of integrins.

3. The resulting integrin{ligand binding anity, which can be reduced by
1 integrin antibodies that block integrin binding epitopes to ECM or
by soluble ligands that compete with ligand binding, or can be enhanced
by integrin{activating agents.

From the mathematical point of view, (1) has been just modeled by varying
the fiber density of the substrate, whereas (2) and (3) by modulating cell-
fiber adhesion parameter J ext

E;F . Indeed, the number and the distribution of
the collagenous threads remain the same as in the cases of Figure 9.1.
As a basic migration{adhesion relationship, the migratory capability of
moving individuals can be sorted into the three regimes of high, intermediate,
or low adhesion strength and in principle is valid for movements both over
a surface or within a 3D matrix (see Figure 9.7). At high integrin engage-
ment (say, J ext

E;F < 3), cells display barely no detectable movement within the
observation period, by being unable to detach from fibers. From an energetic
viewpoint, cells minimize the Hamiltonian H by maintaining such an adhesive
contact. Given the great difference between J ext

E;F and J ext

E;M , moving individ-
uals have in fact no benefit from further movements, meaning that an overly
adhesive substrate causes the formation of integrin clusters on the cell surface
that strongly bind to the substrate and do not allow the detachment needed
for further migration.
Intermediate values of J ext

E;F (say, in the interval [3,6]) yield moderately
high adhesive forces associated with a balance of attachment and detach-
ment, allowing cells to eciently move along 2D surfaces or within the fibrous
network with a maximal distance covered.
Finally, above a certain value of J ext

E;F (say, > 6:5), adhesion is lacking, and
consequently cells display barely detectable movement within the observation
period. Given that J ext

E;M < J ext E;F , cells actually prefer to fluctuate around the

initial position in the interstitial fluid, avoiding contacts with the collagenous
threads. Indeed, if a passive contact occurs, cells soon detach from the fiber
without exerting the traction needed for further movements.
The biphasic distribution of MSD is associated with a similar correspond-
ing distribution in velocity, but only a flat curve in persistence; see Figure
9.7. Therefore, the adhesion-dependent overall motility is mediated mostly by