Biomedical Engineering Reference
In-Depth Information
The model has been able to characterize the chemotactic migration of
a vascular cell and the relative calcium events, to reproduce the activity of
some anti-angiogenic pharmacological compounds, and to suggest the use of
already existing drugs to inhibit cell locomotion. We now can turn to perform
simulations that provide additional insights of the calcium-dependent factors
that control the migratory properties of the tumor-derived vascular cell. In
particular, we focus on some conditions that would be dicult or impossible
to actually establish in vitro, but that can suggest nonintuitive, but potentially
very effective ways to interfere with the motility capacity of the TEC.
The diffusion is clearly a crucial element in the intracellular propagation
of calcium, and therefore affects a number of localized biochemical processes,
as the feedback mechanism included in the kinetic scheme of AA and NO and
the cell chemical sensitivity. A quantification of its importance is tested by
setting D
c
= 0 in Equation (6.10). Without diffusion, the calcium ions en-
tered from the medium are completely sequestered in the inner surface of the
PM, and therefore calcium signals do no longer occur throughout the entire
cell volume; see Figure 6.10(B-C-E). In particular, the cell quickly reaches the
peaks of calcium accumulation, which have the same intensity and localization
(i.e., at the tip of the pseudopodium) as in the standard case. However, the
TEC undergoes only a partial elongation, which results in a lower directional
velocity and a consequent decrement in the final displacement, as x
CM
(t = 6
h) = 165 m; see Figure 6.10(A-D). These results have a clear biological rele-
vance, since they represent a definitive demonstration that the cell migratory
properties are not established by the maximal amplitude of calcium responses
(which, as seen, remains unchanged), but by the overall intracellular concen-
tration of the ion, which is obviously strongly reduced by the exclusion of its
diffusive behavior, as c
(t = 6 h) 0.9.
Modeling allows us to assess the perturbing effect of endogenous buffers
on calcium signaling and on the overall migratory capacity of the cell. In
the absence of buffers (i.e., by imposing K
buff
= 1 in Equation (6.10)), the
spatial dynamics of Ca
2+
events are not affected, but, as expected, the local
concentrations are greater than control, as shown in Figures 6.11(B-C) and
6.12(H). In particular, the intracellular region in which calcium signals are not
detectable decreases in size, as it is now restricted in the close proximity of the
nucleus. In this regards, it is useful to compare the spatial profiles of the ion
in Figures 6.7 and 6.11. The consequent increment in the total intracellular
calcium level (i.e., c
(t = 5 h) 3.9) enhances the migratory capacities of the
EC, as the eective velocity grows up to 46 /h, and the cell reaches the
opposite side of the chamber in nearly 5 h, as shown in Figure 6.11(A) and
6.12(G).
We finally model a spatially inhomogeneous buffer distribution: in partic-
ular, an increasing clusterization of buffers is set toward the central regions of
the cell, where the perinuclear mitochondria are more concentrated (as widely
shown in [7] and confirmed in [283] by staining with mitotracker). Mathemat-
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