Abstract
The migration of endothelial cells (ECs) is critical for various processes including vascular wound
healing, tumor angiogenesis, and the development of viable endovascular implants. EC migration
is regulated by intracellular ATP and recent observations in our laboratory on ECs cultured on line
patterns - surfaces where cellular adhesion is limited to 15 m-wide lines that physically confine
the cells - have demonstrated very different migration behavior from cells on control unpatterned
surfaces. Specifically, while ECs on unpatterned surfaces exhibit random motion in the absence
of flow and persistent directed motion under flow, cells on line patterns both in the presence and
absence of flow exhibit three distinct migration phenotypes: a) running- cells are polarized and
migrate continuously and persistently on the adhesive lines with possible directional changes, b)
undecided- cells are elongated and exhibit periodic changes in the direction of their polarization and
minimal net migration, and c) tumbling-like - cells migrate persistently for a certain amount of time
but then stop and round up for a few hours before spreading again and resuming migration.
We hypothesize that the three migration phenotypes on patterns reflect differences in intracellular
ATP profiles. Specifically, we propose that running ECs have sufficiently high ATP concentrations
at all time in order to elongate, polarize, and migrate. In contrast, we suggest that undecided ECs
have an intermediate level of ATP concentration that is sufficiently high for cell spreading but not for
sustained polarization and migration. Finally, tumbling-like cells are thought to have low levels of
intracellular ATP during the rounding-up phase but manage to "recharge their batteries" so that ATP
levels recover sufficiently for the cells to eventually elongate, polarize, and migrate. To test this hypothesis,
we have developed a mathematical model that describes the time evolution of intracellular
ATP concentration.
The computations provide the time dynamics of both EC length and intracellular ATP concentration.
The results demonstrate that depending on the parameter values adopted for the simulations, the
different hypothesized intracellular ATP profiles can indeed be obtained. Thus, for certain parameter
values, we observe a rapid and sustained increase in ATP concentration, corresponding to the
hypothesized behavior for running cells. For other parameter values, the ATP concentration remains
within an intermediate range throughout, presumably reflecting undecided cells. Finally, for part of
the parameter space, we obtain an initial drop in the concentration followed by recovery, as suggested
for tumbling-like cells. The results are consistent with the notion that changes in intracellular
ATP modulate the phenotype of EC migration on line patterns.
Anno
2019
Autori IAC
Tipo pubblicazione
Altri Autori
N. Roselli, A. Castagnino, D. Andreucci, G. Pontrelli, A. Barakat