Biomedical Engineering Reference
In-Depth Information
1.
INTRODUCTION
Cell migration plays a crucial role in our birth, survival, and death. We are
conceived as amorphous fertilized eggs. It is cell migration, among other proc-
esses, that sculpts a richly structured embryo from a fertilized egg. While we
live, cell migration heals our wounds (1) and protects us from surrounding
pathogens (2). But when we age, cell migration can accelerate death. In some
instances, cancer metastasis is caused by directed migration of tumor cells from
the primary to the preferred sites of metastasis (3). Evidently, a better under-
standing of the mechanism of cell migration will have profound biomedical con-
sequences.
Most eukaryotic cells move by crawling on a surface. The crawling move-
ment occurs in response to an external stimulus, which is frequently a chemical
concentration gradient. The resultant motion propels the cells forward along the
direction of highest increase in concentration. The chemical that induces the
movement is called a
chemoattractant
and the movement itself is called
chemo-
taxis
. Eukaryotic chemotaxis is cyclic, and each cycle consists of four phases
(Figure 1): (1) extension of a protrusion, (2) adhesion of the protrusion to the
surface, (3) contraction of the cell body, and (4) retraction of the tail. Each phase
of the cycle is a complex process involving the coordinated action of a large
constellation of molecules (4). In this work, we confine our attention to
gradient
sensing
, the mechanism that enables the cell to read the external gradient and
extend a protrusion precisely at the
leading edge
, the region exposed to the
highest chemoattractant concentration.
Figure 1
. The four phases of a chemotactic cycle.
The extension of the protrusion involves localized actin polymerization at
the leading edge. Soon after the cells are exposed to a chemoattractant gradient,
the leading edge develops fingerlike actin-based structures called
filopodia
. The
space between the filopods then fills up with an actin mesh to form a wide,
sheetlike
lamellipod
. The localized polymerization of actin at the leading edge
implies that the gradient sensing machinery amplifies the external signal. In-
deed, the chemoattractant gradients imposed in the extracellular space are often
quite small (1-2% concentration change over the length of the cell) (5), but actin
polymers synthesized in response to the gradient are found exclusively at the
leading edge (6). The key problem in the study of gradient sensing is elucidation
