Biomedical Engineering Reference
In-Depth Information
local cell-cell interactions between the SCs. Specifically, Agur and colleagues
assume that cells are able to “count” the numbers of cells in their area and make
decisions accordingly. This counting ability is known to exist in bacteria and is
referred to as quorum sensing (QS). Analysis of this model [
4
,
45
] shows that QS
is sufficient for maintaining the homeostatic properties of a tissue. Moreover, this is
the simplest model capable of retrieving homeostasis.
This model was followed by an effort to study the derangement of homeostasis,
i.e., to learn what causes a normal, homeostatic tissue to become cancerous.
To this end, Agur et al.'s original model was refined to incorporate a specific
three-dimensional structure of the tissue and varying intensities of intracellular
signaling (i.e., variation of the distance at which cells can detect the presence of
other cells) [
3
]. Results confirm that excessive SC proliferation may be triggered by
change in the intensity of intercellular communication.
In a subsequent study, the model was adjusted in order to explore the behavior of
a cancerous tissue containing CSCs [
90
]. Exploring the system behavior under vari-
ous parameter values enabled the authors to identify general therapeutic approaches
that are likely to be effective in targeting CSC populations.
A separate model aimed to identify the molecular mechanism underlying fate
decision control in a single SC, by incorporating intracellular molecular signaling
pathways that are sensitive to microenvironmental signals [
5
,
44
]. This intracellular
model was integrated within the previously studied tissue model, to create a multi-
scale model, which, if verified experimentally, could also serve as a useful tool
for distinguishing specific possible therapeutic targets for eliminating CSCs [
5
].
Mathematical analysis [
44
] and simulations [
5
] of this model show that one of the
key factors for fate decision regulation is the Dickkopf1 (Dkk1) ligand, which is
secreted by SCs into the microenvironment, and may serve as a potential modulator
of the negative feedback (QS) mechanism.
The rest of this chapter is organized as follows. Sections
2
and
3
provide
background about the SC fate decision mechanism and about the theory of CSCs.
Section
4
discusses mathematical modeling of SC fate decision. Section
5
discusses
the tissue models, and Sect.
6
discusses the molecular mechanism model. Section
7
discusses the results of the analysis of these models, the implications of considering
the concept of feedback regulation through SC-to-SC interactions, and possible
future applications for these models in CSC research.
2
Fate Decision in Stem Cells: Managing
the Replication-Differentiation Balance
Tissues containing SCs are organized as cellular hierarchies, in which SCs make
up a small fraction of the cell population [
34
]. SCs can divide either symmetrically
or asymmetrically. In symmetric division, two similar SCs are produced, i.e., the
SC proliferates. Asymmetric division, in contrast, yields one SC and one daughter
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