Embryonic Stem Cells as a Module for Systems Biology - Systems Biology: Networks, Models, and Applications - page 297

programs of genes recruited for driving the progression of differentia-
tion and the migration of clusters of embryonic cells. The timing of
activation and repression of genetic pathways is central to this process.
There is also a specific spatial orientation of cellular populations
during development in which signals from the environment and cues
to individual cells are critical to the three-dimensional growth of the
embryo. Large data sets can and are being collected for these primary
components of development.
One way to discover the nature of the interaction between these com-
ponents is to envisage each collection of cells in time and space as having
its own set of rules guiding the genetic elements from which we can
derive all possible information exhaustively. As the embryo increases in
cellular and tissue complexity, new genetic elements and networks are
brought into play while established genetic pathways are shut down or
continue to work the same way or take on new interactive functions. The
integration of these many layers of high-density genetic information to
reveal natural laws governing the propelling of development by the
genome can only be possible with an approach that incorporates the
computational underpinnings of systems biology (figure 10.1).
Embryonic stem (ES) cells, first characterized from the mouse in 1981
[6,7], are derived from one of the three cell types present in the blasto-
cyst. The blastocyst (figure 10.2), consisting of approximately 64 cells in
the mouse, is the cellular structure that forms approximately 3.5 days
after fertilization over which time the highly differentiated oocyte and
sperm haploid genomes have reprogrammed to initiate the new zygotic
genome's genetic regulatory program.
Within the blastocyst, the trophectoderm (the outer cell layer) and
the primitive endoderm give rise to extraembryonic structures whereas
the epiblast (also referred to as the inner cell mass, ICM) gives rise to
all cell types of the embryo proper and of the resulting adult. In culture,
in addition to replicating indefinitely in the undifferentiated state, ES
cells maintain this pluripotent developmental potential of the epiblast
and indeed, if injected back in the blastocyst, ES cells are capable of
giving rise to all these cell types.
These characteristics of mammalian ES cells provide us with a great
resource for molecular and biochemical studies aimed at understand-
ing the earliest events in mammalian development. In practical terms,
human ES cells, first derived in 1998 [8], hold enormous potential for
regenerative medicine. The molecular mechanisms governing the fate
decisions of ES cells are minimally understood, yet an understanding
of this machinery is fundamental to the successful applications of stem
cells in regenerative medicine and other potential clinical applications
[9]. This is why there is great interest in expanding our knowledge to a
systems level of understanding of the ES cell and its developmental
derivatives (figure 10.2).