Biomedical Engineering Reference
In-Depth Information
the inner cell mass (ICM), that then produces all the structures of the embryo and
subsequently the adult organism. In mammals, the totipotent zygote also gives rise to
cells that will give rise to the extraembryonic lineages including the trophoblast that
will support the development of the embryo in the postimplantation period. During
development derivatives of the pluripotent ICM become more specialized or differenti-
ated and typically lose the ability to give rise to a wide variety of differentiated deriva-
tives. But the pluripotent ICM also gives rise to a new population of germ cells,
specialized cells committed to giving rise to gametes, which can recapitulate the whole
process over and over again. Thus, the germ cells go through a period of extreme dif-
ferentiation in which they can truly be considered specialized cells. Indeed it is difficult
to imagine two cells types, an egg and a sperm, that are more different from each other.
Yet the unique properties of these two highly specialized cells types somehow carry
the genome in a way that allows reprogramming of the genome in order that it can be
utilized to re-create a totipotent zygote that can in turn create a new organism. In the
normal lifecycle of most organisms there is no other cell type that has that ability.
Until relatively recently, it was thought that the genome of other specialized cells
in the embryo and adult was maintained in such a way that did not allow it to be
easily reprogrammed to give rise to either totipotent or pluripotent cells. But over
the last several years important advances have been made in understanding the
molecular mechanisms controlling developmental potency. Remarkably, studies
carried out in the last few years have demonstrated that differentiated cells, thought
to be restricted in their developmental potential, can be induced to return to a pluri-
potent state (Takahashi and Yamanaka
2006
). In this way, specialized cells are
turned into so-called induced pluripotent stem cells (iPSCs). These studies have
implicated a number of key genes as being important in the “reprogramming”
process. Included among those genes are key transcription factors already known
to control developmental potency such as Oct4, Nanog, and Sox2. In addition, these
studies identified the Kruppel-like factor-4 (Klf4) and Myc as also being important
for reprogramming of differentiated cells back to a pluripotent state (Takahashi and
Yamanaka
2006
). But these remarkable studies have not been the first to demon-
strate that specialized cells can be programmed into pluripotent stem cells. Previous
studies have shown that germ cells can be reprogrammed into pluripotent stem cells
both
in vivo
and
in vitro
(Matsui et al.
1992
; Resnick et al.
1992
; Stevens
1967a
).
Indeed pluripotent stem cells derived from germ cells were the first pluripotent
stem cells to be described (Stevens
1967a
). Unlike the reprogramming of differenti-
ated somatic cells, which involves introduction of genes or proteins into cells,
reprogramming of germ cells into pluripotent stem cells
in vitro
only requires the
addition of growth factors to the cells (Matsui et al.
1992
; Resnick et al.
1992
).
Importantly, the reprogramming of germ cells in this way provides an important
insight into how reprogramming might be achieved more efficiently and how
specific signaling pathways act to reprogram cells to a pluripotent state. Additionally,
the analysis of how germ cells can give rise to pluripotent stem cells may provide
important information about how normal germ cell development proceeds and how
it sometimes can go wrong. Following is a review of the current knowledge of germ
cell reprogramming and how studies of germ cell reprogramming might be used to
develop methods for growth factor-mediated reprogramming of somatic cells.
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