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a report by Sullivan and colleagues showing that ESCs enriched for G2 (by
growing to confluence) have an enhanced capacity to generate pluripotent
hybrid cells when fused to differentiated fibroblasts or primary thymocytes
(
Sullivan, Pells, Hooper, Gallagher, & McWhir, 2006
). Collectively, these
reports provide evidence that the cell-cycle stage of the “reprogrammers”
and their targets is likely to be important for reprogramming success and
that transition through S phase may facilitate the epigenetic remodeling
of differentiated cells.
6. CONCLUDING REMARKS
In this chapter, we have outlined data suggesting that altered cell-cycle
structure may be important for maintaining pluripotency and for successful
reprogramming. How cell cycle is controlled in ESCs is still unclear and it
seems likely that this will be the subject of intensive research in the future.
It is worth noting that the truncation of cell-cycle gap phases observed in
ESCs is reminiscent of what is seen in the early stages of developmental
of many other organisms. For example, in frogs and flies, embryogenesis
begins with multiple rounds of rapid cell cleavage that occur ahead of zygotic
transcription and cell specialization (
Etkin, 1988
). At this early stage in these
organisms, embryonic development is dictated largely by maternally derived
factors. In mouse and human, however, transcription from the zygote begins
earlier (at the 2- to 8-cell stage) (reviewed in
Tadros & Lipshitz, 2009
) and
cell specification begins as the inner cell mass is formed. It is intriguing
to speculate that the atypical cell-cycle structure of ESCs may represent
a developmental compromise or adaptation that enables the extensive
cell proliferation needed to generate the mammalian embryo to occur,
while simultaneously protecting pluripotent function. Somatic cell repro-
gramming is achieved by a range of approaches that appear to lock into
(or imitate) the circuitry of pluripotent self-renewal used by ESCs. Our
future challenge will be to better understand these circuits and how they
are dismantled as ESCs differentiate. This knowledge will become critical
in determining whether human ESCs and iPSCs have the potential for safe
use in future cell replacement therapies.
ACKNOWLEDGMENTS
We would like to thank our colleagues for discussions and the Medical Research Council,
UK, and Human Frontier Science Program for support.
