A fertilized egg is thought to possess full developmental potential,
able to generate all cell types required for embryo gestation,
including the developing embryo and its extra-embryonic tissues. A
unique feature of placental mammals, extra-embryonic tissues such as the
placenta and yolk sac are vital for nutrient and waste exchange between
the fetus and mother.
By contrast, most embryonic and induced pluripotent stem cells are
more restricted in their developmental potential, able to form embryonic
cell types, but not extra-embryonic tissues. The ability of a
fertilized egg to generate both embryonic and extra-embryonic tissues is
referred to as "totipotency," an ultimate stem cell state seen only
during the earliest stages of embryonic development.
‘A way to reprogram mouse embryonic stem cells so that they exhibit developmental characteristics resembling those of fertilized eggs, or zygotes, has been developed by researchers.’
way to reprogram mouse embryonic stem cells so that they exhibit
developmental characteristics resembling those of fertilized eggs, or
zygotes, has been developed by researchers from the University of California, Berkeley.
These "totipotent-like" stem cells are able to generate not only all
cell types within a developing embryo, but also cell types that
facilitate nutrient exchange between the embryo and the mother.
For now, the new stem cell lines UC Berkeley researchers have
created will help scientists understand the first molecular decisions
made in the early embryo. Ultimately, however, these insights could
broaden the repertoire of tissues that can be generated from stem cells,
with significant implications for regenerative medicine and stem
"Studies on embryonic development greatly benefit from the culture
system of embryonic stem cells and, more recently, induced pluripotent
stem cells. These experimental systems allow scientists to dissect key
molecular pathways that specify cell fate decisions in embryonic
development," said team leader Lin He, a UC Berkeley associate professor
of molecular and cell biology. "But the unique developmental potential
of a zygote, formed right after the sperm and egg meet, is very, very
difficult to study, due to limited materials and the lack of a
cell-culture experimental system."
He's new study not only reveals a novel mechanism regulating the
"totipotent-like" stem cell state, but also provides a powerful
cell-culture system to further study totipotency.
She and her colleagues reported their research online Jan. 12 in advance of print publication in the journal Science
MicroRNAs and stem cells
Embryonic stem (ES) cells, harvested from three-and-a-half-day-old
mouse embryos or five-and-a-half-day-old human embryos, are referred to
as pluripotent because they can become any of the thousands of cell
types in the body. They have generated excitement over the past few
decades because scientists can study them in the laboratory to discover
the genetic switches that control the development of specialized tissues
in the embryo and fetus, and also because of their potential to replace
body tissues that have broken down, such as pancreatic cells in those
with diabetes or heart muscle cells in those with congestive heart
failure. These stem cells can also let researchers study the early
stages of genetic disease.
As an alternative to harvesting them from embryos, scientists can
also obtain pluripotent stem cells by treating mature somatic cells with
a cocktail of transcription factors to regress them so that they are
nearly as flexible as embryonic stem cells. These artificially derived
stem cells are called induced pluripotent stem (iPS) cells.
Neither ES nor iPS cells, however, are as flexible as the original
fertilized egg, which can form extra-embryonic as well as embryonic
tissues. By the time embryonic stem cells are harvested from a mouse or
human embryo, the cells have already committed to either an embryonic or
an extra-embryonic lineage.
MicroRNAs are small, non-coding RNAs that do not translate into
proteins, yet have a profound impact on gene expression regulation. He
and her colleagues found that a microRNA called miR-34a appears to be a
brake preventing both ES and iPS cells from producing extra-embryonic
tissues. When this microRNA was genetically removed, both ES and iPS
cells were able to expand their developmental decisions to generate
embryo cell types as well as placenta and yolk sac linages. In their
experiments, about 20 percent of embryonic stem cells lacking the
microRNA exhibited expanded fate potential. Furthermore, this effect
could be maintained for up to a month in cell culture.
"What is quite amazing is that manipulating just a single microRNA
was able to greatly expand cell fate decisions of embryonic stem cells,"
He said. "This finding not only identifies a new mechanism that
regulates totipotent stem cells, but also reveals the importance of
non-coding RNAs in stem cell fate."
Additionally, in this study, He's group discovered an unexpected
link between miR-34a and a specific class of mouse retrotransposons.
Long regarded as "junk DNA," retrotransposons are pieces of ancient
foreign DNA that make up a large fraction of the mammalian genome. For
decades, biologists assumed that these retrotransposons serve no purpose
during normal development, but He's findings suggest they may be
closely tied to the decision-making of early embryos.
"An important open question is whether these retrotransposons are
real drivers of developmental decision making," said Todd MacFanlan, a
co-author of the current study and a researcher at the Eunice Kennedy
Shriver National Institute of Child Health and Human Development in
Co-authors with He are graduate student Yong Jin Choi, postdoctoral
fellows Chao-Po Lin and Davide Risso, graduate student Sean Chen and
undergraduate Thomas Aquinas Kim, along with statistics professor
Terence Speed of UC Berkeley. Meng How Tan and Jin Li of Stanford
University, Yalei Wu of Thermo Fisher Scientific in South San Francisco,
Caifu Chen of Integrated DNA Technologies in Redwood City, Zhenyu Xuan
of the University of Texas at Dallas, Weiqun Peng of George Washington
University in Washington, D.C., Kent Lloyd of UC Davis and Sang Yong Kim
of the New York University School of Medicine, all contributed to this