Gene that directs fate of many embryonic stem cells identified

Scientists have identified the gene that prompts embryonic stem cells to
generate precursors to most internal organs. The finding suggests a potent new
way of coaxing stem cells to produce high numbers of specialized cells that can
form medically needed tissues such as insulin-producing pancreatic cells, the
scientists say.

The research led by University of California, San Francisco scientists is based
on studies of zebrafish, an animal that has become a powerful model of early
human embryo development. Strong evidence indicates that the pivotal gene plays
the same role in humans as it does in zebrafish: inducing embryonic stem cells
to produce endoderm, the source material for many specialized cells and
tissues, including the pancreas, liver, thymus and thyroid.

“Exploiting this master gene, we can control stem cell differentiation from the
inside, as opposed to trying to boost differentiation from the outside with
growth factors,” said Didier Stainier, PhD, UCSF associate professor of
biochemistry and biophysics and senior author on a paper reporting the
research.

The study is published in the June 15 issue of Genes and Development.

Embryonic stem cells are the focus of intense research interest because their
ability to give rise to all tissues of the body make them a potentially vital
player in regenerative medicine.
The researchers dubbed the master gene they isolated casanova because mutant
animals lacking the gene have a split heart. Casanova or cas, the team found,
is essential and sufficient to prod embryonic stem cells into making endodermal
cells. These, in turn, give rise to many internal organs, as well as the lining
of the lungs and gut.

Ambitious new efforts to restore the insulin-producing capacity in people with
type 1 diabetes rely on injections of insulin-producing beta cells. But the
supply of these cells is severely limited. Endoderm gives rise to these beta
cells, and also to the liver’s hepatocytes. By harnessing casanova’s potent
effect, researchers would have a certain way to boost the supply of these vital
cells needed to cure rather than treat Type 1 diabetes and various forms of
liver disease, Stainier said.

“If you can gain access to the earliest stages of cell specialization through
the genes that directly control the process from within the cell,” Stainier
says, “you have a much more powerful tool to generate desired cells than if you
simply try to increase the numbers of needed cells after they have
specialized,” he concluded.

In the last two years, the UCSF team isolated two other genes central to
embryonic stem cell fate, named faust and bonnie and clyde. Like the first two,
casanova codes for a protein that directly controls gene expression in the
nucleus. Known as transcription factors, these proteins contact selected genes
and turn them on in response to some other signal. Casanova, the scientists
found, is the most potent director of stem cell fate into endoderm. It is the
“central regulator” of endoderm formation, they conclude.

In experiments that sound philosophical as well as biological, the researchers
demonstrated that they could change the fate of early embryonic cells by lacing
them with the cas gene. They first showed that mutant zebrafish lacking the
casanova gene failed to develop endoderm at all. In a second round of
experiments, embryonic stem cells that normally develop into mesoderm—source
material for the heart, kidney and muscles in all organisms—were
“transfated” into endoderm - the source for an entirely different set of
tissues. When just-fertilized embryos were injected with the cas gene, 100
percent of the embryonic stem cells that normally form mesoderm instead gave
rise to endoderm.

“The complete transformation of embryonic cell fate under the influence of the
casanova gene’s product, combined with the mutant experiments, demonstrate that
this gene is the central regulator of embryonic stem cell development into
endoderm,” Stainier said. “This gene appears to be a potent candidate to
improve the efficiency of directing embryonic stem cells to produce medically
needed cells and tissues.”

“Our next step is to demonstrate that the human casanova gene has the same
properties as the zebrafish gene.” Stainier said he fully expects this is the
case.

Lead authors on the paper are Yutaka Kikuchi, PhD, a postdoctoral scientist in
Stainier’s lab, and Antoine Agathon, a graduate student at the Institut de
Genetique et Biologie Moleculaire et Cellualaire in Strasbourg, France.
Co-authors and collaborators in the research are Deborah Yelon, PhD, a
postdoctoral scientist; Jonathan Alexander, graduate student, and Steven
Waldron, research associate, all in Stainier’s lab; and Christine and Bernard
Thisse, directors of research at the Institute in Strasbourg.

The research was funded by the National Institute of Health and the Packard
Foundation.