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New stem cell line provides safe, prolific source for disease modeling and transplant studies

April 6, 2012 By AxoGen, Inc.

Researchers have generated a new type of human stem cell
that can develop into numerous types of specialized cells, including
functioning pancreatic beta cells that produce insulin. Called endodermal
progenitor (EP) cells, the new cells show two important advantages over
embryonic stem cells and induced pluripotent stem cells: they do not form
tumors when transplanted into animals, and they can form functional pancreatic
beta cells in the laboratory.

“Our cell line offers a powerful new tool for modeling
how many human diseases develop,” said study leader Paul J. Gadue, Ph.D.,
a stem cell biologist in the Center for Cellular and Molecular Therapeutics at
The Children’s Hospital
of Philadelphia.
“Additionally, pancreatic beta cells generated from EP cells display
better functional ability in the laboratory than beta cells derived from other
stem cell populations.”

In addition to producing beta cells, the researchers also
directed EP cells to develop into liver cells and intestinal cells—both of
which normally develop from the endoderm tissue layer early in human
development.

Gadue and colleagues are publishing their study Friday,
April 6 in the journal Cell Stem Cell.

The researchers manipulated two types of human stem
cells—embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)—to
become EP cells. Because both stem cell populations proliferate in great
numbers and potentially generate all types of tissue, they offer enormous
promise for scientists to precisely control cell development, both for the
study of basic biology and for future cell-based treatments.

ESCs are derived from human embryos, typically unused
embryos from fertility treatments that are donated for research purposes, while
iPSCs are engineered from human somatic cells, such as skin cells or blood
cells. Researchers have learned how to reprogram somatic cells to become
pluripotent. Like ESCs, iPSCs are able to develop into many other types of
human cells. However, when undifferentiated ESCs or iPSCs are transplanted in
animal studies, they form teratomas, tumors containing many different cell
types. Therefore, it has been critical that any cell type generated from ESCs
or iPSCs and used for transplantation is stringently purified to exclude
undifferentiated cells with tumor-forming potential.

In the current study, the researchers used signaling
molecules called cytokines to steer ESCs and iPSCs into becoming EP cells,
committed to developing into endoderm, one of the three tissue layers found in
early human development. The EP cells have nearly unlimited potential for
growth in the laboratory.

Both in cell cultures and when transplanted into animals,
the study team showed that EP cells can differentiate into multiple cell types,
representing those found in the liver, pancreas and intestine. Importantly,
undifferentiated EP cells did not form teratomas in the team’s transplantation
studies.

In cell culture, the researchers differentiated the EP cells
into beta cells—insulin-expressing cells similar to those found in the
pancreas. Those engineered beta cells passed an important test—when stimulated
by glucose, they were able to release insulin, a function that is impaired or
absent in patients with diabetes. While the cells achieved only 20 percent of
normal function, this result is an improvement over that seen in similar cells
derived directly from ESCs or iPSCs, which typically respond very poorly or not
at all to glucose.

Gadue stressed that these promising early results are only
the first steps in researching EP cells. Further work may focus on taking cells
from individual patients with genetic forms of diabetes or liver disease to
derive EP cell lines. The EP cell lines can then be used to model the
development and progression of the patient’s disease and discover new therapies
for that particular disease.

Finally, although applying this science to cell therapy is
years away from practical clinical use, EP cells may offer a powerful starting
point for developing tissue replacement treatments, such as supplying beta
cells for diabetes patients or hepatocytes (liver cells) for patients with
liver disease. “While more work is needed to characterize EP cells, they
may offer a potential source of safe, abundant cells for future diabetes
treatments,” said Gadue.

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