Scientists Discover Chemical that Turns Mouse Stem Cells
into Heart Muscles
By Jason Socrates Bardi
A group of researchers from The Skaggs Institute for Chemical
Biology at The Scripps Research Institute and from the Genomics
Institute of the Novartis Research Foundation (GNF) has identified
a small synthetic molecule that can control the fate of embryonic
stem cells.
This compound, called cardiogenol C, causes mouse embryonic
stem cells to selectively differentiate into "cardiomyocytes,"
or heart muscle cells, an important step on the road to developing
new therapies for repairing damaged heart tissue.
Normally, cells develop along a pathway of increasing specialization.
In humans and other mammals, these developmental events are
controlled by mechanisms and signaling pathways we are only
beginning to understand. One of scientists' great challenges
is to find ways to selectively differentiate stem cells into
specific cell types.
"It's hard to control which specific lineage the stem cells
differentiate into," says Xu Wu, who is a doctoral candidate
in the Kellogg School of Science and Technology at Scripps
Research. "We have discovered small molecules that can [turn]
embryonic stem cells into heart muscle cells."
Wu is the first author of the study to be published in an
upcoming issue of the Journal of the American Chemical
Society and which was conducted under the direction of
Peter G. Schultz, who is a professor of chemistry and Scripps
Family Chair of the Skaggs Institute for Chemical Biology
at The Scripps Research Institute, and Sheng Ding, who is
an assistant professor in the Department of Chemistry at Scripps
Research.
Regenerative Medicine and Stem Cell Therapy
Stem cells have huge potential in medicine because they
have the ability to differentiate into many different cell
types—potentially providing cells that have been permanently
lost by a patient. For instance, neurodegenerative diseases
like Parkinson's, in which dopaminergic neurons in the brain
are lost, may be ameliorated by regenerating neurons. And
Type I diabetes—in which beta cells are lost—might
be treated by generating new beta cells.
Likewise, a damaged heart, which is composed mainly of cardiac
muscle cells that the body may be unable to replace once lost,
could potentially be repaired with new muscle cells derived
from stem cells.
Scripps Research scientists reasoned that if stem cells
were exposed to certain synthetic chemicals, they might selectively
differentiate into particular types of cells. In order to
test this hypothesis, the scientists screened some 100,000
small molecules from a combinatorial small molecule library
that they synthesized. Just as a common library is filled
with different books, this combinatorial library is filled
with different small organic compounds.
From this assortment, Wu, Ding, and Schultz designed a method
to identify molecules able to differentiate the mouse embryonic
stem cells into heart muscle cells. They engineered embryonal
carcinoma (EC) cells with a reporter gene encoding a protein
called luciferase, and they inserted this luciferase gene
downstream of the promoter sequence of a gene that is only
expressed in cardiomyocytes. Then they placed these EC cells
into separate wells and added different chemicals from the
library to each. Any engineered EC cells induced to become
heart muscle cells expressed luciferase. This made the well
glow, distinguishing it from tens of thousands of other wells
when examined with state-of-the-art high-throughput screening
equipment. These candidates were confirmed using more rigorous
assays.
In the end, Wu, Ding, Schultz, and their colleagues found
a number of molecules that were able to induce the differentiation
of EC cells into cardiomyocytes, and they chose one, called
Cardiogenol C, for further studies. Cardiogenol C proved to
be effective at directing embryonic stem cells into cardiomyocytes.
Using Cardiogenol C, the scientists report that they could
selectively induce more than half of the stem cells in their
tests to differentiate into cardiac muscle cells. Existing
methods for making heart muscle cells from embryonic stem
cells are reported to result in merely five percent of the
stem cells becoming the desired cell type.
Now Wu, Ding, Schultz, and their colleagues are working
on understanding the exact biochemical mechanism whereby Cardiogenol
C causes the stem cells to differentiate into cardiomyocytes,
as well as attempting to improve the efficiency of the process.
The article, "Small Molecules that Induce Cardiomyogenesis
in Embryonic Stem Cells" was authored by Xu Wu, Sheng Ding,
Qiang Ding, Nathanael S. Gray, and Peter G. Schultz and is
available to online subscribers of the Journal of the American
Chemical Society at: http://pubs.acs.org/cgi-bin/asap.cgi/jacsat/asap/abs/ja038950i.html.
The article will also be published in an upcoming issue of
the Journal of the American Chemical Society.
This work was supported by The Skaggs Institute for Research
and the Novartis Research Foundation.
Send comments to: jasonb@scripps.edu
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