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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, Ph.D.,
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, Ph.D, 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. |
