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| These are cardiomyocytes (heart muscle cells) generated from stem cells and expressing a green fluorescent protein. (Credit: Sanford-Burnham Medical Research Institute) |
For years, scientists have been looking for a good source of
heart cells that can be used to study cardiac function in the lab, or perhaps
even to replace diseased or damaged tissue in heart disease patients.
To do this, many are looking to stem cells. Researchers at
Sanford-Burnham Medical Research Institute (Sanford-Burnham), the Human
BioMolecular Research Institute, and ChemRegen, Inc. have been searching for
molecules that convert stem cells to heart cells for about eight years -- and
now they've found one.
Writing in the August 3 issue of Cell Stem Cell,
the team describes how they sifted through a large collection of drug-like
chemicals and uncovered ITD-1, a molecule that can be used to generate
unlimited numbers of new heart cells from stem cells.
"Heart disease is the leading cause of death in this
country. Because we can't replace lost cardiac muscle, the condition
irreversibly leads to a decline in heart function and ultimately death. The
only way to effectively replace lost heart muscle cells -- called
cardiomyocytes -- is to transplant the entire heart," said Mark Mercola,
Ph.D., director of Sanford-Burnham's Muscle Development and Regeneration
Program and senior author of the study. "Using a drug to create new heart
muscle from stem cells would be far more appealing than heart
transplantation."
Searching for a needle in a haystack
Stem cells are important because they do two unique things –
1) self-renew, producing more stem cells and
2) differentiate, becoming other, more specialized cell types.
To obtain a large number of a certain cell type, such as
heart cells, the hard part is figuring out the signals that direct them to
become the desired cell type.
Mercola's group has been hunting for heart-inducing signals
for 15 years -- in embryos and in stem cells. To find a synthetic molecule that
might one day lead to a drug therapy to regenerate the heart, they joined
forces with a team of medicinal chemists at the Human BioMolecular Research
Institute led by John Cashman, Ph.D.
With funding from the California Institute for Regenerative
Medicine, they used sophisticated robotic technology to methodically test a
large collection of drug-like chemicals, looking for that needle in a haystack
that, when added to stem cells, results in cardiomyocytes. The winning compound
was ITD-1.
Therapeutic applications
There's no shortage of therapeutic possibilities for ITD-1.
"This particular molecule could be useful to enhance stem cell
differentiation in a damaged heart," explained Erik Willems, Ph.D.,
postdoctoral researcher in Mercola's lab and first author of the study.
"At some point, it could become the basis for a new
therapeutic drug for cardiovascular disease -- one that would likely limit scar
spreading in heart failure and promote new muscle formation."
Mercola, Willems, and Cashman are now working with San Diego
biotech company ChemRegen, Inc. to further develop ITD-1 into a drug that one
day might be used to treat patients.
More scientific detail
The researchers discovered that ITD-1 blocks a cellular
process known as TGFϐ signaling. TGFϐ (short for transforming growth factor-ϐ)
is a protein produced by one cell type to influence others' behaviors, such as
proliferation, scarring, and even stem cell differentiation.
TGFϐ works from outside the cell, binding to a receptor on
the surface of a responding cell to initiate an intracellular signaling cascade
that causes genes to be switched on or off, ultimately altering cellular
behavior -- in this case making heart muscle.
ITD-1 triggers degradation of the TGFϐ receptor, thus
inhibiting the whole process. With TGFϐ signaling turned off, stem cells are
set on a course toward cardiogenesis. ITD-1 is the first selective inhibitor of
TGFϐ, meaning that it might also have applications in many other processes
controlled by TGFϐ.
Story Source:
The above story is reprinted from materials provided by Sanford-Burnham Medical Research
Institute, via EurekAlert!, a service of AAAS.
Note: Materials may be edited for content and length. For
further information, please contact the source cited above.
Journal Reference:
1.
Erik Willems, Joaquim
Cabral-Teixeira, Dennis Schade, Wenqing Cai, Patrick Reeves, Paul J.
Bushway, Marion Lanier, Christopher Walsh, Tomas Kirchhausen, Juan Carlos
Izpisua Belmonte, John Cashman, Mark Mercola. Small
Molecule-Mediated TGF-β Type II Receptor Degradation Promotes Cardiomyogenesis
in Embryonic Stem Cells. Cell Stem Cell, 2012; 11 (2): 242 DOI: 10.1016/j.stem.2012.04.025
