It has been many years that scientists have been looking for a good source of heart cells in order to study cardiac function in the lab, or perhaps even to replace diseased or damaged tissue in heart disease patients; a lot of people are looking to stem cells.
Now, researchers at Sanford-Burnham Medical Research Institute, the Human BioMolecular Research Institute, and ChemRegen, Inc. have discovered a molecule that converts stem cells into heart cells. It could be used to replace diseased or damaged tissue in heart disease patients.
A paper in the August 3 issue of Cell Stem Cell, describes how the team sorted through a large collection of drug-like chemicals and uncovered ITD-1. This molecule 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," says Mark Mercola, Ph.D., senior author of the study. "Using a drug to create new heart muscle from stem cells would be far more appealing than heart transplantation."
Stem cells are significant for doing two unique things; first of all, they self-renew, producing more stem cells, and second, they differentiate, becoming other, more specialized cell types. To get hold of 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 team has been tracking heart-inducing signals for 15 years, in both 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.
Using sophisticated robotic technology, they methodically tested 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 possibilities for ITD-1 are wide-ranging. "This particular molecule could be useful to enhance stem cell differentiation in a damaged heart," said 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."
San Diego biotech company ChemRegen, Inc.is now working with Mercola, Willems, and Cashman to advance ITD-1 into a drug that one day might be used to treat patients.
The researchers determined that ITD-1 blocks a cellular process known as TGFϐ signaling. TGFϐ, which is an acronym 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, eventually altering cellular behavior; in this case, making heart muscle.
ITD-1 triggers degradation of the TGFϐ receptor, thus inhibiting the entire 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.
Small Molecule-Mediated TGF-β Type II Receptor Degradation Promotes Cardiomyogenesis in Embryonic Stem Cells
Cell Stem Cell, Volume 11, Issue 2, 242-252, 3 August 2012.