Feb. 19, 2004 Scientists have found a way to turn mouse embryonic stem cells into beating heart muscle cells - a result that could lead to the use of embryonic stem cells in cardiac therapy, and possibly even drugs that can prompt the body to regenerate heart cells on its own.
The research, which appears in the Feb. 18 print edition of the Journal of the American Chemical Society, a peer-reviewed journal of the world's largest scientific society, tackles a number of the obstacles thwarting practical applications of embryonic stem cells, while also pointing to a viable path around the ethical and political concerns encompassing the debate.
Because embryonic stem cells can turn into any type of cell in the body, many scientists believe they hold incredible promise for treating a variety of degenerative diseases. Quite a few scientific hurdles, however, stand in the way of tangible therapies for such maladies as diabetes, Alzheimer's, Parkinson's and heart disease.
"We have discovered a synthetic chemical, named cardiogenol, which can selectively differentiate embryonic stem cells into beating cardiac muscle cells," says Xu Wu, a graduate student in the lab of Peter G. Schultz, Ph.D, professor of chemistry at The Scripps Research Institute in La Jolla, Calif. Embryonic stem cells represent a potentially unlimited source of cardiomyocytes - cells that can repair damaged heart tissue in the body - but until now scientists have been unable to control the direction of embryonic stem cells to use them in the treatment of heart disease.
Schultz and his coworkers at Scripps, including Wu and assistant professor Sheng Ding, Ph.D., screened a vast library of compounds in search of molecules with the potential to cause stem cells to grow into heart muscle cells. They found four such molecules, which they named cardiogenol A-D.
They tested the cardiogenol compounds by using embryonic stem cells from mice. After seven days growing in a tissue culture dish, the majority of the stem cells were converted into beating cardiac muscle cells.
While the tests were done only with mouse cells, the fundamental biology should transfer well to higher organisms. "By using these molecules to understand the underlying biology, it should be possible to extend this discovery to humans," Wu says.
In a different paper published recently in the Journal of the American Chemical Society, Ding and his colleagues reported the discovery of another small molecule - called reversine - that appears to convert adult cells normally programmed to create skeletal muscles back into precursor cells with similar properties as stem cells.
"This type of research may ultimately facilitate development of drugs that can stimulate tissues to regenerate themselves, without any need to harvest external stem cells," Ding says. "We think this represents an exciting medical opportunity."
Much more work is required to understand the biological properties and mechanisms of reversine, but these preliminary results raise the tantalizing possibility that it may be possible to synthesize a compound that creates viable stem cells from adult tissue, Ding says. Such cells would not be rejected by the immune system, since they come directly from the patient who needs them.
A molecule like reversine could be combined with a cardiogenol-type molecule to produce a drug that kindles regeneration of heart tissue. "Almost every tissue has its own reserve of stem cells, so ultimately we hope we don't have to isolate those cells from the body," Ding says. "We can stimulate tissue to regenerate by just stimulating cells within the body."
This type of regeneration already occurs in a number of natural processes. In lower organisms, for example, urodele amphibians can regenerate lost limbs and tails. "In humans and other mammals, the liver can regenerate naturally," Ding says. "And young children can even regenerate fingertips."
All of these processes are directed by molecular signaling. "If people can develop small molecule therapeutics to precisely mimic and control those signals for correcting defects or repairing damaged tissues, you could eventually buy those in a pharmacy as a prescription drug," Ding says.
Not only would this alleviate some of the ethical concerns surrounding stem cells, but also a less-frequently discussed downside to stem cell treatments: their invasiveness. Small-molecule therapies involving regenerative medicine are probably years away from clinical use. At present, Schultz, Wu and other coworkers are focusing on understanding cardiogenol's mechanism of action, and designing future experiments to test these molecules in disease models.
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