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.

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