February 23, 2004
Compound Converts Stem Cells To Heart Muscle Cells

Scripps Research Institute researchers have discovered a molecule called cardiogenol C that will turn mouse embryonic stem cells into heart muscle cardiomyocyte cells. (same article here)

A group of researchers from The Skaggs Institute for Chemical Biology at The Scripps Research Institute and from the Genomics Institute of the Novartis Research Foundation (GNF) has identified a small synthetic molecule that can control the fate of embryonic stem cells.

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.

The researchers developed a means to test 100,000 molecules in a fairly automated fashion to find a few compounds that appeared to have the ability to cause stem cells to convert into heart muscle 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.

The article, "Small Molecules that Induce Cardiomyogenesis in Embryonic Stem Cells" was authored by Xu Wu, Sheng Ding, Qiang Ding, Nathanael S. Gray, and Peter G. Schultz and is available to online subscribers of the Journal of the American Chemical Society at: http://pubs.acs.org/cgi-bin/asap.cgi/jacsat/asap/abs/ja038950i.html. The article will also be published in an upcoming issue of the Journal of the American Chemical Society.

This is not the first use by Scripps researchers of an automated method to screen tens of thousands of compounds for activity that changes the diferentiation state of cells. Fairly recently some of the same Scripps researchers (Sheng Ding and Peter Schultz mentioned above) have also recently also discovered a molecule called reversine that will dedifferentiate (convert into a less specialized form) muscle cells into stem cells.

A group of researchers from The Scripps Research Institute has identified a small synthetic molecule that can induce a cell to undergo dedifferentiation--to move backwards developmentally from its current state to form its own precursor cell.

This compound, named reversine, causes cells which are normally programmed to form muscles to undergo reverse differentiation--retreat along their differentiation pathway and turn into precursor cells.

The technique involved in the search for reversine also was able to test tens of thousands of compounds.

The team hit upon reversine by systematically treating mouse muscle cells with some 50,000 different candidate molecules that they hoped might stick to and switch on enzymes capable of producing dedifferentiation

To do stem cell therapies we need the ability to put cells into various states of differentiation. Adult stem cells and progenitor cells can be thought of as being in partially differentiated states. We need the ability to put cells into those partially differentiated states in order to be able to replenish adult stem cell reservoirs. We also need the ability to shift cells into fully differentiated states. There are likely hundreds and perhaps even thousands of different states that cells can be in and we need the ability to put cells into many of those states. The Scripps researchers are making progress developing tools and techniques that automate the testing of compounds for the ability to change the differentiation state of cells into different cell types.

Automation is speeding up the rate of advance of biological science and biotechnology.

See this previous post for more on reversine.

Share |      Randall Parker, 2004 February 23 12:49 AM  Biotech Organ Replacement

L. REGIS BARRETO said at June 20, 2004 7:24 PM:

Im working at UNESP-S. Paulo-Brazil with some models to treat enlarged heart of childrens with muscular distrophy and failure heart because this kids dont have distrophyn.
Im very interesting to know more about Cardiogenol C, and how to do to get it.

Best regards
L. Regis Barreto,M.D.

PS.Id like if its possible to visit your laboratory to learn more about reversine and Cardiogenol.

Ken H said at August 14, 2004 8:05 AM:

I am curious if there is any supstantial information on stem cell research for ms.. If so what are the guidelines for getting involved in this.
If anyone has any information on this please email me with the information.
thank you.

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