"We found molecules that can direct the embryonic stem cells to [become] neurons," says Sheng Ding, who recently completed his Ph.D. work at TSRI and is becoming an assistant professor in the chemistry department. Ding is the lead author on the study, which is described in an upcoming issue of the journal Proceedings of the National Academy of Sciences.

"This is an important step in our efforts to understand how to modulate stem cell proliferation and fate," says Peter Schultz, Ph.D., TSRI professor of chemistry and Scripps Family Chair of TSRI's Skaggs Institute for Chemical Biology.

The Promise of Stem Cell Therapy Stem cells have huge potential in medicine because they have the ability to differentiate into many different cell types--potentially providing doctors with the ability to regenerate cells that have been permanently lost by a patient.

For instance, the damage of neurodegenerative diseases like Parkinson's, in which dopaminergic neurons in the brain are lost, may be ameliorated by regenerating neurons.

Another example is Type 1 diabetes, an autoimmune condition in which pancreatic islet cells are destroyed by the body's immune system. Because stem cells have the power to differentiate into islet cells, stem cell therapy could potentially cure this chronic condition.

However bright this promise, many barriers must be overcome before stem cells can be used in medicine. Scientists have yet to understand the natural signaling mechanisms that control stem cell fate and to develop ways to manipulate these controls.

"We still have much to learn about how to direct stem cells to specific lineages," says Ding.

In order to address this problem, Schultz and Ding sought to find small chemical molecules that could permit precise control over the fate of pluripotent mouse embryonic stem cells--which, like human embryonic stem cells, have the ability to differentiate into all cell types.

The scientists screened some 50,000 small molecules from a combinatorial small molecule library that they synthesized at GNF. Just as a common library is filled with different books, this combinatorial library is filled with different small organic compounds.

From this assortment, Schultz and Ding designed a method to identify molecules able to differentiate the cells into neurons. 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 neuronal cells.

Then they placed these EC cells into separate wells and added different chemicals from the library to each. If the engineered EC cells in any particular well were induced to become neurons, the neurons would express luciferase--which can convert a non-luminescent substrate to a luminescent product. This product makes that well easy to detect from tens of thousands of other wells with GNF's state-of-the-art high-throughput screening equipment.

Once they found some cells they believed to be neurons by treatment with certain small molecules, the scientists used more rigorous assays to confirm this, including staining the cells for characteristic markers and examining the shape of individual cells under the microscope. Neurons have a characteristic round soma body and asymmetric multiple processes.

In the end, Schultz and Ding found a number of molecules that were able to induce neuronal differentiation, and they chose one, called TWS119, for further studies.

When they examined the mechanism of TWS119 in detail, they found that it binds to a cellular kinase enzyme called glycogen synthase kinase-3beta (GSK-3beta). This is a multifunctional "signaling" enzyme involved in a number of physiological signaling processes whereby it modulates other enzymes by attaching a phosphate group to them.

The fact that modulating GSK-3beta leads the cells to become neurons reveals basic information on the complicated signaling cascade that turns a stem cell into a neuron. And the fact that TWS119 modulates the activity of GSK-3beta suggests that TWS119 is likely to provide new insights into the molecular mechanism that controls stem cell fate, and may ultimately be useful to in vivo stem cell therapy.

Schultz and Ding are still working on describing the exact mechanism whereby this binding directs the cell to become a neuron.

The article, "Synthetic Small Molecules that Control Stem Cell Fate" is authored by Sheng Ding, Tom Y.H. Wu, Achim Brinker, Eric C. Peters, Wooyoung Hur, Nathanael S. Gray, and Peter G. Schultz and will be available online next week at: http://www.pnas.org/cgi/10.1073/pnas.0732087100. The article will also be published in an upcoming issue of the journal Proceedings of the National Academy of Sciences.

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