Vol 5. Issue 38 / December 12, 2005

Scientists Discover Small Molecule That Generates Neurons from Adult Stem Cells

By Eric Sauter

A group of scientists from The Scripps Research Institute and the Salk Institute for Biological Studies have uncovered a synthetic small molecule that generates functional neurons from adult neural stem cells.

The molecule, named neuropathiazol, selectively and potently induces neuronal differentiation of neural stem or progenitor cells. The results of this study, published in the December issue of the international edition of the journal Angewandte Chemie, may ultimately help in the development of future small molecule therapeutics that could stimulate the regeneration of neurons in patients suffering from neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, or brain injuries.

The study was led by Sheng Ding, an assistant professor in the Scripps Research Department of Chemistry and The Skaggs Institute for Chemical Biology.  Co-authors included Scripps Research investigators Peter G. Schultz, Masaki Warashina, and Kyung Hoon Min; and Tomoko Kuwabara, Alexis Huynh, and Fred H. Gage of The Salk Institute for Biological Studies. The study was supported by funding from Scripps Research and the Novartis Research Foundation.

Stem Cells and Small Molecules

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 produce 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 of a potential medical application 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 the promise of this type of therapy, 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.

The research team led by Ding has been taking a discovery approach to finding small molecules that can control stem cell fate. Previously, the scientists reported discoveries of various small molecules that can turn embryonic stem cells into neurons or cardiac muscle cells; turn mesenchymal stem cells into bone cells; and induce a cell to undergo dedifferentiation, moving cells backwards developmentally from its current state to form its own precursor cell.

As part of this effort, Ding and his colleagues have created extensive chemical and genomic libraries. In fact, their combinatorial chemical library contains more than 100,000 discrete and diverse bioactive small molecules, and high throughput screening uses various automated assays to search such large numbers of substances for a specific activity.

For the current study, the researchers tested tens of thousands of small molecules in the process of identifying neuropathiazol, which they found can highly selectively turn more than 90 percent of primary adult hippocampal neural progenitors into neurons in tissue culture.

The researchers believe this study provides an important step forward, opening new avenues to understanding how to control neural stem cell fate.

Still, many questions remain. What are the precise molecular mechanisms of action? What would be the best way to translate such discoveries into therapies? Is cell replacement therapy necessary, or could small molecule therapeutics be developed to target the neural progenitor cells already in our brains, stimulating our body's own regenerative capabilities? 

Ding, for one, believes in the regenerative approach. "Ultimately, small molecule drugs that control the fate of existing stem/progenitor cells in our body could represent a new form of future regenerative medicine," he said.


Send comments to: mikaono[at]scripps.edu





Assistant Professor Sheng Ding led the study published in this month's edition of the journal Angewandte Chemie. Photo By Kevin Fung.




A synthetic small molecule, neuropathiazol, selectively induces neuronal differentiation of primary hippocampal neural progenitor cells. (Red: beta-III tubulin staining of neurons.)