The findings, reported in this week's Proceedings of the National Academy of Sciences, should accelerate stem cell research and offer new insights into cell biology that could aid in the development of treatments for diseases such as cancer and Parkinson's.
Embryonic stem cell research has been plagued by problems arising from undefined conditions for growing and differentiating stem cells. Embryonic stem cell culture dishes are commonly coated with inactivated fibroblast cells known as "feeder cells." These feeder cells offer embryonic stem cells a suitable attachment surface and also release largely uncharacterized nutrients into the culture medium that support stem cell growth in the undifferentiated state. A variety of other factors are also added to promote stem cell growth and, most importantly, force the cells to maintain their pluripotency-their ability to become a variety of other final, specialized types of cells.
The end result is that such conventional culture conditions often suffer large variability, and make it extremely difficult for scientists to tease out the impact of individual molecules on experimental results.
"Stem cell applications and studies have been hampered by using undefined culture conditions" says Sheng Ding, an assistant professor at Scripps Research who led the research.
Feeder cells can also introduce viral and other forms of contamination that may lead to rejection of stem cells by the human immune system, among other problems.
Ding and his colleagues set out to solve these culturing problems using high-throughput screening of a Scripps Research library of tens of thousands of synthetic small molecules in search of a compound that could eliminate the need for feeder cells and added factors. This initial screening led to the discovery of a class of pyrimidines that improved cell growth. Later, the team produced a library of analogs of this class that proved to include a single compound, dubbed "pluripotin," that supports self-renewal of mouse embryonic stem cells and maintains their pluripotency alone with only the addition of standard cell culture basal medium.
The Ding group has also shown that pluripotin improves the growth of human embryonic stem cells, although other factors are still required to maintain their pluripotency. However, the team is already screening the Scripps Research library to identify a synthetic compound or compounds that will single-handedly maintain the human cells as pluripotin does for mouse cells. Ongoing research with pluripotin has revealed that the compound controls the stem cells via a novel mechanism. Pluripotin appears to simultaneously block the activity of the proteins RasGAP and ERK1, both of which have cell differentiation inducing activity.
"The mechanism of pluripotin suggests new strategies for maintaining and propagating stem cells," says Ding. "Such a discovery of a single small molecule that operates through two different classes of targets to achieve a desired biological effect also has fundamental implications for drug discovery."
Work with pluripotin and compounds that may follow should dramatically improve researchers' ability to work effectively with stem cell lines, Ding says, and should facilitate the practical application of stem cell research in developing therapies.
The work also offers benefits beyond improved stem cell culture. "Pluripotin and other such molecules are likely to provide insights into the molecular mechanisms that control stem cell fate and ultimately may be useful for in vivo stem cell biology and therapy studies," says Ding.
In addition to Ding, authors of the paper, titled "Self-renewal of embryonic stem cells by a small molecule," are: Shuibing Chen, Qisheng Zhang, and Shuyuan Yao of The Scripps Research Institute; Jeong Tae Do and Hans R. Schöler of the Max Planck Institute for Molecular Biomedicine; Feng Yan and Eric C. Peters of the Genomics Institute of the Novartis Research Foundation; and Peter G. Schultz of The Scripps Research Institute and the Novartis Research Foundation.
The project was supported by the Genomics Institute of the Novartis Research Foundation.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.
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