JDRF Research
Producing Beta Cell Precursors From Stem Cells
Using a novel screening method, JDRF-funded researcher Shuibing Chen and colleagues from the Harvard Stem Cell Institute identified a small molecule that can help drive human embryonic stem cells along the path to becoming insulin-producing beta cells.
When embryonic stem cells were combined with the molecule and a key growth factor, nearly half of them developed into an essential, early precursor cell from which all of the specialized cells of the pancreas are derived, including beta cells. Other research that has sought to form insulin precursor cells from embryonic stem cells were far less effective.
Embryonic stem cells have the ability to develop into any type of cell or tissue as they mature, and hold the promise of being turned into insulin-secreting cells that could be transplanted into people with type 1 diabetes.
By uncovering a better way to generate pancreatic progenitor cells from human embryonic stem cells, this research could lead to less costly and faster ways of creating the large, unlimited supply of cells that would be needed for testing and treatment.
The research, published in the journal Nature Chemical Biology, was funded through a postdoctoral fellowship award to Dr. Chen and took place in the laboratory of Dr. Douglas Melton, one of the world's preeminent stem cell scientists.
How and Why
Adapting a method that is widely used to discover new drugs, Dr. Chen and colleagues screened a chemical library of 5,000 different compounds for their ability to increase the production of a key pancreatic precursor cell from embryonic stem cells. Dr. Chen's approach was atypical in that her search focused on small molecules rather than only on traditional growth factors and related compounds. Small-molecule inducers, as they are called, are typically less expensive to produce and, according to most experts, more easily controlled and possibly more effective in driving the differentiation of stem cells.
Dr. Chen's long-term objective is to identify the right combination of compounds that would allow her to mimic the natural signals occurring during the development of the pancreas. With this information, she hopes to create a clinically useful protocol for differentiating stem cells into functional, transplantable beta cells.
Main Findings
A compound called ILV stood out in its ability to move embryonic stem cells further toward beta cells. ILV directed the differentiation of a starting stem cell population to the next-step pancreatic progenitor cell stage. This effect became more pronounced (greater numbers of progenitor cells were formed) when more of the compound was used and when it was combined with a specific growth factor.
The researchers also showed that by adding additional agents, the stem cells were able to develop even further into various mature cells of the pancreas, including those that produce insulin.
Animal tests strongly supported ILV's potential. When ILV-treated stem cells were transplanted into mice, some of the cells matured and began to produce both insulin and c-peptide, suggesting that the ILV- and growth-factor treated stem cells are "capable of progressing through the pancreatic differentiation program in vivo [once transplanted into a body]."
On Deck
Next steps for the researchers will be to identify, at each step of the differentiation pathway, other small molecules that might promote the development of embryonic stem cell to beta cell. Studies are needed to determine the best cell stage at which to transplant-that is, what will have the best possible outcome for people with diabetes.
