ES cell model could provide clues to causes, cures for diabetes

By studying embryonic stem cells from a mouse, researchers at UW–Madison have identified a potential model system for elucidating the stages of normal pancreatic development, as well as for developing a much-needed source of insulin-producing cells for the millions of people who need them to treat their diabetes.

The findings are published in the July 25 issue of Diabetes, the journal of the American Diabetes Association (ADA).

The ADA estimates that 17 million people in the United States have diabetes. Between five and 10 percent of them are younger than 20 years old and have a form of this disease called Type I diabetes. This type develops when the body’s immune system destroys pancreatic islet cells that make the hormone insulin, which regulates blood-sugar levels. To control these levels, people with Type I diabetes must inject themselves daily with multiple insulin shots. Without these shots, many could die.

“Patients with Type I diabetes need a replacement of islet cells or whole pancreas transplants,” says Jon Odorico, a UW–Madison Medical School transplant surgeon and senior author of the paper. But, he adds, “There’s a huge shortage of cadaver donors – the main source for the transplants. A lot of people are looking for alternatives.”

According to the latest study, embryonic stem cells – cells that have the ability to differentiate into, or form, any adult cell – could be one of them. “They could be a source for replacing the patient’s own damaged islet cells,” says the Wisconsin surgeon.

In the study, the researchers watched mouse embryonic stem cells differentiate into a variety of cells with specific functions. Of most interest to them were those cells involved in the formation of the pancreas, including its clusters of hormone-producing islet cells. The researchers found that the mouse stem cells, cultured in serum with no added growth factors, differentiated into pancreatic precursor cells and islet cells producing four types of hormones, including insulin and glucagon.

But the study goes beyond confirming the ability of embryonic stem cells to form cells critical to regulating the body’s blood sugar. The researchers say it offers a much-needed model for studying normal pancreatic development.

“In the process of identifying differentiated cell types, we carefully characterized the stages of their development,” says Odorico. “These stages appear to recapitulate many aspects of normal development.” In other words, islet and pancreatic precursor cells that were differentiated from embryonic stem cells in vitro, or outside the body, developed in ways similar to those differentiated in vivo, or inside the body.

For example, the cultured cells, just like those in the body, began to show features of early embryonic pancreas cells, such as the expression of specialized early transcription factors important for the formation of the pancreas. They also showed similar patterns of islet hormones, expressed genes that help regulate islet cells and ultimately generated insulin-producing cells.

“If human embryonic stem cells can be shown to differentiate to islets in this way with this culture system, then we can use this system to compare mouse and human pancreas developmental pathways for the first time,” explains Odorico. Because access to fetal pancreatic material is limited, he adds, “most of what we think we know about human pancreatic development is merely extrapolated from mouse studies.”

This model based on mouse embryonic stem cells that identifies their differentiation into pancreatic precursor cells and islet cell types, says Odorico, “should provide a valuable tool to study normal islet and pancreatic development. One could potentially use this model to identify novel genes and learn how islets form.”

From all this, he adds, researchers could gain better insight into the causes of pancreas-related disorders, such as diabetes, and possibly develop better stem cell-based therapies.

The work was supported in part through grants from the Roche Organ Transplant Research Foundation, the Juvenile Diabetes Research Foundation, the National Institutes of Health and the UW Medical School under the Howard Hughes Medical Institute Research Resources Program for Medical Schools.