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Cracking the code

Stem Cell Institute director Jakub Tolar, M.D., Ph.D., is making a cure for diabetes a top research priority. (Photo: Scott Streble)

Regenerating islet cells may lead to a cure for diabetes—which is why it’s a priority for the University’s Stem Cell Institute

For decades, researchers have focused much of their energy on minimizing the impact of diabetes. Because people with diabetes do not have functioning pancreas islet cells—essential for producing the insulin our bodies need—physicians and scientists have found ways to help them manage their blood sugar levels through lifestyle changes, medications, and insulin injections.

But Jakub Tolar, M.D., Ph.D., director of the University of Minnesota’s Stem Cell Institute, wants to think much bigger. He doesn’t just want to make it easier for patients to live with their diabetes; he wants to cure them of it. And that means replacing not insulin, but the nonfunctioning islet cells themselves.

“It’s not that different from replacing a part on a broken engine,” he explains. “If we can replace islet cells in high enough numbers, in high enough quality, [patients] will be cured of diabetes.”

Tolar’s goal is bold, and he’s putting the full weight of his organization behind it: he’s made diabetes a top-three priority of the Stem Cell Institute, where scientists are currently working on key projects to regenerate islet cells—and perhaps cure diabetes once and for all.

Assistant professors James Dutton, Ph.D., and Anannya Banga, Ph.D., for example, are working to convert stem cells in the liver into insulin-producing cells. Over the past five years, they have learned how to directly reprogram liver cells by using vectors that deliver genetic material into cells to “overexpress” specific genes in liver cells. If the process is done right, these reprogrammed cells can produce significant amounts of insulin.

The most recent combination vector these researchers have created, known as Ad-PNM, has proved to be the most potent ever produced. While scientists in the past have been encouraged when their work resulted in a cell that produced even one ten-thousandth of the amount of insulin a typical islet cell produces, the cells generated by Dutton and Banga produce about one-fifth of what’s made by a typical islet cell.

Scientist James Dutton, Ph.D., and colleagues are coaxing stem cells in the liver into becoming insulin-producing cells. (Photo: Shawn Sullivan)

“It’s a bit like Goldilocks,” Dutton says of the process. “The levels of gene expression provided by the vector are ‘just right.’”

More important, the resulting cells are having an impact. When the vector was injected into diabetic mice, the reprogrammed cells essentially restored the rodents’ normal glycemic levels.

While the researchers are hesitant to call the mice cured—only further long-term studies can help make that claim—they say early results are promising: “Our research now is focused on why this works so well and how we can translate it to patients.”

Meanwhile, researcher Meri Firpo, Ph.D., is teaming up with other scientists on two stem cell-linked projects. With researcher Anindya Bagchi, Ph.D., she is applying the lessons of cancer cells, which seem to defy death, to regenerating islet cells that have been destroyed or have failed.

Firpo and Bagchi are currently working to unravel the mechanisms of cell growth and death by studying the cellular pathways of healthy and dying islet cells in mice. They’re hopeful that they can eventually manipulate these cells to prevent their deaths. “We want to take advantage of those regulatory mechanisms in islets to get them to survive—or even regenerate,” Firpo explains.

Firpo is also working with Melanie Graham, Ph.D., M.P.H., on projects that use stem cell-derived islets in new transplantation technologies.

Islet transplantation can reverse some cases of diabetes, but the “containers” that hold the islet cells during and after transplantation have flaws. The pair is working closely with engineers to create a small device made from silicone that allows stem cell-derived islets to more effectively “read” how much glucose is in the blood and then secrete insulin in proportion to that reading.

Firpo’s team is one of three U groups working to develop and perfect the “containers” that would potentially hold transplanted or regenerated human, pig, or stem cell-derived islets.

For Tolar, groundbreaking projects like these give the University an edge in diabetes research.

“Our goal,” he says, “is to contribute in a unique way to this collective knowledge and collective effort to cure diabetes.”

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