Using a new technique, researchers produced human insulin-producing beta cells from stem cells and used them to cure mice with severe diabetes for at least nine months.
“These mice had very severe diabetes with blood sugar readings of more than 500 milligrams per deciliter of blood—levels that could be fatal for a person—and when we gave the mice the insulin-secreting cells, within two weeks their blood glucose levels had returned to normal and stayed that way for many months,” says principal investigator Jeffrey R. Millman, assistant professor of medicine at the School of Medicine and of biomedical engineering at the McKelvey School of Engineering at Washington University in St. Louis.
Several years ago, the same researchers discovered how to convert human stem cells into pancreatic beta cells that make insulin. When such cells encounter blood sugar, they secrete insulin. Still, the previous work had its limitations and had not effectively controlled diabetes in mice.
Now, the researchers show the new technique can more efficiently convert human stem cells into insulin-producing cells that do a better job controlling blood sugar.
“A common problem when you’re trying to transform a human stem cell into an insulin-producing beta cell—or a neuron or a heart cell—is that you also produce other cells that you don’t want,” Millman says. “In the case of beta cells, we might get other types of pancreas cells or liver cells.”
Off-target pancreas and liver cells don’t hurt anything when implanted into a mouse, but they don’t fight diabetes either.
“The more off-target cells you get, the less therapeutically relevant cells you have,” Millman says. “You need about a billion beta cells to cure a person of diabetes. But if a quarter of the cells you make are actually liver cells or other pancreas cells, instead of needing a billion cells, you’ll need 1.25 billion cells. It makes curing the disease 25% more difficult.”
Using the new technique, the researchers found far fewer off-target cells were produced while the beta cells that were made had improved function. The technique targets the cells’ internal scaffolding, called the cytoskeleton—what gives a cell its shape and allows the cell to interact with its surrounding environment, converting physical cues into biochemical signals.
“It’s a completely different approach, fundamentally different in the way we go about it,” Millman says. “Previously, we would identify various proteins and factors and sprinkle them on the cells to see what would happen. As we have better understood the signals, we’ve been able to make that process less random.”
Understanding that process has allowed Millman’s team to produce more beta cells. Importantly, the new technique works efficiently across stem cells from multiple sources, greatly expanding the ability of this technique in the study of disease.
“We were able to make more beta cells, and those cells functioned better in the mice, some of which remained cured for more than a year,” Millman says.
There still is much to do before researchers can use the strategy to treat people with diabetes, researchers say. They will need to test the cells over longer periods of time in larger animal models and work to automate the process to have any hope of producing beta cells that can help the millions of people who currently require insulin injections to control their diabetes.
The study appears in Nature Biotechnology. The National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of General Medical Sciences, the National Cancer Institute, and the National Center for Advancing Translational Sciences of the National Institutes of Health funded the work.
