research frontline, october 2009

Beta Cells Survive and Flourish in an Encapsulation Device

Key Point: The study provides proof-of-concept that insulin-producing cell progenitors can survive, proliferate, and mature in an encapsulation device to the point where they can correct diabetes. "This approach may be an important step in our ability to translate the transplantation of human embryonic stem cell-derived progenitors into clinical testing," said Julia Greenstein, Ph.D., Director of JDRF's Replacement research program.

JDRF-funded researchers have made important discoveries in encapsulation that could improve the success of islet transplantation.

In a study in mice, scientists showed for the first time that transplanted cells that become insulin-producing cells can survive being encapsulated in a durable "device" that protects the cells against an immune attack. Equally important, those cells then developed into insulin-producing cells that could control rising blood sugar levels. By contrast, adult insulin-producing cells that were encapsulated in the same way exhibited poor survival.

The results suggest that encapsulating cells before they are differentiated and become beta cells-using stem cells, for example-may be a more successful approach to replacing insulin-producing cells in people with type 1 diabetes and a new way to take advantage of emerging cell-based therapies.

"Our data suggest that long-term protection of human beta cells in type 1 diabetic patients without immunosuppression is a realistic goal," said Pamela Itkin-Ansari and colleagues from the University of California, San Diego and the Burnham Institute for Medical Research in La Jolla, California. Their findings were reported in the journal Transplantation.

Transplanting insulin-producing cells is an important treatment option for adults with type 1 diabetes who have hypoglycemia unawareness, a life-threatening condition in which people can no longer sense dangerously low blood sugar levels. But the procedure has two main limitations. First, people who get transplants need to take immunosuppressive drugs for the rest of their lives to prevent the rejection of the donated islets, even though these drugs can cause health problems and damage the transplanted cells. Second, there are too few donors to make transplantation a widely available option.

A solution to both problems would be to transplant cells from another source and to encapsulate these cells in a material that protects them from the immune response. Shielding the transplanted cells would mean there is no need for immunosuppressive drugs-and by using stem cells as the transplant source, people with type 1 diabetes would have access to a potentially unlimited supply of transplantable cells. To date, however, most islet encapsulation studies have used delicate devices made of semi-solid materials that may deteriorate over time. Such encapsulation is not ideal for stem cells in people because there is a concern that stem cell preparations may harbor cells with the potential to cause cancer.

With their principal goal to identify a way to safely deliver stem cell-derived therapies, Dr. Itkin-Ansari and her team set out to test a durable "macroencapsulation" device made by TheraCyte, Inc. The device, already shown to be biologically inert in people, has an inner layer with pores small enough to allow insulin, but not the enclosed cells, to flow out.

Main findings

To see whether cells within the encapsulation device would survive and function well, the researchers first tested it in mice that are unable to mount a strong immune response. This allowed them to eliminate the variable of immune rejection. They transplanted the mice with either encapsulated adult human islets or cells that would become insulin-producing cells. Other mice were transplanted with unencapsulated islets.

The encapsulated, insulin-producing cell precursors thrived within the device. Ten weeks after transplantation, they were producing insulin, glucagon, and other hormones that indicated normal function. In fact, the fraction of encapsulated cells producing insulin had nearly tripled since the transplantation.

The percentage of replicating cells was strikingly high-almost four times as high as in the mice that did not receive encapsulated cells. This suggests that the environment within the device not only allowed the cells to replicate, but may also have promoted the process.

In most of the mice, the encapsulated cells were able to produce insulin in response to glucose by five months after transplantation. This was considered slow compared with the mice that received unencapsulated cells. However, when the mice were given a drug that selectively killed only mouse insulin-producing cells, the encapsulated, transplanted human precursor cells produced enough insulin to control the inevitable rise in blood glucose. Untransplanted mice became diabetic within 48 hours.

Significant cell death, then recovery

The researchers also did mouse-to-mouse transplants to assess how well the encapsulated tissue "took" and to see whether the new encapsulation device would provoke the immune system into an attack. They monitored the encapsulated precursor cells over a 50-day period.

What they observed was a dynamic process of cell death followed by regrowth and ultimately, robust long-term survival of the transplant.

Perhaps most noteworthy was that the encapsulation device did not stimulate a detectable immune response.

"In transplanted mice," they explained, immune cells "were not recruited to the tissue surrounding the device. This was somewhat surprising, given that severe insulitis [inflammation] was readily apparent in pancreases from the same mice. The data suggest that the encapsulated beta cells are invisible to the immune system, and this bodes well for long-term clinical translation of the technology."

Next steps

Dr. Itkin-Ansari will use funding from the California Institute of Regenerative Medicine to follow up on this work. She will conduct similar tests of the encapsulation device using progenitor cells derived from embryonic stem cells, working in collaboration with the biotechnology company Novocell, which recently developed a method for producing pancreatic precursor cells from human stem cells.