Diabetes Research Institute Pioneers Safer Approach for Creating Insulin-Producing Cells

Scientists at the Diabetes Research Institute at the University of Miami Miller School of Medicine have successfully converted non-insulin-producing cells of the pancreas into insulin-producing cells using a single agent, bone morphogenetic protein-7 (BMP-7), which is already approved by the Food and Drug Administration for clinical use.

Their findings, published in the December issue of Diabetes, demonstrate for the first time that non-endocrine pancreatic tissue (NEPT) can be reprogrammed to respond to blood glucose without the use of any genetic manipulation, representing a safer and more efficient method to increase the limited supply of insulin-producing islet cells for transplant into people with type 1 diabetes.

Scientists have known for some time that one of the interesting features of NEPT (which comprises nearly 98 percent of the organ and is not a primary target of autoimmunity in type 1 diabetes) is its high plasticity, meaning that the non-endocrine pancreatic cells can be reprogrammed, or turned into, other cell types or tissues. However, conventional approaches to cell reprogramming entail genetic modification, which poses health risks to patients and has other drawbacks. The DRI team has pioneered the use of a novel, non-invasive means of cell reprogramming, which is expected to have a shorter path for testing in clinical transplantation trials.

“We discovered that the exposure of human pancreatic exocrine cells to BMP-7 alone results in their efficient conversion into insulin-producing clusters that respond to glucose both in the laboratory setting and after transplantation into diabetic rodents,” said Juan Dominguez-Bendala, Ph.D., Director of Stem Cell Development for Translational Research at the Diabetes Research Institute (DRI) and the study’s co-lead investigator. “Cells generated in this manner produced insulin levels between 50 and 250 times higher than previously published by other teams, which used genetically engineered viruses plus treatment with additional agents that are known to cause unpredictable genetic patterns in cells.

“What we’ve accomplished, a non-genetic conversion of human pancreatic exocrine-to-endocrine cells, is a safer and simpler alternative to genetic reprogramming. The relative simplicity of our approach, coupled with its high efficiency, makes it a prime candidate for translation to patients with diabetes.”

Dominguez-Bendala conducted the research with co-lead investigator Ricardo Pastori, Ph.D., Director of the DRI’s Molecular Biology Laboratory, and his team.

In type 1 diabetes, the insulin-producing islet cells of the pancreas have been mistakenly destroyed by the immune system, requiring patients to manage their blood sugar levels through a daily regimen of insulin therapy. Islet transplantation has allowed many patients to live without the need for insulin injections after receiving a transplant of donor cells. Some patients who have received islet transplants at the DRI have been insulin-independent for more than a decade.

The procedure, however, remains limited to the most severe cases of type 1 diabetes due to several factors, among them the limited supply of insulin-producing islet cells. Currently, transplanted islets come from donated cadaver pancreases. DRI researchers continue to build on progress in islet transplantation by developing the DRI BioHub, a bioengineered mini organ that mimics the native pancreas, as a means of overcoming the remaining challenges. These newly created insulin-producing cells could potentially be implanted within a DRI BioHub, expanding the ability to treat many more patients than can now be treated using islets alone.

However, overcoming the shortage of donor islet cells is not the only challenge this research strategy addresses. According to DRI Director Camillo Ricordi, M.D., the objective of this technology lies in its regenerative possibilities.

“The real potential of this initiative is in targeting the native pancreas in vivo after you restore self-tolerance and halt autoimmunity,” he said. “Enabling the insulin-producing cells to regenerate within the patient’s body may eliminate the need to transplant donor cells altogether and circumvent the challenge of immune rejection.”

Achieving in vivo regeneration is an important next step for Dominguez-Bendala and his fellow researchers.

“We are now working on improving the cellular reprogramming process,” he said, “and we hope to have a more clinically viable protocol that we could offer to patients living with this disease in the near future.”

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