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New Technique may Increase Limited Supply Available for Transplant in Patients with Type 1 Diabetes

Using BMP-7, the DRI team induced islet-like clusters from exocrine cells.
Using BMP-7, the research team induced islet-like clusters from the exocrine cells as shown by several markers, including insulin expression (green, top left) and  C-peptide (red, top right).
C-peptide is a by-product of insulin expression by the cells and is used to demonstrate the production of natural insulin as opposed to the possibility that cells are simply absorbing insulin from the culture medium. Additionally, the reprogrammed cells show the expression of PDX1, a key marker of beta cell function (red, bottom right).

MIAMI, Florida – November 24, 2015 – Scientists from the Diabetes Research Institute (DRI) 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, BMP-7 (bone morphogenetic protein-7), which is already approved by the Food and Drug Administration (FDA) 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 near 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. 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,” explained Juan Dominguez-Bendala, Ph.D., the study’s co-lead investigator and director of stem cell development for translational research at the DRI. “The relative simplicity of our approach, coupled with its high efficiency, makes it a prime candidate for translation to patients with diabetes.” Dr. Dominguez-Bendala worked together with co-lead investigator Dr. Ricardo Pastori, director of molecular biology, and his team.

In type 1 diabetes, the insulin-producing islets 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. However, the procedure 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 with 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. 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." 

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

About the Diabetes Research Institute

The Diabetes Research Institute at the University of Miami Miller School of Medicine leads the world in cure-focused research. As the largest and most comprehensive research center dedicated to curing diabetes, the DRI is aggressively working to develop a biological cure by restoring natural insulin production and normalizing blood sugar levels without imposing other risks. Researchers have already shown that transplanted islet cells allow patients to live without the need for insulin therapy. The DRI is now building upon these promising outcomes by developing the DRI BioHub, a bioengineered mini organ that mimics the native pancreas, and is testing various BioHub platforms in preclinical and clinical studies. For more information, please visit DiabetesResearch.org or call 800-321-3437. You can tweet DRI at @Diabetes_DRI.
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Lori Weintraub, APR

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