Contact: Mitra Zehtab, MD, MBA
February 24, 2005
Diabetes Research Institute Demonstrates New Approach to Transform Stem Cells Into Insulin-Producing Cells
First Reported Success Using Protein Transduction Technology for Pancreatic Differentiation
Combining their respective expertise, molecular biologists and stem cell experts from the Diabetes Research Institute (DRI) at the University of Miami Leonard M. Miller School of Medicine reported the first successful use of protein transduction domains (PTD) to promote pancreatic cell differentiation. The technology uses small membrane-crossing proteins to facilitate the penetration of much larger "piggy-backed" molecules that would otherwise not be able to enter targeted cells. Using these PTDs, DRI scientists demonstrated that a critical developmental factor involved in the development of insulin-producing cells, neurogenin 3, can be introduced into pancreatic stem/progenitor cells, successfully promoting their differentiation into endocrine cell types capable of producing both insulin and glucagon as in the normal pancreas.
The findings appear in the March issue of the journal Diabetes, and have already drawn considerable attention from the scientific community. The study is proof of principle that the approach is indeed successful, and the findings open a promising new avenue of science that could quickly advance stem cell research and enable the development of more insulin-producing cells, or islets, for transplant into patients with Type 1 diabetes.
"Even though we know which genes are activated in normal pancreatic development, and in which order, our understanding of the molecular signals that turn them on is still very limited," explains Juan Dommnguez-Bendala, PhD, and lead scientist in the study. "Here we've demonstrated that "protein theray" can be used successfully to accelerate stem cell differentiation, bypassing the need for signaling events that we don't fully understand yet."
The PTD study uses Neurogenin 3 (ngn3), a protein known to 'prime' the formation of islets during pancreatic development, and tags it with a small "facilitating" peptide called TAT. This tag carries ngn3 into the stem cells in culture. The resulting protein is then purified and added to the culture medium of immature pancreatic cells, where it enhanced their differentiation into islet cell types with both high efficiency and speed.
Scientists at the DRI have been using PTD technology for quite some time to preserve and enhance islet cell function. "The TAT/PTD, is perhaps the best characterized PTD," adds Ricardo Pastori, PhD, Director of Molecular Biology at the DRI and Co-investigator in the study, "and it has been proved to efficiently deliver peptides as well as full-length proteins to a wide variety of cells and tissues. This novel strategy raises the possibility of designing "self-carrying" proteins that can sequentially educate human embryonic stem cells to fully functioning pancreatic cells, perhaps resulting in a limitless supply of islet cells for transplantation. That is our aim."
The DRI team has already begun testing this approach in human embryonic stem cells, and other TAT-fused proteins that are known to be involved in islet development are already in the pipeline.
"Yesterday we knew what the key genes were that make a stem cell turn into an insulin-producing pancreatic cell; today we have demonstrated a 'short cut' that may work to unravel the complicated signals involved in their activation. We can now turn on the genes, and do so in the right order, in order to get functioning cells," adds Dr. Dommnguez-Bendala. "This approach lets us easily add and remove proteins as needed from the developmental process, and might therefore have significant advantages over other less flexible approaches such as gene therapy."
The Diabetes Research Institute at the University of Miami is a recognized world leader in cure-focused research. Pioneering new technologies in islet transplantation and other cellular therapies since the early 1970's, the DRI has successfully reversed diabetes in patients participating in ongoing clinical trials. The most comprehensive diabetes research facility of its kind, the DRI conducts a broad range of scientific programs focused on pancreatic stem cell development, molecular biology, immune tolerance, and transplant immunology among others, to speed the most promising findings from the lab to the patient. For the millions of families affected by diabetes who are looking to the world of science for answers, the DRI is the best hope for a cure.
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