October 22, 2013 | by Nicole White
Transplantation of insulin-producing islet cells is a potentially powerful tool for treating type 1 diabetes, but coming up with enough healthy donor cells for the procedure is difficult – at least for now.
Currently, one transplant can require cells from two donor pancreases, and the precious organs are in short supply. Of the approximately 200,000 patients with advanced diabetes that can no longer be sufficiently managed with insulin shots, only 1 percent will be able to receive a transplant.
, an associate professor in the Department of Diabetes and Metabolic Diseases Research at City of Hope, and her team have been exploring how to supplement islet cells harvested from donated organs with islet cells grown from stem cells. A new discovery in her lab may help expedite that process. As described in a paper published recently in the Proceedings of the National Academy of Sciences, researchers found that overexpressing a specific small RNA molecule enhances the differentiation of pancreatic cells growing from stem cells.
That discovery could prove crucial to growing islet cells for transplant: In a healthy pancreas, islet cells make up only about 3 to 4 percent of the pancreas. The most plentiful cells within the islets are glucagon-producing alpha cells and insulin-producing beta cells. In diabetes, those beta cells are destroyed by the immune system, leaving the diabetic patient unable to produce insulin, the hormone that lower blood glucose levels. And it's those beta cells that researchers desperately want to grow.
Recent research had already identified certain proteins called ten eleven translocation, or TET, enzymes. These enzymes mediate a process known as DNA demethylation, an important part of the process cells go through to evolve from a stem cell to a specific kind of cell. However, how these TET enzymes were regulated has been unknown.
The new City of Hope paper found that a microRNA, specifically miR-26a, can directly target these enzymes and modulate part of the demethylation process. Furthermore, by regulating these TET enzymes, researchers were able to promote pancreatic cell differentiation both in an animal model and also in cells grown in a dish.
“Basically, we saw that there are more beta cells coming from the stem cells,” said Ku, a senior author on the study. “We’re hoping to further study the mechanism so we can understand exactly how that is happening, and potentially increase the number of beta cells we can reap from stem cells, so we could use those for transplantation.”Wendong Huang, Ph.D., who studies metabolic regulation, cancer and aging at City of Hope, and , chair of the Department of Diabetes and Metabolic Diseases Research and professor in the Department of Cancer Biology in the Graduate School of Biological Sciences, are also senior authors on the study. Xianghui Fu, Ph.D., staff scientist, and Liang Jin, Ph.D., postdoctoral fellow, were co-first authors on the study.
The next step in the research will be to study how the overexpression of microRNA is able to result in a greater number of islet cells – a precious resource. Finding a better way to grow these cells could mean greater access to islet cell transplantation, Ku says – a critical need when only 1 percent of the patients who can benefit from the transplants can access them.