In work published in Nature Communications today, a team led by Dr. Maria Cristina Nostro, Scientist at Toronto General Hospital Research Institute and the Harry Rosen Chair in Diabetes and Regenerative Medicine Research, McEwen Centre, identified a specific marker found on the cell surface of pancreatic progenitor cells, which allowed them to generate pure pancreatic progenitor cells from human pluripotent stem cells and demonstrate how these purified cells could produce beta cells for diabetes treatment.
Pluripotent stem cells have the potential to differentiate into more than 200 different cell types that make up every tissue and organ in the body. They also have the potential to create an endless supply of insulin-producing beta cells, found in the pancreas.
Finding ways to restore destroyed beta cells in the pancreas in patients with type 1 diabetes, or even restore their function in those with type 2 diabetes, is a “holy grail” in diabetes research. Although transplantation of islets from deceased donors has shown that cell replacement therapy – along with immunosuppression – restores beta cell function and decreases the number of insulin injections needed, there are still a number of hurdles.
Widespread use of islet cell transplantation for patients with type 1 diabetes is hampered by the limited supply and quality of donor islets and the effects of immunosuppression medication. The requirement for two to three donors per transplantation and the scarcity of donor pancreata has launched a world-wide search for an alternative source of beta cells. Laboratories are in a race to try and find ways to generate large numbers of functioning, insulin-producing beta cells that are safe and pure.
In their quest to purify and generate large quantities of beta cells, the researchers set out to find a highly specific new marker on the human pancreatic progenitor cell, since generating these specific cells from human stem cells can be challenging and variable. Pancreatic progenitor cells are able to generate insulin-producing beta cells.
Dr. Nostro teamed up with Dr. Thomas Kislinger, a Senior Scientist at the Princess Margaret Cancer Centre and Professor in the Department of Medical Biophysics at the University of Toronto. Together they developed a way to identify markers that would help them distinguish the pancreatic progenitors from cells that lacked the potential to generate beta cells.
“This is of particular importance, as it provides a way to eliminate contaminants,” says Dr. Nostro, who is also an Assistant Professor in the Department of Physiology at the University of Toronto. “The long-term goal is to cure type 1 diabetes with transplants of insulin-producing cells, so it is crucial to have pure cells that we can use for these and other therapies”.
The researchers used a specific antibody-based and magnetic technique to isolate the pancreatic progenitors using their newly identified marker. A specific antibody which binds to the marker on the surface of the pancreatic progenitors was linked to a magnetic bead. A magnet was then used to purify the pancreatic progenitors from other cells by attracting the magnetic beads linked to the pancreatic progenitor cells.
“Now we have a system that allows us to quantify and control the purity of the cells that will enter clinical trials for the treatment of type 1 diabetes,” says Dr. Nostro.
In Canada, more than 3 million people live with diabetes. It is estimated that this number will grow to 4.2 million by 2020. Diabetes and its complications constitute a serious financial burden for the publicly funded healthcare system. Direct healthcare costs due to diabetes and its complications have been estimated at $3 billion for 2015.
Moreover, people with diabetes are more than three times more likely to be hospitalized with cardiovascular disease, 12 times more likely to be hospitalized with end-stage renal disease and more than 20 times more likely to be hospitalized for a non-traumatic lower limb amputation compared to the general population.
For this project, the team collaborated with scientists at Vanderbilt University, Oregon Health and Science University and Sunnybrook Research Institute. This work was supported by funding from the McEwen Centre for Regenerative Medicine and the Toronto General and Western Hospital Foundation, a Pilot Grant from the Banting and Best Diabetes Centre, grants from the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long Term Care, the National Institute of Health, JDRF, the Department of Veterans Affairs and the Vanderbilt Diabetes Research and Training Center.