2021 marked the 100th anniversary of the discovery of insulin – a Canadian breakthrough that has saved the lives of countless people with diabetes. It seems only fitting that 100 years later, we take a moment to reflect on how far Canadian diabetes research has come, with a focus on stem cells and regenerative medicine of course!
Diabetes is a disorder where the body’s cells are unable to process glucose (sugar) properly. Normally, the beta islet cells of the pancreas produce and secrete insulin in response to high glucose levels in the bloodstream. Insulin signals the body’s cells to increase uptake and metabolism of glucose (a process that fuels all cellular functions), thereby lowering blood glucose levels. In Type 1 diabetes (T1DM – previously known as Juvenile Diabetes), the beta islet cells are destroyed by an autoimmune reaction, preventing the production of insulin. Persistently high glucose levels lead to starvation at the cellular, then physiological levels. Long term consequences of untreated diabetes can include retinopathy (blindness), nephropathy (kidney disease, and eventual failure), heart disease (including heart attacks), peripheral vascular disease (ulcer formation, and eventual limb amputation), and, of course, death.
The above paints a pretty bleak picture for someone with diabetes, and prior to the discovery and use of insulin to treat T1DM, such a diagnosis was a death sentence.
By the early 1900s, scientists had discovered that the pancreas was involved in T1DM, and had narrowed it down to little cellular structures called pancreatic islets. Knowing this, Dr. Frederick Banting hypothesized a new way to isolate the islets, in hopes to prepare an extract that could be administered to those with diabetes.
In 1921, with graduate student Charles Best, Banting was successful in preparing a canine-derived pancreatic islet extract that, when given to a diabetic dog, significantly reduced its blood sugar within the hour. Banting, Best and additional stakeholders then worked to refine the process, isolating larger and purified quantities of insulin from the pancreas of a cow. By early 1922, bovine insulin was being administered to human patients.
Daily injections of insulin (now produced by genetically-engineered bacteria or yeast) remain the mainstay of T1DM treatment. In severe cases, whole pancreas or islet cell transplantation may be offered. However, as these organs/cells come from deceased donors, there are significant “supply” limitations. Additionally, recipients are required to take life-long immunosuppressive medications to prevent rejection. And many of these patients are already suffering from some of the irreversible long-term consequences of their diabetes. There is still no widely available cure, but Canadian stem cell researchers continue their efforts to find one.
2021 was a very successful year for diabetes stem cell research across the country. Here is a look at some of the highlights.
Dr. Timothy Kieffer (University of British Columbia, Vancouver)
Dr. Kieffer is working on creating tissue constructs that can replace the dysfunctional islets in patients with T1DM. Pancreatic endoderm cells (PECs) are derived from human embryonic stem cells, and have the ability to differentiate into mature beta islet cells with the ability to produce insulin. To improve transplantation of this plentiful source of cells, PECs are incorporated into a matrix-like device that can then be implanted into a recipient. The incorporation of such a “backbone” allows for a host’s own vasculature to grow in and around the device, improving oxygen and nutrient delivery to implanted PECs, which in turn increase PEC growth and survival.
Currently, Dr. Kieffer is leading a group of researchers in conducting a Phase I/II clinical trial that is testing “the safety and efficacy of [PECs] implanted in non-immunoprotective macroencapsultation devices.” The group just published (Cell Stem Cell) the results from 15 patients one-year post-implantation of the device. In terms of safety, no patients developed a teratoma (stem cell tumour), and there were no severe graft-related adverse events. Most adverse reactions were related to the implantation procedure and/or use of immunosuppressive therapy. In terms of efficacy, patients had increased levels of insulin production markers, which were observed to change in response to meals (as insulin production normally fluctuates with meals). From a clinically relevant perspective, patients required less injected insulin and had blood sugar levels in the normal range more frequently. These results are promising for continuing the trial.
Dr. James Shapiro (University of Alberta, Edmonton)
Dr. Shapiro is well-known for pioneering the Edmonton Protocol for pancreatic islet transplantation (as opposed to whole pancreas transplants). However, as with other organ transplants, the Protocol still requires the use of donor cells, which are in limited supply and recipients are required to take life-long immunosuppressive medication. His team is now focusing on removing these barriers, while increasing the scalability of islet transplantation.
By using autologous (patient-derived) induced pluripotent stem cells (iPSCs) as the source of islet cells, the need for donors is negated, as is the need for immunosuppressive therapy. iPSCs are stem cells that are derived from genetically-reprogrammed adult somatic (terminally differentiated and functional) cells, usually harvested from skin or fat tissue. Dr. Shapiro plans to direct iPSCs – with the stem cell ability to differentiate into any cell type – into becoming pancreatic islet cells.
In an associated publication in Cell Reports Medicine with Dr. Kieffer and colleagues, Dr. Shapiro demonstrated favorable results for the potential scalability of his PEC-01/VC-02 implant. Assessment of explanted (removed) devices from three to 12 months post-implantation demonstrated engraftment into the host (as measured by vascularization of the device) and insulin production. As PEC-01 cells are able to be grown to any desired cell number, the early success of the implant is promising for reducing the dependency on donors.
Dr. Cristina Nostro (University Health Network, Toronto)
Dr. Nostro is also interested in using iPSCs to create pancreatic beta islet cells. Her lab aims to identify the genetic and epigenetic programs that dictate pancreatic development and beta cell maturation from their stem cell origins. By identifying these programs, scientists may more easily produce the islet cells of interest.
Earlier this year, Dr. Nostro’s team published a Cell Stem Cell article describing a technique that could be used to improve the engraftment rates of islet cell transplantation. They developed the use of ready-made “microvessels:” small blood vessel fragments that are able to connect with host vasculature, allowing for increased oxygen and nutrient delivery to transplanted islets. The team co-transplanted pancreatic progenitors derived from human embryonic stem cells with microvessels into mice with T1DM. The inclusion of the microvessels improved early engraftment of the pancreatic cells, and allowed for earlier normalization of blood glucose levels, while reducing the number of islet cells needed to achieve these results.
Dr. Corinne Hoesli (McGill University, Montréal)
Dr. Hoesli’s lab is bioengineering encapsulation techniques to improve the islet cell transplantation process. An issue with many devices is fibrotic overgrowth of the device (think scar formation), which crowd out functional islet cells and prevent the formation of useful structures like blood vessels. As an implanted device is going to be “foreign” to the host body, immunosuppressive medication is also required. The group is trying to make a physical barrier that is non-immunogenic, reduces fibroblast deposition, and allows for improved oxygenation and nutrient delivery to the implanted islet cells.
The team developed a new bioink (biological “inks” used in 3D-printing), by incorporating pectin into their usual alginate-based hydrogel (a grid structure to house cells). Alginate is a commonly used biomaterial for pancreatic cell encapsulation, as it increases graft survival; however, it is difficult to use as a bioink. Polymers can be added to alginate to improve its “printability.” Another issue with alginate-based hydrogels is that they promote foreign body immune responses. The group first determined the ideal combination of alginate and Pluronic polymer to make a bioink that would print with high fidelity, while producing stable hydrogels that maintained their structure during the pancreatic beta cell incorporation phase. The addition of pectin to the alginate-Pluronic bioink produced a hydrogel that maintained higher beta islet cell viability, with improved longevity and reduced fibroblast growth in implanted mice.
New funding for postdocs
In keeping with this Canadian vendetta against diabetes, the Stem Cell Network just announced its new partnership with JDRF Canada to create the JDRF-SCN National Fellowship Program in Type 1 Diabetes. This program aims to provide post-doctoral funding and training for those interested in T1DM research. Applications officially opened January 15, 2022.
So, Canada, as we continue to welcome in the New Year, let’s make 2022 another successful one in our tradition of the fight against diabetes.
Sara M. Nolte
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