An international team including the University of Sydney has reprogrammed human stem cells to generate insulin-producing HILOs (human islet-like organoids). When transplanted into mice, HILOs restore glucose control.
Research published today in Nature has shown that human stem cells can be used to create insulin-producing pancreatic islets. When transplanted into diabetic mice, these islets can control blood glucose levels.
The cells used in this therapy are also able to evade detection by the immune system. This means that they can potentially reduce the incidence of transplant rejection and the need for recipients to take immunosuppressant drugs for the rest of their life.
Type 1 diabetes is an autoimmune disease. It can occur at any age, although most commonly in children and young adults. We do not know why the immune system of a person with type 1 diabetes mis-identifies the insulin-producing cells of the pancreas as invading cells and destroys them. This means that people with type 1 diabetes require lifelong insulin replacement (usually via injection) to survive.
It is estimated that more than 122,800 Australians are currently living with type 1 diabetes.
Professor Chris Liddle is a Principal Investigator at the Storr Liver Centre at University of Sydney School of Medicine and The Westmead Institute for Medical Research and The Westmead Institute for Medical Research and also a clinician at Westmead Hospital. He is a co-author of the study, which was led by researchers from the Salk Institute for Biological Studies in La Jolla, California.
Using stem cells to create insulin-producing pancreatic islets
According to Professor Liddle, this study used stem cells derived from human umbilical vein and human fat that were re-programmed to generate ‘human islet-like organoids’ (HILOs).
Pancreatic islets are regions in the pancreas responsible for the production of hormones and insulin.
“Pancreatic islets contain multiple cell types, not just insulin-producing beta cells. The research team created three-dimensional HILOs that not only include beta-like cells (the cells that produce, store and release insulin in the islets of the pancreas), but also other supporting cell types found in normal islets,” said Professor Liddle.
“Under the microscope, and using gene sequencing analysis, we are able to show that the three-dimensional HILOs are very similar to human islets. When the HILOs are transplanted into diabetic mice, they secrete insulin when blood glucose levels are high, just as normal islets would.”
While human pancreatic islet transplantation has been a major advancement in treating severe cases of type 1 diabetes, the availability, quality and limited cellular longevity of this approach limits its application.
Pancreatic islet transplantation currently involves implanting insulin-producing islet cells from a deceased human donor into the liver of a person with type 1 diabetes. When successful, the procedure can control blood glucose levels, reduce the frequency and severity of hypoglycaemic episodes and potentially eliminate the need for regular insulin injections. A number of transplants are usually needed, and immunosuppressant drugs to prevent the immune system from attacking the transplanted cells are also required.
While the procedure is now funded by the Australian Government, pancreatic islet transplantation is currently limited to people with severely unstable type 1 diabetes, particularly those for whom insulin therapy alone is not effective and who experience recurrent and severe hypoglycaemic episodes.
Professor Philip O’Connell is Executive Director at The Westmead Institute for Medical Research and pioneered pancreatic islet transplantation in Australia. Almost 20-years ago, he led Australia’s first pancreatic islet transplantation trials at Westmead Hospital and The Westmead Institute for Medical Research. Today, he continues his research, aiming to improve this procedure and develop islet transplantation as a mainstream treatment for type 1 diabetes.
Professor O’Connell, who was not involved in this research study, said, “Pancreatic islet transplantation has saved hundreds of lives around the globe however, it has its limitations. For example, pancreatic islets are taken from deceased donors, and the wait for donor islets can be lengthy. Once donor islets are obtained, not all are suitable for transplantation.
“This research indicates the potential to alleviate some of these issues. Stem cells derived from readily available human tissues can be expanded then re-programmed into potentially unlimited numbers of islets that are suitable for transplantation.”
Cells designed to evade immune detection
This research study also demonstrates that increasing PD-L1 (a protein that acts to suppress the immune system, especially in the instances of autoimmune disease and tissue grafts) helps to protect the transplanted cells. Essentially, transplanted HILOs are able to ‘hide’ from the immune system.
Professor Liddle said that the team then sought a way to maintain PD-L1 expression without the need for genetic engineering.
“We did this by treating the HILOs with pulses of the protein interferon gamma. This process induced natural PD-L1 expression in the HILOs, restricting the ability to form an immune response and reducing the incidence of graft rejection.
“When these HILOs are transplanted into diabetic mice, they provide sustained glucose control in mice with healthy immune systems for at least 50 days,” said Professor Liddle.
Professor O’Connell said that this finding addresses a significant barrier to islet transplantation – the destruction of transplanted cells by the body’s own immune system.
“The body’s normal immune response is to attack any foreign cells, such as transplanted islets. So, patients who currently undergo pancreatic islet transplantation need to take immunosuppressant drugs for the rest of their lives in order to prevent this.
“However, immunosuppressant drugs can have significant side effects and can impact the individual’s quality of life.
“More research is needed, but if we are able to find a way to re-establish long-term pancreatic islet function and return blood glucose levels to normal, as well as reduce the need for immunosuppressants, that would be a game-changer for patients with type 1 diabetes.
Professor Liddle agrees that more research is needed before this approach is ready for human clinical trials.
“The HILOs need to be tested in the laboratory for longer periods to confirm that their effects are long-lasting. More work will also need to be done to ensure safety for use in humans.
“However, we believe this is a significant step toward an injection-free or device-free future for people with type 1 diabetes.”
