Hope in the fight against type 1 diabetes: Using stem cell technology, researchers have generated transplantable human islet cell units that can automatically regulate blood sugar in a mouse model. The organoids are also protected from rejection reactions by a protective function, which means that no immune system-suppressing drugs are necessary after the transplant. The system now has to prove its performance and tolerability before it can be used in humans, say the researchers.
Blood sugar is our body’s fuel – an energy source that needs to be dosed well. The most important regulator is the hormone insulin. It brings the sugar from the blood into the body’s cells in order to supply them with energy. The so-called beta cells, which are located in island-like cell clusters in the pancreas, are responsible for the production of insulin. They register the level of blood sugar and increase the production of the hormone when there is an excess. As a result, the body cells absorb more sugar and the concentration in the blood drops. This is important because too much glucose in the blood can damage organs.
Exactly this system is disturbed in patients with diabetes: Their beta cells are damaged or even completely destroyed. In order to regulate the blood sugar level, you have to get insulin from outside. In the case of type 1 diabetes, in which the beta cells are usually completely destroyed by autoimmune reactions, this means that the hormone has to be injected. This is not only uncomfortable and annoying, the dosage often does not work as well as with the natural regulation system. It is possible to transplant beta cells into diabetic patients, but as with other donor tissues, rejection reactions occur that have to be suppressed by immunosuppressants, which in turn has a significant impact on health.
Cultured replacement beta cells
For some time now, a research team at the Salk Institute for Biological Studies in La Jolla has been trying to use stem cell technology to grow replacement beta cells that can be implanted in diabetes patients. In theory, they could be made from the patient’s own tissues to avoid rejection later. But as the researchers explain, this individual solution would be associated with high costs. Thus, breeding lines of substitute beta cell tissues that are generally not attacked by the immune system could represent a cheap alternative. The researchers have now come several steps closer to this goal.
So far, the team had already succeeded in growing beta-like cells from stem cells – but they were not fully functional: the cells did not release insulin in response to glucose because they lacked the strength to do so, the researchers explain. As they report, they have now discovered a genetic switch called ERR-gamma, which, when turned on, puts the cells in operational readiness. They then identified a protein called WNT4 that can activate this ripening switch. “When ERR-gamma is active, the cells get the energy they need to do their work,” says co-author Michael Downes. So they were able to overcome a previously crucial hurdle on the way to the goal. “Our cells are now healthy and robust and can release insulin when they perceive high glucose levels,” said Downes.
Another important challenge was to develop a method to bring the beta-like cells into a three-dimensional arrangement that approximates the islet cell system in the human pancreas. This has now also been successful, the researchers report: They succeeded in producing human organoids (HILOs) from induced pluripotent stem cells, which are similar to human pancreatic islets and are suitable for transplants.
Rejection reactions suppressed
Next, the scientists looked at the problem of immune rejection. To do this, they carried out experiments on diabetic mice into which the organoids were implanted. During their investigations, they first discovered that a special control protein called PD-L1 can protect cells if they are genetically engineered with it. “By expressing PD-L1, which acts as an immune blocker, the transplanted organoids are able to hide from the immune system,” says the study’s lead author Eiji Yoshihara.
The researchers then discovered a way of triggering the formation of the protein in the organoids without genetic manipulation: treatment with interferon gamma accordingly equips them with the protective function over the long term. Experiments on diabetic mice then showed: If the organoids treated in this way were used in the animals, they could regulate the blood sugar level in the long term without causing symptoms of rejection. “If we could establish this as therapy in humans, diabetes patients would no longer need to take immunosuppressive drugs,” says Downes.
Until then, however, some research is needed, the scientists emphasize: The transplanted organoids now have to be tested further on mice to confirm that their effects are long-lasting. Then it must be ensured that they can also be used safely in humans. But the researchers are confident. So it will be interesting to see what will develop from this promising approach.
Source: Salk Institute, technical article: Nature, doi: 10.1038 / s41586-020-2631-z