In severe diabetes, the beta cells of the pancreas no longer produce insulin – so far the decline of these cells is irreversible. However, new approaches to growing beta cells from stem cells are raising hope. Researchers have now succeeded in cultivating human beta cells that not only produce insulin, but also release it in doses depending on the blood sugar level. Once implanted in mice, these clumps of cells managed to properly regulate the animals’ blood sugar levels and keep blood sugar levels at normal levels. This also raises hopes for later use in humans.
In severe type 2 diabetes, but also in the mostly congenital autoimmune disease type 1 diabetes, the insulin-producing beta cells in the pancreas no longer work. In type 1 diabetes, these cells are usually mistakenly attacked and destroyed by endogenous antibodies during childhood. Because the insulin is now missing, the blood sugar level is no longer regulated and shoots up to unhealthy levels after a meal. In order to avoid organ damage and fatal abnormalities in blood sugar levels, patients have to check their blood sugar levels regularly and inject the necessary insulin – a complex procedure that is particularly stressful for children.
The problem of immature cells
Scientists have therefore been looking for ways to replace the defective beta cells in the pancreas for some time – including by breeding the appropriate cells from stem cells. “The production of functional pancreatic beta cells from human pluripotent stem cells is one of the main goals of stem cell research,” explain Diego Balboa from the University of Helsinki and his colleagues. Several research groups have already succeeded in cultivating clumps of cells in this way, which are very similar to the islet cells of the pancreas and also produce insulin. However, these still immature breeding cells have not yet managed to react adequately to the blood sugar in their environment and to release insulin reliably and in the correct dose. “Immature beta cells are not yet able to stop their insulin secretion at low glucose levels,” explains the team.
The scientists therefore looked for ways to bring the beta cells developed from the stem cells beyond the immature stage and thus to breed fully-grown, correctly functioning insulin regulators. To do this, they tested various methods of cell culture and the addition of nutrients and messenger substances until they finally found what they were looking for. It has been shown that the beta cells obtained from stem cells reach the mature stage if they are subjected to multiple changes in the culture environment and, in the final step, some inhibitors are added while others are left out. The result was beta cells that hardly differed in appearance and behavior from natural beta cells that had grown in the human pancreas.
Blood sugar regulation as in the natural model
However, the decisive question was whether these beta cells, which were cultivated in the laboratory, also function in relation to their insulin production in the same way as the body’s own. To do this, the researchers expose the cell cultures to glucose levels of different levels, which are typically also found when a person’s blood sugar fluctuates. “The cells showed normal insulin regulation and responded even better to changes in glucose levels than islet cells, which we took from the pancreas of organ donors as controls,” reports Balboa’s colleague Väinö Lithovius. According to closer analyses, the cultured beta cells also corresponded to their natural models in many, if not all, aspects of their physiology and the details of their reactions: “The analyzes showed that the beta cells obtained from stem cells have the necessary ion channels, exocytosis components and also the possess intracellular signaling machinery to fine-tune insulin secretion,” the researchers write.
This was also confirmed in a subsequent experiment with mice. The researchers implanted small clumps of the cultured pancreatic cells into these animals after chemically killing their own beta cells. If the mice were given sugar water to drink, the blood sugar level in the non-transplanted animals rose sharply, while the animals with the implanted beta cells secreted insulin and were able to regulate their blood sugar levels. As a result, the blood sugar level in these mice remained stable in the normal range, as the team reports. “This proves that the stem cell-derived transplant was able to correctly regulate the glucose levels in the mice,” says Balboa’s colleague Jonna Saarimäki-Vire. According to the research team, their method represents an important step towards the development of replacement beta cells for diabetic patients.
However, it will be a while before such beta cells obtained from stem cells can also be used in humans. Because even the beta cells produced by Balboa and his team still showed some differences to the natural insulin cells of the pancreas. In addition, not all breeding cells make it to full maturation, and many of them continued to alter their physiology and gene activity in the months following their transplantation into the mice. Exactly what this means, and whether it can lead to potentially negative consequences, remains to be investigated. Nevertheless, the scientists see in their further development of cell cultivation an important advance on the way to fully functional and implantable beta cells from the laboratory.
Source: Diego Balboa (University of Helsinki) et al., Nature Biotechnology, doi: 10.1101/2021.03.31.437748