Type 1 diabetes, which occurs when the pancreas does not make enough insulin to control blood sugar levels, is a disease that is currently incurable and difficult to treat for most patients. Scientists at the Salk Institute are developing a promising approach to treatment: insulin-producing cells (so-called beta cells) are to be made from stem cells, which could replace non-functioning pancreatic cells.
In a study published June 7, 2021 in the journal Nature Communications, the researchers reported that they had developed a new way to make beta cells that is much more efficient than previous methods. When these beta cells were tested in a mouse model for type 1 diabetes, the animals’ blood sugar was also brought under control within about two weeks.
Stem cells are an extremely promising approach to developing many cell therapies, including better treatments for type 1 diabetes. This process of producing large numbers of safe and functional beta cells is an important step forward. “
Juan Carlos Izpisua Belmonte, Director of Studies and Professor, Salk Institute
In the current work, the researchers started with human pluripotent stem cells (hPSCs). These cells, which can be obtained from adult tissue (mostly skin), have the potential to become any type of cell in the adult body. Using various growth factors and chemicals, researchers gradually coaxed hPSCs into beta cells to mimic pancreatic development.
The production of beta cells from hPSCs in the laboratory is not new, but in the past the yields of these valuable cells have been low. With existing methods, only about 10 to 40 percent of the cells become beta cells. For comparison: Techniques for producing nerve cells from hPSCs have yields of around 80 percent. Another problem is that if undifferentiated cells were left in the mixture, they could eventually turn into another type of cell that would be undesirable.
“For beta-cell-based treatments to eventually become a viable option for patients, it is important to simplify the manufacture of these cells,” says co-lead author Haisong Liu, a former member of the Belmonte laboratory. “We have to find a way to optimize the process.”
To address the problem, the researchers took a step-by-step approach to create beta cells. They identified several chemicals that are important in making hPSCs become more specialized cells. They eventually identified several cocktails of chemicals that resulted in beta cell yields of up to 80 percent.
They also looked at how these cells are grown in the laboratory. “Usually cells are grown on a flat plate, but we allowed them to grow in three dimensions,” says co-lead author Ronghui Li, a postdoctoral fellow at the Belmonte laboratory. This cultivation of the cells creates more common surface area between the cells and allows them to influence each other, just as they did during human development.
After the cells were generated, they were transplanted into a mouse model of type 1 diabetes. The model mice had a modified immune system that would not reject transplanted human cells. “We found that these mice had their high blood sugar levels returned to normal within two weeks,” says co-first author Hsin-Kai Liao, a member of the Belmonte laboratory. “The transplanted hPSC-derived beta cells were biologically functional.”
The researchers will continue to study this technique in the laboratory to further optimize the production of beta cells. Further research is needed to assess safety issues before human clinical trials can be initiated. The researchers say the methods outlined in this paper could also be useful in developing specialized cells to treat other diseases.
Source:
Journal reference:
Liu, H., et al. (2021) Chemical combinations potentiate human pluripotent stem cell-derived 3D pancreas precursor clusters in the direction of functional β cells. Nature communication. doi.org/10.1038/s41467-021-23525-x.