Researchers led by Maike Sander, scientific director of the Max delbrück Center, have developed a vascularized organoid model of hormone secretory cells in the pancreas. The advance, published in Development cellIt promises to improve diabetes research and cell -based therapies.
An international team of researchers led by the scientific director of the Max delbrück Center, Professor Maike Sander, has first developed an organid model of pancreatic islets derived from human pluripotent stem cells (SC-islets) with integrated vasculature. The islets are groups of cells in the pancreas that house several different types of hormone secretory cells, including insulin producing beta cells. Researchers at the Sander laboratory at the University of California, San Diego, found that the SC-Islet organoids with blood vessels contained a greater number of mature beta cells and secreted more insulin than their non-vascularized counterparts. Vascularized organoids masite the islet cells found more in the body. The study was published in “Development cell”.
“Our results highlight the importance of a vascular network to support the function of pancreatic islet cells,” says Sander. “This model brings us closer to replicating the natural environment of the pancreas, which is essential to study diabetes and develop new treatments.”
Vascularized stem cell islet engineering
SC-ISLET cell organoids (mini-ores that reflect the groups of insulin producing cells outside the body) are widely used to study diabetes and other pancreatic endocrine diseases. But beta cells in these organoids are typically immature, which makes them subopym for the in vivo environment, says Sander. Although several approaches have been developed to promote the maturation of beta cells, their effects have been modest, he adds.
To better imitate the in vivo environment, the researchers added human endothelial cells, which border the blood vessels and fibroblasts, cells that help form connective tissue, to the organoids of the islets grown from stem cells. The team experimented with different cell culture media until they found a cocktail that worked. The cells not only survived, but matured and cultivated a network of blood vessels similar to tubes that wrapped and penetrated the SC islets.
“Our advance was to devise the recipe,” says Sander. “He took five years of experimenting with various conditions, involving a dedicated biologists and bioingeners of stem cells.”
The organoids of vascularized stem cell islets are more mature
When the researchers compared vascularized organoids with non -vascularized organids, they found that the first secret more insulin when exposed to high levels of glucose. “Beta immature cells do not respond well to glucose. This told us that the vascularized model contained more mature cells,” says Sander.
Then, the researchers wanted to explore how specifically the vasculature helps the organoids to mature. They found two key mechanisms: endothelial cells and fibroblasts help build the extracellular matrix: a protein and carbohydrate network on cell surfaces. The formation of the matrix itself is a signal that indicates the cells to mature. Secondly, endothelial cells secrete bone morphogenetic protein (BMP), which in turn stimulates beta cells to mature.
Recognizing that mechanical forces also stimulate insulin secretion, the equipment integrated organoids into microfluidic devices, allowing the nutrient medium directly pumping through its vascular networks. They discovered that the proportion of mature beta cells increased even more.
“We find a gradient,” says Sander. “Non -vascularized organoids had the most immature cells, a greater proportion matured with vascularization, and even more matured by adding the flow of nutrients through blood vessels. A model of human cells of pancreatic islets that closely replicates the physiology in vivo opens new avenues to investigate the underlying mechanisms of diabetes,” he adds.
In a final step, the researchers showed that vascularized SC islets also secrete more insulin in vivo. The grafted diabetic mice with non-vascularized SC islet was badly compared to grafts with vascularized SC-Islet cells, and some mice do not show signs of the disease at 19 weeks after the transplant. Research supports other studies that have shown that prevascularization improves the function of transplanted SC islets.
A better model to study type 1 diabetes
Sander now plans to use Vascularized organoid models of SC-islet to study type 1 diabetes, which is caused by immune cells that attack and destroy beta cells in the pancreas, in contrast to type 2 in which the pancreas produces less insulin with time and cells of the body become resistant to the effects of insulin.
She and her equipment at the Max delbrück center are growing vascularized organoids from patients with type 1 diabetes. They are transferring organoids to microfluidic chips and adding patient immune cells. “We want to understand how immune cells destroy beta cells,” explains Sander. “Our approach provides a more realistic model of the function of islet cells and could help develop better treatments in the future.”