A team led by Professor Maike Sander, Scientific Director at the Max Delbrück Center, has created a new organoid model of pancreatic hormone-producing cells with integrated blood vessels. This breakthrough promises to improve diabetes research and the development of cell-based therapies. The study was published in the journal Developmental Cell.
The researchers developed human stem cell-derived pancreatic islet organoids (SC-islets) that include vascular structures. Pancreatic islets are clusters of cells that produce hormones, including insulin from beta cells. The team, including scientists from the University of California, San Diego, found that vascularized organoids contained more mature beta cells and released more insulin compared to non-vascularized versions. These organoids closely resemble the islets found naturally in the body.
SC-islet organoids, which are mini-organs grown from stem cells, are commonly used to study diabetes and other pancreatic diseases. However, the beta cells in these organoids are usually immature, limiting their usefulness as models of real human biology. While previous methods have tried to promote beta cell maturity, their success has been limited, explained Professor Sander.
To better simulate the natural environment, the team added human endothelial cells, which form blood vessels, and fibroblasts, which create connective tissue, to the stem cell organoids. After testing many cell culture recipes over five years, the researchers found a combination that allowed the cells to survive, mature, and form a network of blood vessels that surrounded and penetrated the organoids.
Professor Sander said, “Our breakthrough was devising the recipe. It took years of work by stem cell biologists and bioengineers.”
The vascularized organoids responded better to high glucose levels by releasing more insulin, showing their beta cells were more mature. In contrast, immature beta cells react poorly to glucose.
The researchers identified two main ways vascularization helps cell maturity. First, endothelial cells and fibroblasts build an extracellular matrix—a web of proteins and sugars on cell surfaces—which signals the cells to mature. Second, endothelial cells release Bone Morphogenetic Protein (BMP), which also stimulates beta cell development.
To further improve the model, the team placed the organoids into microfluidic devices. These devices pump nutrient-rich fluids through the blood vessel networks, which increased the number of mature beta cells even more.
“We saw a clear gradient,” said Sander. “Organoids without blood vessels had the most immature cells. Adding vascularization matured more cells, and adding nutrient flow matured even more. This model closely mimics real human pancreatic islets and opens new paths to study diabetes.”
In tests on diabetic mice, those grafted with vascularized SC-islets showed better insulin secretion and health outcomes than mice with non-vascularized grafts. Some mice remained disease-free for up to 19 weeks. These results support previous findings that pre-vascularizing transplanted islets improves their function.
Looking ahead, Professor Sander plans to use these vascularized organoids to study Type 1 diabetes. This disease occurs when the immune system attacks and destroys beta cells, unlike Type 2 diabetes, which involves insulin resistance and gradual loss of insulin production.
Her team is growing vascularized organoids from patients with Type 1 diabetes. They are also adding immune cells from these patients onto microfluidic chips to study how immune cells destroy beta cells.
Sander said, “This approach provides a more realistic model of islet function. It could help us understand disease mechanisms better and develop improved treatments in the future.”
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