First vascularized model of stem cell islet cells

An international team of researchers led by Max Delbrück Center Scientific Director Professor Maike Sander has for the first time developed an organoid model of human pluripotent stem cell-derived pancreatic islets (SC-islets) with integrated vasculature. Islets are cell clusters in the pancreas that house several different types of hormone-secreting cells, including insulin-producing beta cells. Researchers in the Sander lab at the University of California, San Diego, found that SC-islet organoids with blood vessels contained greater numbers of mature beta cells and secreted more insulin than their non-vascularized counterparts. The vascularized organoids more closely mimicked islet cells found in the body. “Our results highlight the importance of a vascular network in supporting pancreatic islet cell function,” says Sander. “This model brings us closer to replicating the natural environment of the pancreas, which is essential for studying diabetes and developing new treatments.” 

Engineering vascularized stem cell islets
SC-islet cell organoids are widely used to study diabetes and other pancreatic endocrine diseases. But beta cells in these organoids are typically immature, making them suboptimal models for the in-vivo environment, says Sander. Although several approaches have been developed to promote beta cell maturation, their effects have been modest, she adds.  To better mimic the in vivo environment, the researchers added human endothelial cells, which line blood vessels, and fibroblasts, cells that help form connective tissue, to islet organoids 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 grew a network of tube-like blood vessels that engulfed and penetrated the SC-islets.  “Our breakthrough was devising the recipe,” Sander says. “It took five years of experimenting with various conditions, involving a dedicated team of stem cell biologists and bioengineers.”

Vascularized stem cell islet organoids are more mature 
When the researchers compared vascularized organoids to non-vascularized organoids, they found the former secreted more insulin when exposed to high levels of glucose. “Immature beta cells don’t respond well to glucose. This told us that the vascularized model contained more mature cells,” says Sander. The researchers next wanted to explore how specifically vasculature helps organoids to mature. They found two key mechanisms: Endothelial cells and fibroblasts help build the extracellular matrix. The formation of the matrix itself is a cue that signals 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 team then integrated the organoids into microfluidic devices, allowing nutrient medium to be pumped directly through their vascular networks. They found that the proportion of mature beta cells increased even further.  “We found a gradient,” says Sander. “Non-vascularized organoids had the most immature cells, a greater proportion matured with vascularization, and even more matured by adding nutrient flow through blood vessels. A human cell model of pancreatic islets that closely replicates in-vivo physiology opens up novel avenues for investigating the underlying mechanisms of diabetes,” she adds. In a final step, the researchers showed that vascularized SC-islets also secrete more insulin in-vivo. Diabetic mice grafted with non-vascularized SC-islets fared poorly compared to those grafted with vascularized SC-islet cells, with some mice showing no signs of the disease at 19-weeks post-transplant. The research supports other studies that have shown that pre-vascularization improves the function of transplanted SC-islets.  

A better model to study Type 1 diabetes
Sander now plans to use vascularized SC-islet organoid models to study Type-1 diabetes, which is caused by immune cells attacking and destroying beta cells in the pancreas – in contrast to Type-2 in which the pancreas produces less insulin over time and the body’s cells become resistant to the effects of insulin. She and her team at the Max Delbrück Center are growing vascularized organoids from the cells of patients with Type-1 diabetes. They are transferring the organoids onto microfluidic chips and adding patients’ immune cells. “We want to understand how the immune cells destroy beta cells,” Sander explains. “Our approach provides a more realistic model of islet cell function and could help develop better treatments in the future.”