BOSTON – A groundbreaking study has introduced a vascularized organoid model of hormone-secreting cells within the pancreas, developed by researchers under the guidance of Maike Sander, Scientific Director of the Max Delbrück Centre. Published in Developmental Cell, this innovation holds significant potential for advancing both diabetes research and cell-based therapeutic interventions.

An international team,spearheaded by Professor Maike Sander,has successfully engineered an organoid model featuring human pluripotent stem cell-derived pancreatic islets (SC-islets) that are fully integrated with vasculature. These islets, clusters of cells in the pancreas, are responsible for housing various hormone-secreting cells, notably insulin-producing beta cells. The Sander lab’s research at the University of California, San Diego, revealed that SC-islet organoids containing blood vessels exhibited a higher concentration of mature beta cells and secreted more insulin compared to their non-vascularized counterparts. These vascularized organoids more accurately replicate islet cells as they exist within the body. The findings were detailed in the journal “developmental Cell.”

“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

“Our results highlight the importance of a vascular network in supporting pancreatic islet cell function.”

SC-islet cell organoids, miniature organs mirroring insulin-producing cell clusters, are commonly employed in the study of diabetes and other pancreatic endocrine disorders. However, Sander notes that beta cells within these organoids often lack maturity, rendering them less than ideal for replicating the in-vivo environment. While various strategies have been explored to promote beta cell maturation,their impact has been limited.

To more faithfully replicate the in-vivo environment, the research team incorporated human endothelial cells, which line blood vessels, along with fibroblasts, cells crucial for forming connective tissue, into islet organoids derived from stem cells.Through meticulous experimentation with diffrent cell culture media, they identified a successful combination. The cells not only survived but also matured, developing a network of tube-like blood vessels that enveloped 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.”

Enhanced Maturity in Vascularized Stem Cell Islet Organoids

Comparative analysis between vascularized and non-vascularized organoids revealed that the former secreted a greater amount of insulin when exposed to elevated glucose levels. “Immature beta cells don’t respond well to glucose. This told us that the vascularized model contained more mature cells,” says Sander.

Further investigation into the mechanisms by which vasculature aids organoid maturation identified two key processes: Endothelial cells and fibroblasts contribute to the formation of the extracellular matrix, a network of proteins and carbohydrates on cell surfaces. The formation of this matrix serves as a signal for cells to mature. Additionally, endothelial cells secrete Bone Morphogenetic Protein (BMP), which stimulates beta cell maturation.

Recognizing the role of mechanical forces in stimulating insulin secretion, the team integrated the organoids into microfluidic devices, enabling the direct pumping of nutrient medium through their vascular networks. This resulted in an even greater proportion of mature beta cells.

“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 demonstration, the researchers confirmed that vascularized SC-islets also exhibit increased insulin secretion in-vivo. Diabetic mice receiving grafts of non-vascularized SC-islets showed poorer outcomes compared to those receiving vascularized SC-islet cells, with some mice showing no signs of the disease at 19-weeks post-transplant. These findings align with previous studies indicating that pre-vascularization enhances the functionality of transplanted SC-islets.

Improved Model for Type 1 Diabetes Studies

Sander intends to utilize vascularized SC-islet organoid models to investigate Type-1 diabetes, an autoimmune condition characterized by the destruction of beta cells in the pancreas by immune cells, as opposed to type-2 diabetes, where the pancreas gradually produces less insulin and the body’s cells develop resistance to insulin’s effects.

Sander and her team are cultivating vascularized organoids from cells obtained from patients with Type-1 diabetes. These organoids are then transferred onto microfluidic chips, and patient-derived immune cells are introduced.”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.”