Innovative Vascularized Stem Cell Islet Organoids Enhance Diabetes Research Models

A team of researchers at the Max Delbrück Center for Molecular Medicine has pioneered a groundbreaking model for studying diabetes, featuring vascularized organoids derived from human pluripotent stem cells. This significant advancement, detailed in the journal Developmental Cell, is expected to enhance the understanding of diabetes and facilitate the development of cell-based therapies.

The research, spearheaded by Professor Maike Sander, focuses on creating a model that closely resembles the natural pancreatic environment. The new organoid model includes integrated vasculature, allowing for more accurate representation of pancreatic islets, which consist of various hormone-secreting cells, notably insulin-producing beta cells. These vascularized organoids demonstrated a higher maturity level and insulin secretion capability compared to non-vascularized versions.

In their experiments, the team found that the presence of blood vessels within the organoids supported the maturation of beta cells, significantly enhancing their functionality. Sander emphasized the critical role of a vascular network in maintaining islet cell function, asserting that this innovative model brings researchers closer to replicating the pancreas's natural state, which is crucial for advancing diabetes studies and therapeutic approaches.

The researchers focused on improving the maturity of beta cells within the organoids, which has been a challenge due to their typically immature state in previous models. They incorporated human endothelial cells--responsible for lining blood vessels--and fibroblasts, which aid in forming connective tissue, into the organoid cultures. After considerable experimentation with various culture conditions over five years, the team successfully developed a formulation that not only supported cell survival but also promoted the growth of a vascular network within the organoids.

Upon comparison, the vascularized organoids exhibited a more robust response to glucose exposure, indicating a higher presence of mature beta cells. The team identified two essential mechanisms through which the vasculature contributed to beta cell maturation: the formation of an extracellular matrix that signals cells to mature and the secretion of bone morphogenetic protein (BMP) by endothelial cells, which further stimulates beta cell development.

Moreover, the researchers utilized microfluidic devices to integrate the organoids, allowing for direct nutrient flow through the vascular systems. This setup not only enhanced the maturation of beta cells but also provided valuable insights into the dynamics of insulin secretion in response to nutrient gradients.

In a notable demonstration of their findings, the team observed that diabetic mice receiving transplants of vascularized SC-islets exhibited significantly better outcomes compared to those receiving non-vascularized counterparts, with some mice showing no signs of diabetes 19 weeks post-transplantation. This reinforces previous research suggesting that pre-vascularization is crucial for improving the functionality of transplanted islet cells.

Looking ahead, Sander's research team plans to use these vascularized organoid models to delve into type 1 diabetes, a condition characterized by the immune system's attack on beta cells. By cultivating organoids from type 1 diabetes patients and incorporating their immune cells, the team aims to explore the mechanisms underlying the destruction of beta cells, potentially leading to more effective treatments in the future.