Duct cells in development, regeneration, and transplantation: charting a path to new islets

Abstract

Type 1 diabetes mellitus is an autoimmune disease characterized by the destruction of insulin-producing β-cells in the islets of Langerhans. A promising curative strategy involves the replacement of β-cells, such as through islet transplantation. However, limited donor tissue restricts its scalability, creating the need for alternative sources of β-cells. Whether adult human pancreatic duct cells—epithelial cells lining the ducts—can act as β-cell progenitors remains debated. This thesis investigates their plasticity potential.

We first examined the role of non-endocrine cells in clinical islet transplants. While high-purity grafts showed better early outcomes, no sustained metabolic benefit was observed in lower-purity grafts, offering no clear evidence of new β-cell formation in this context. To further explore duct cell plasticity potential, we developed a 3D organoid culture system for human islet-depleted pancreatic tissue. These organoids exhibited stem-like properties and limited capacity for endocrine differentiation. Furthermore, we show that endocrine differentiation from duct cells can be improved using β-cell neogenesis agents, optimized lentiviral gene delivery, and studied transcriptional regulators such as SOX9 during human pancreas development, revealing insights into β-cell development.

Together, these findings provide a detailed analysis of duct cell plasticity and contribute to ongoing efforts to develop regenerative therapies for T1DM.