Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells

Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.

Automated summary

Transplanting pancreatic islet cells derived from human pluripotent stem cells has great potential for treating diabetes. This study generated functionally mature stem-cell-derived islets (SC-islets) using an optimized protocol and compared them comprehensively to primary adult islets. The results showed that SC-islets exhibited similar functional properties to adult islets in terms of insulin secretion, electrophysiology, signaling, and exocytosis. Additionally, single-cell transcriptomics revealed a continuous maturation trajectory of SC-islets in vitro and during engraftment in mice, closely resembling that of primary islets.